Association of peak factor VIII levels and area under the curve with bleeding in patients with haemophilia A on every third day pharmacokinetic-guided prophylaxis.

PubMed

Valentino, L A; Pipe, S W; Collins, P W; Blanchette, V S; Berntorp, E; Fischer, K; Ewenstein, B M; Oh, M; Spotts, G

2016-07-01

We previously showed that pharmacokinetic-guided prophylaxis (PKP) allows the dosing interval to be extended while maintaining a specific trough level. However, the associations of peak factor VIII (FVIII) levels and area under the curve (AUC) with breakthrough bleeding have not been investigated. The aim of this study was to analyse data from the PKP arm to determine whether peak FVIII levels, AUC and time with FVIII levels in a haemostatically effective range are independent predictors of bleeding during prophylaxis. Post hoc analysis of the association of FVIII levels and AUC with annualized bleeding rate in 34 patients on PKP. During 1 year of PKP, 131 bleeding episodes occurred in 24/34 patients. Average peak FVIII levels ranged from 24 to 168 IU dL(-1) , with higher values associated with a decreased risk for all bleeding (joint and non-joint; P < 0.01) and joint bleeding (P < 0.01). Following rFVIII infusion, median percent of time spent with FVIII levels >20 IU dL(-1) was 22%; median AUC was 1363. Both values were significantly associated with a lower ABR when targeting a 1% trough at 72 h. When PKP was administered every third day, higher peak FVIII levels, higher AUC and more time spent per week with FVIII levels >20 IU dL(-1) provided increased protection from joint and non-joint bleeding. These data highlight the potential impact of variability in individual pharmacokinetic and bleeding risk and support the need for high peak levels and AUC in some patients treated every third day. The findings do not necessarily apply to alternate-day or other prophylactic dosing regimens. © 2016 The Authors. Haemophilia Published by John Wiley & Sons Ltd.

Factor VIII-bypassing activity of bovine tissue factor using the canine hemophilic model.

PubMed Central

O'Brien, D P; Giles, A R; Tate, K M; Vehar, G A

1988-01-01

The bleeding disorder of hemophilia A currently treated by replacement therapy of the missing coagulation factor, factor VIII, is frequently complicated by the development of neutralizing antibodies. The therapeutic potential of attenuated forms of the lipid-associated glycoprotein tissue factor, a known initiator of coagulation, was investigated as a factor VIII-by-passing activity. The protein moiety of tissue factor (Apo-TF) was partially purified and exhibited minimal procoagulant activity before relipidation in vitro. In pilot studies, Apo-TF injection into rabbits previously anticoagulated with an antibody to factor VIII was found to have a procoagulant effect. The efficacy of the material was further demonstrated when injection of Apo-TF in hemophilic dogs resulted in a normalization of the cuticle bleeding time. Little or no change in the blood parameters associated with disseminated intravascular coagulation was observed at lower doses, although mild to moderate effects were seen at higher doses. These data suggest a novel role for Apo-TF preparations as a potential therapeutic agent for hemophiliacs with antibodies to factor VIII once the potential thrombogenicity of such materials is evaluated. Images PMID:3134399

Platelet binding sites for factor VIII in relation to fibrin and phosphatidylserine

PubMed Central

Novakovic, Valerie A.; Shi, Jialan; Rasmussen, Jan; Pipe, Steven W.

2015-01-01

Thrombin-stimulated platelets expose very little phosphatidylserine (PS) but express binding sites for factor VIII (fVIII), casting doubt on the role of exposed PS as the determinant of binding sites. We previously reported that fVIII binding sites are increased three- to sixfold when soluble fibrin (SF) binds the αIIbβ3 integrin. This study focuses on the hypothesis that platelet-bound SF is the major source of fVIII binding sites. Less than 10% of fVIII was displaced from thrombin-stimulated platelets by lactadherin, a PS-binding protein, and an fVIII mutant defective in PS-dependent binding retained platelet affinity. Therefore, PS is not the determinant of most binding sites. FVIII bound immobilized SF and paralleled platelet binding in affinity, dependence on separation from von Willebrand factor, and mediation by the C2 domain. SF also enhanced activity of fVIII in the factor Xase complex by two- to fourfold. Monoclonal antibody (mAb) ESH8, against the fVIII C2 domain, inhibited binding of fVIII to SF and platelets but not to PS-containing vesicles. Similarly, mAb ESH4 against the C2 domain, inhibited >90% of platelet-dependent fVIII activity vs 35% of vesicle-supported activity. These results imply that platelet-bound SF is a component of functional fVIII binding sites. PMID:26162408

The Chapel Hill hemophilia A dog colony exhibits a factor VIII gene inversion

PubMed Central

Lozier, Jay N.; Dutra, Amalia; Pak, Evgenia; Zhou, Nan; Zheng, Zhili; Nichols, Timothy C.; Bellinger, Dwight A.; Read, Marjorie; Morgan, Richard A.

2002-01-01

In the Chapel Hill colony of factor VIII-deficient dogs, abnormal sequence (ch8, for canine hemophilia 8, GenBank no. AF361485) follows exons 1–22 in the factor VIII transcript in place of exons 23–26. The canine hemophilia 8 locus (ch8) sequence was found in a 140-kb normal dog genomic DNA bacterial artificial chromosome (BAC) clone that was completely outside the factor VIII gene, but not in BAC clones containing the factor VIII gene. The BAC clone that contained ch8 also contained a homologue of F8A (factor 8 associated) sequence, which participates in a common inversion that causes severe hemophilia A in humans. Fluorescence in situ hybridization analysis indicated that exons 1–26 normally proceed sequentially from telomere to centromere at Xq28, and ch8 is telomeric to the factor VIII gene. The appearance of an “upstream” genomic sequence element (ch8) at the end of the aberrant factor VIII transcript suggested that an inversion of genomic DNA replaced factor VIII exons 22–26 with ch8. The F8A sequence appeared also in overlapping normal BAC clones containing factor VIII sequence. We hypothesized that homologous recombination between copies of canine F8A inside and outside the factor VIII gene had occurred, as in human hemophilia A. High-resolution fluorescent in situ hybridization on hemophilia A dog DNA revealed a pattern consistent with this inversion mechanism. We also identified a HindIII restriction fragment length polymorphism of F8A fragments that distinguished hemophilia A, carrier, and normal dogs' DNA. The Chapel Hill hemophilia A dog colony therefore replicates the factor VIII gene inversion commonly seen in humans with severe hemophilia A. PMID:12242334

Physician preferences for medication attributes for the prophylactic treatment of patients with severe haemophilia A with inhibitors to factor VIII.

PubMed

Gelhorn, H; Merikle, E; Krishnan, S; Nemes, L; Leissinger, C; Valentino, L

2013-01-01

Prophylaxis may be beneficial for patients with severe haemophilia A who have developed inhibitors to factor VIII. The aim of this study was to determine physicians' preferences for medication attributes in the prophylactic treatment of this patient population. Haematologists from Europe (EU) and the United States (US) participated in a discrete choice exercise to explore their preferences for medication attributes (efficacy, cost, scientific evidence, dosing frequency and administration time) associated with prophylaxis for severe haemophilia A in patients with inhibitors to factor VIII. Physicians' preferences for medication attributes were assessed through completion of 25 trade-off tasks that included a choice between two hypothetical medications each comprised of one randomized level of each medication attribute. Participants also completed a sociodemographic questionnaire. Data were analysed using a random effects logit model. Participants (N = 36: US = 19; EU = 17) were 80.6% men, had a mean of 19.8 years (SD ± 8.1) [range 6-35] of practice experience. The physicians treated an average of 5.7 (± 5.5) patients with severe haemophilia A and inhibitors per month and reported treating 36.2% of these patients prophylactically. The most important medication attributes for prophylactic treatment were efficacy [Relative Importance (RI) = 35.0%] and scientific evidence (RI = 34.1%), whereas treatment cost (12.0%), dosing frequency (10.8%) and administration time (8.2%) were less important. Results were similar across the EU and US. Efficacy and scientific evidence are the primary considerations for physicians' choice of prophylactic medications for use in this patient population. © 2012 Blackwell Publishing Ltd.

Antihuman factor VIII C2 domain antibodies in hemophilia A mice recognize a functionally complex continuous spectrum of epitopes dominated by inhibitors of factor VIII activation

PubMed Central

Meeks, Shannon L.; Healey, John F.; Parker, Ernest T.; Barrow, Rachel T.

2007-01-01

The diversity of factor VIII (fVIII) C2 domain antibody epitopes was investigated by competition enzyme-linked immunosorbent assay (ELISA) using a panel of 56 antibodies. The overlap patterns produced 5 groups of monoclonal antibodies (MAbs), designated A, AB, B, BC, and C, and yielded a set of 18 distinct epitopes. Group-specific loss of antigenicity was associated with mutations at the Met2199/Phe2200 phospholipid binding β-hairpin (group AB MAbs) and at Lys2227 (group BC MAbs), which allowed orientation of the epitope structure as a continuum that covers one face of the C2 β-sandwich. MAbs from groups A, AB, and B inhibit the binding of fVIIIa to phospholipid membranes. Group BC was the most common group and displayed the highest specific fVIII inhibitor activities. MAbs in this group are type II inhibitors that inhibit the activation of fVIII by either thrombin or factor Xa and poorly inhibit the binding of fVIII to phospholipid membranes or von Willebrand factor (VWF). Group BC MAbs are epitopically and mechanistically distinct from the extensively studied group C MAb, ESH8. These results reveal the structural and functional complexity of the anti-C2 domain antibody response and indicate that interference with fVIII activation is a major attribute of the inhibitor landscape. PMID:17848617

Cost-effectiveness analysis of pharmacokinetic-driven prophylaxis vs. standard prophylaxis in patients with severe haemophilia A.

PubMed

Iannazzo, Sergio; Cortesi, Paolo A; Crea, Roberto; Steinitz, Katharina; Mantovani, Lorenzo G; Gringeri, Alessandro

2017-09-01

: The objective of this study was to assess the cost-effectiveness of pharmacokinetic-driven prophylaxis in severe haemophilia A patients. A microsimulation model was developed to evaluate the cost-effectiveness of pharmacokinetic-driven prophylaxis vs. standard prophylaxis and estimate cost, annual joint bleed rate (AJBR), and incremental cost-effectiveness ratio over a 1-year time horizon for a hypothetical population of 10 000 severe haemophilia A patients. A dose of 30 IU/kg per 48 h was assumed for standard prophylaxis. Pharmacokinetic prophylaxis was individually adjusted to maintain trough levels at least 1 and 5 IU/dl or less. AJBR was estimated on the relationship between factor VIII (FVIII) levels and bleeding rate reported in the literature. Sensitivity analyses were performed to assess the stability of the model and the reliability of results. The FVIII dose was reduced in the 27.8% of patients with a trough level more than 5 IU/dl on standard prophylaxis, with a negligible impact on AJBR (+0.1 bleed/year). The FVIII dose was increased in the 10.6% of patients with trough levels less than 1 IU/dl on standard prophylaxis, with a significant reduction of AJBR (-1.9 bleeds/year). On average, overall, pharmacokinetic-driven prophylaxis was shown to decrease the AJBR from 1.012 to 0.845 with a slight reduction of the infusion dose of 0.36 IU/kg, with total saving of 5 197&OV0556; per patient-year. Pharmacokinetic-driven prophylaxis was preferable (i.e. more effective and less costly) compared with standard prophylaxis, with savings of 31 205&OV0556; per bleed avoided. Pharmacokinetic-driven prophylaxis, accounting for patients' individual pharmacokinetic variability, appears to be a promising strategy to improve outcomes with efficient use of available resources in severe haemophilia A patients.

Development of freeze-dried albumin-free formulation of recombinant factor VIII SQ.

PubMed

Osterberg, T; Fatouros, A; Mikaelsson, M

1997-07-01

To develop a stable freeze-dried formulation of recombinant factor VIII-SQ (r-VIII SQ) without the addition of albumin. Different formulations were evaluated for their protective effect during sterile filtration, freeze-thawing, freeze-drying, reconstitution and long term storage. Factor VIII activity (VIII:C), visual inspection, clarity, solubility, moisture content and soluble aggregates and/ or fragments were assayed. A combination of non-crystallising excipients (L-histidine and sucrose), a non-ionic surfactant (polysorbate 80) and a crystalline bulking agent (sodium chloride) was found to preserve the factor VIII activity during formulation, freeze-drying and storage. Calcium chloride was included to prevent dissociation of the heavy and light chains of r-VIII SQ. Sodium chloride was chosen as the primary bulking agent since the concentration of sodium chloride necessary for dissolution of r-VIII SQ in the buffer will inhibit the crystallization of many potential cake formers. It was found that L-histidine, besides functioning as a buffer, also protected r-VIII SQ during freeze-drying and storage. A pH close to 7 was found to be optimal. Some potential macromolecular stabilisers, PEG 4000, Haes-steril and Haemaccel, were evaluated but they did not improve the recovery of VIII:C. The freeze-dried formulation was stable for at least two years at 7 degrees C and for at least one year at 25 degrees C. The reconstituted solution was stable for at least 100 hours at 25 degrees C. The albumin-free formulation resulted in consistently high recovery of VIII:C, very low aggregate formation and good storage stability. The stability of the reconstituted solution makes the formulation suitable for continuous administration via infusion pump. The formulation strategy described here may also be useful for other proteins which require a high ionic strength.

Successful Pregnancy in a Patient with Combined Deficiency of Factor V and Factor VIII.

PubMed

El Adib, Ahmed Ghassan; Majdi, Farah; Dilai, Mohamed Othmane; Asmouki, Hamid; Bassir, Ahlam; Harou, Karam; Soumani, Abderraouf; Younous, Said; Mahmal, Lahoucine

2014-01-01

Inherited combined factor V and factor VIII deficiency (F5F8D) is autosomal recessive transmission disorder. Epistaxis, postsurgical bleeding, and menorrhagia are the most common symptoms. The risk of miscarriage and placental abruption is consequent. We report a case of successful pregnancy in a patient with F5F8D. 20-year-old woman, born of consanguineous parents, third gestate, first parity, two miscarriages, admitted for child birth of a spontaneous pregnancy estimated at 38 weeks and was diagnosed with F5F8D. At admission, patient was hemodynamically stable, with good obstetric conditions. The biologic results showed low levels of PT (52%), factor V (7%), and factor VIII (5%), and the activated partial thromboplastin time was prolonged (68,6%). Parturient was admitted in intensive care unit, maternal and fetal monitoring was performed. Fresh frozen plasma (FFP) and factor VIII concentrates were perfused at the induction of labor. Analgesia used fentanyl titration. The delivery gave birth to a newborn male, with Apgar 10/10 and 3000 g. The puerperium was simple without any important bleeding. Laboratory tests for the newborn were acceptable. Little literature is available on this subject and there are no guidelines available concerning pregnancy; we chose to prescribe a combination of factor VIII concentrate and FFP in pre-, per- and postpartum. The same protocol was successfully used in a patient before dental extraction and prostatectomy. Vaginal delivery is possible, as our case. Management by multidisciplinary team is recommended.

Acquired high titre factor VIII inhibitor with underlying polyarteritis nodosa.

PubMed

Snowden, J A; Hutchings, M; Spearing, R; Patton, W N

1997-05-01

We here present the case of a 70-year-old woman referred to our unit for investigation of bleeding. Investigations confirmed a high titre acquired Factor VIII inhibitor. In association there was relapse of systemic illness associated with anti-neutrophil cytoplasmic antibodies (atypical pattern) for which she had been treated five years previously. Immunosuppression was attempted, but it failed to have an impact both on the inhibitor titre and on the underlying disorder. The patient died from multi-organ failure and massive chest hemorrhage. Post-mortem showed necrotizing vasculitis of medium sized vessels at several sites, including the kidney, consistent with a diagnosis of polyarteritis nodosa. Although it is well recognised that Factor VIII inhibitors are found in conjunction with autoimmune disorders, this case is significant in that it is the first associated with histologically proven polyarteritis nodosa type vasculitis. The case illustrates the difficulties in the investigation and management of patients with acquired high titre Factor VIII inhibitors.

Chromogenic Factor VIII Assays for Improved Diagnosis of Hemophilia A.

PubMed

Rodgers, Susan; Duncan, Elizabeth

2017-01-01

Hemophilia A is an inherited bleeding disorder caused by a reduced level of factor VIII coagulant activity (FVIII:C) in blood. Bleeding episodes may occur spontaneously in the severe form of hemophilia or after trauma in the milder forms. It is important that patients are diagnosed correctly, which includes placing them into the correct severity category of the disorder so that appropriate treatment can be given. Diagnosis is made by determination of the amount of FVIII:C in the blood, usually using a one-stage factor VIII:C assay. However, approximately one third of patients with mild or moderate hemophilia will have much lower results by the chromogenic assay, with some of them having normal results by the one-stage assay. The chromogenic factor VIII assay is used in some specialized hemophilia reference centers and is recommended for the diagnosis of mild hemophilia A, as this assay is considered to better reflect the severity status of hemophilia patients than the one-stage assay.

[Long distance-PCR for detection of factor VIII gene inversion in patients with severe hemophilia A].

PubMed

Ding, Pei-Fang; Sun, Wei-Sheng; Wang, Qin-You; Liu, De-Chun; Zhang, Xue-Qin; Teng, Bin; Shen, Fa-Kui

2003-08-01

The aim of current study was to detect intron 22 inversion of factor VIII gene in severe hemophilia A (HA) patients and screen the carriers of the gene inversion. Fifty-five cases of severe HA were involved and factor VIII gene inversion was detected and identified by long distance-PCR (LD-PCR) and 0.6% agarose gel electrophoresis. The 11 kb and 12 kb bands indicate the factor VIII gene inversion and non-inversion, respectively. Occurring of both 11 kb and 12 kb bands indicates a carrier of the inversion. The results showed that factor VIII gene inversion existed in 22 out of 55 cases, which accounted for about 40% of total detected patients. Five carriers of factor VIII gene inversion were diagnosed from the members in 15 families. In conclusion, LD-PCR assay is a simple, rapid and accurate method for detection of factor VIII gene inversion, and this approach is helpful in screening, carrier testing, and prenatal diagnosis of severe hemophilia A.

Abnormal factor VIII coagulant antigen in patients with renal dysfunction and in those with disseminated intravascular coagulation.

PubMed Central

Weinstein, M J; Chute, L E; Schmitt, G W; Hamburger, R H; Bauer, K A; Troll, J H; Janson, P; Deykin, D

1985-01-01

Factor VIII antigen (VIII:CAg) exhibits molecular weight heterogeneity in normal plasma. We have compared the relative quantities of VIII:CAg forms present in normal individuals (n = 22) with VIII:CAg forms in renal dysfunction patients (n = 19) and in patients with disseminated intravascular coagulation (DIC; n = 7). In normal plasma, the predominant VIII: CAg form, detectable by sodium dodecyl sulfate polyacrylamide gel electrophoresis, was of molecular weight 2.4 X 10(5), with minor forms ranging from 8 X 10(4) to 2.6 X 10(5) D. A high proportion of VIII:CAg in renal dysfunction patients, in contrast, was of 1 X 10(5) mol wt. The patients' high 1 X 10(5) mol wt VIII: CAg level correlated with increased concentrations of serum creatinine, F1+2 (a polypeptide released upon prothrombin activation), and with von Willebrand factor. Despite the high proportion of the 1 X 10(5) mol wt VIII:CAg form, which suggests VIII:CAg proteolysis, the ratio of Factor VIII coagulant activity to total VIII:CAg concentration was normal in renal dysfunction patients. These results could be simulated in vitro by thrombin treatment of normal plasma, which yielded similar VIII:CAg gel patterns and Factor VIII coagulant activity to antigen ratios. DIC patients with high F1+2 levels but no evidence of renal dysfunction had an VIII:CAg gel pattern distinct from renal dysfunction patients. DIC patients had elevated concentrations of both the 1 X 10(5) and 8 X 10(4) mol wt VIII:CAg forms. We conclude that an increase in a particular VIII:CAg form correlates with the severity of renal dysfunction. The antigen abnormality may be the result of VIII:CAg proteolysis by a thrombinlike enzyme and/or prolonged retention of proteolyzed VIII:CAg fragments. Images PMID:3932466

Long-term safety and efficacy of recombinant factor VIII Fc fusion protein (rFVIIIFc) in subjects with haemophilia A.

PubMed

Nolan, B; Mahlangu, J; Perry, D; Young, G; Liesner, R; Konkle, B; Rangarajan, S; Brown, S; Hanabusa, H; Pasi, K J; Pabinger, I; Jackson, S; Cristiano, L M; Li, X; Pierce, G F; Allen, G

2016-01-01

The safety, efficacy and prolonged half-life of recombinant factor VIII Fc fusion protein (rFVIIIFc) in previously treated patients with severe haemophilia A was demonstrated in the phase 3 A-LONG and Kids A-LONG studies. Here, we report interim safety and efficacy data from the rFVIIIFc extension study, ASPIRE (ClinicalTrials.gov #NCT01454739). Eligible subjects could enrol in ASPIRE upon completing A-LONG or Kids A-LONG. There were four treatment groups: individualized prophylaxis; weekly prophylaxis; modified prophylaxis (for subjects in whom optimal treatment could not be achieved with individualized or weekly prophylaxis); and episodic treatment. The primary endpoint was development of inhibitors. A total of 150 A-LONG subjects and 61 Kids A-LONG subjects enrolled in ASPIRE. As of the interim data cut (6 January 2014), the median time on study was 80.9 (A-LONG) and 23.9 (Kids A-LONG) weeks. The majority of subjects (A-LONG, 92.0%; Kids A-LONG, 57.4%) had ≥100 cumulative rFVIIIFc exposure days. No inhibitors were observed. Adverse events were generally consistent with those expected in the general haemophilia A population. Median annualized bleeding rates (ABRs) were low with individualized [A-LONG: 0.66; Kids A-LONG: 0.00 (<6 years old), 1.54 (6 to <12 years old)], weekly (A-LONG: 2.03) and modified (A-LONG: 1.97) prophylaxis. There was no change in prophylactic infusion frequency or total weekly prophylactic dose in the majority of subjects from A-LONG and Kids A-LONG. Interim data from ASPIRE confirm the long-term safety of rFVIIIFc and the maintenance of a low ABR with extended-interval prophylactic dosing in patients with severe haemophilia A. © 2015 The Authors. Haemophilia Published by John Wiley & Sons Ltd.

Two distinct forms of Factor VIII coagulant protein in human plasma. Cleavage by thrombin, and differences in coagulant activity and association with von Willebrand factor.

PubMed Central

Weinstein, M J; Chute, L E

1984-01-01

We have characterized Factor VIII coagulant protein, present in normal human plasma, that reacts with a specific human 125I-labeled anti-human VIII:C antigen Fab antibody fragment. Two major Factor VIII coagulant antigen populations were present. The first, approximately 85% of the total antigen, was bound to von Willebrand factor and when tested in a standard one-stage assay had Factor VIII coagulant activity. The second antigenic population, eluting near fibrinogen when plasma was gel filtered, was not bound to von Willebrand protein, did not have Factor VIII coagulant activity unless activated, but did block anti-VIII:C Fab neutralization of clotting activity. The two antigenic populations were separable by cryoprecipitation and agarose gel electrophoresis. Although the two antigenic populations differed in their Factor VIII coagulant activity and in their binding to von Willebrand factor, the principal member of both populations is of mol wt 2.4 X 10(5). Both antigens, when proteolyzed by thrombin, were quickly converted to a 1 X 10(5)-mol wt form in association with the appearance of VIII:C activity. The 1 X 10(5)-mol wt antigen was further slowly degraded to an 8 X 10(4)-mol wt form while Factor VIII coagulant activity declined. These results demonstrate the presence of an inactive Factor VIII coagulant protein in plasma, not associated with von Willebrand factor, that can react with thrombin to yield Factor VIII coagulant activity. Images PMID:6421875

A Budget Impact Model of Hemophilia Bypassing Agent Prophylaxis Relative to Recombinant Factor VIIa On-Demand.

PubMed

Mehta, Darshan A; Oladapo, Abiola O; Epstein, Joshua D; Novack, Aaron R; Neufeld, Ellis J; Hay, Joel W

2016-02-01

Hemophilia patients use factor-clotting concentrates (factor VIII for hemophilia A and factor IX for hemophilia B) for improved blood clotting. These products are used to prevent or stop bleeding episodes. However, some hemophilia patients develop inhibitors (i.e., the patient's immune system develops antibodies against these factor concentrates). Hence, these patients do not respond well to the factor concentrates. A majority of hemophilia patients with inhibitors are managed on-demand with the following bypassing agents: recombinant factor VIIa (rFVIIa) and activated prothrombin complex concentrate (aPCC). The recently published U.S. registries Dosing Observational Study in Hemophilia (DOSE) and Hemostasis and Thrombosis Research Society (HTRS) reported higher rFVIIa on-demand use for bleed management than previously described. To estimate aPCC and rFVIIa prophylaxis costs relative to rFVIIa on-demand treatment cost based on rFVIIa doses reported in U.S. registries. A literature-based cost model was developed assuming a base case on-demand annual bleed rate (ABR) of 28.7 per inhibitor patient, which was taken from a randomized phase 3 clinical trial. The doses for rFVIIa on-demand were taken from the median dose per bleed reported by the DOSE and HTRS registries. Model inputs for aPCC and rFVIIa prophylaxis (i.e., dosing and efficacy) were derived from respective randomized clinical trials. Cost analysis was from the U.S. payer perspective, and only direct drug costs were considered. The drug cost was based on the Medicare Part B 2014 average sale price (ASP). Two-way sensitivity and threshold analyses were performed by simultaneously varying on-demand ABR, prophylaxis efficacy, and unit drug cost. In addition to studying relative costs associated with on-demand and prophylaxis treatments, relative cost per bleeding episode avoided were also calculated for aPCC and rFVIIa prophylaxis treatments. The prophylaxis efficacy reported in the trials were used to

Effects of moderate-intensity physical exercise on pharmacokinetics of factor VIII and von Willebrand factor in young adults with severe haemophilia A: a pilot study.

PubMed

Zourikian, N; Merlen, C; Bonnefoy, A; St-Louis, J; Rivard, G E

2016-05-01

In persons with severe haemophilia A (pwshA), infused factor VIII (FVIII) half-life can vary according to such determinants as blood group, von Willebrand factor (VWF) level or age; however, FVIII pharmacokinetics (PK) has not been well studied in pwshA during exercise. To investigate FVIII PK in pwshA performing moderate-intensity aerobic exercise. Twelve young-adult pwshA with the intron-22 inversion mutation, on relatively low-dose FVIII prophylaxis regimens, and relatively good musculoskeletal status were recruited. Abbreviated PK of FVIII activity and von Willebrand factor antigen (VWF:Ag) level were compared - during rest, and with 60-min exercise (2 × 15 min each of moderate-intensity stationary cycling and treadmill walking). During rest and exercise visits, a baseline blood specimen was drawn, routine prophylaxis FVIII infused; then six blood specimens were taken over the following 24 h. For all subjects, mean half-life of infused FVIII did not change significantly with exercise vs. at rest (577 ± 190 vs. 614 ± 163 min; P = 0.4131). VWF:Ag rose transiently by 40-50% for 6-8 h with exercise (P < 0.01), particularly in non-O blood group subjects. No musculoskeletal bleeds occurred during the study. Four × 15 min of moderate-intensity aerobic exercise increased VWF:Ag levels for 6-8 h, and showed no evidence of accelerated FVIII clearance or of musculoskeletal bleeding in these young-adult pwshA with relatively good musculoskeletal status, on relatively low-dose FVIII prophylaxis regimens. However, O blood group impact would merit larger studies, with longer durations of similar or more vigorous exercise intensities. © 2016 John Wiley & Sons Ltd.

Recombinant factor VIII Fc fusion protein for immune tolerance induction in patients with severe haemophilia A with inhibitors-A retrospective analysis.

PubMed

Carcao, M; Shapiro, A; Staber, J M; Hwang, N; Druzgal, C; Lieuw, K; Belletrutti, M; Thornburg, C D; Ahuja, S P; Morales-Arias, J; Dumont, J; Miyasato, G; Tsao, E; Jain, N; Pipe, S W

2018-03-01

Immune tolerance induction (ITI) is the gold standard for eradication of factor VIII inhibitors in severe haemophilia A; however, it usually requires treatment for extended periods with associated high burden on patients and healthcare resources. Review outcomes of ITI with recombinant factor VIII Fc fusion protein (rFVIIIFc) in patients with severe haemophilia A and high-titre inhibitors. Multicentre retrospective chart review of severe haemophilia A patients treated with rFVIIIFc for ITI. Of 19 patients, 7 were first-time ITI and 12 were rescue ITI. Of 7 first-time patients, 6 had at least 1 high-risk feature for ITI failure. Four of 7 first-time patients were tolerized in a median of 7.8 months. The remaining 3 patients continue on rFVIIIFc ITI. Of 12 rescue patients, 7 initially achieved a negative Bethesda titre (≤0.6) in a median of 3.3 months, 1 had a decrease in Bethesda titre and continues on rFVIIIFc ITI and 4 have not demonstrated a decrease in Bethesda titre. Of these 4, 3 continue on rFVIIIFc ITI and 1 switched to bypass therapy alone. Two initially responsive patients transitioned to other factors due to recurrence. Overall, 16 of 19 patients remain on rFVIIIFc (prophylaxis or ITI). For those still undergoing ITI, longer follow-up is needed to determine final outcomes. No adverse events reported. Recombinant factor VIII Fc fusion protein demonstrated rapid time to tolerization in high-risk first-time ITI patients. For rescue ITI, rFVIIIFc showed therapeutic benefit in some patients who previously failed ITI with other products. These findings highlight the need to further evaluate the use of rFVIIIFc for ITI. © 2018 The Authors. Haemophilia Published by John Wiley & Sons Ltd.

A high-potency, single-donor cryoprecipitate of known factor VIII content dispensed in vials.

PubMed

McLeod, B C; Sassetti, R J; Cole, E R; Scott, J P

1987-01-01

Current factor VIII products expose recipients to many donors and hence to a high risk of acquiring blood-borne infections. Plasma-exchange donation of cryoprecipitate can reduce donor exposure by repeatedly obtaining large yields of factor VIII from individual donors. In this study, donor factor VIII levels were stimulated with desmopressin before donation. Mean yield per donation increased from 1399 +/- 425 IU in controls to 3818 +/- 1350 IU in stimulated donations (p less than 0.001), and mean factor VIII concentration in the cryoprecipitate increased from 8.2 +/- 3 IU/mL to 24 +/- 12 IU/mL (p less than 0.001). A new packaging system dispenses assayed aliquots of stimulated cryoprecipitate in plastic vials. The direct cost of production for this material is $.065 per unit. The cryoprecipitate is hemostatically active and convenient to use, and the aggregate yields from sequential donations by stimulated persons are high enough to allow long-term, single-donor support of many adults with hemophilia.

Hemodialysis in a patient with severe hemophilia A and factor VIII inhibitor.

PubMed

Gopalakrishnan, Natarajan; Usha, Thiruvengadam; Thopalan, Balasubramaniyan; Dhanapriya, Jeyachandran; Dineshkumar, Thanigachalam; Thirumalvalavan, Kaliaperumal; Sakthirajan, Ramanathan

2016-10-01

Hemophilia A is a hereditary X-linked recessive disease caused by mutations in the gene encoding factor VIII (FVIII), occurring in 1 out of 10,000 persons. Life expectancy and quality of life have dramatically improved recently in patients with hemophilia. Chronic kidney disease and need for renal replacement therapy in these patients are rare. The development of inhibitors to FVIII is the most serious complication of hemophilia and makes treatment of bleeds very challenging. We describe here a 28-year-old male patient with severe hemophilia A with presence of factor VIII inhibitor, who had end stage renal disease. Central venous access device was inserted along with infusion of factor eight inhibitor bypass activity before and after the procedure. He is currently on thrice weekly hemodialysis and doing well for 6 months without bleeding episodes. To our knowledge, hemophilia A with factor VIII inhibitor managed with hemodialysis has not been reported so far. © 2016 International Society for Hemodialysis.

Identification of a His54Gln substitution in von Willebrand factor from a patient with defective binding of factor VIII.

PubMed

Rick, M E; Krizek, D M

1996-04-01

A patient with type 2N ("Normandy" variant) von Willebrand's disease is described. Her von Willebrand factor level was borderline low, while her factor VIII was markedly decreased to 7%. Her plasma von Willebrand factor demonstrated a decreased ability to complex with factor VIII in vitro, binding less than 10% when compared to normal plasma von Willebrand factor. The factor VIII released into the circulation after the patient received DDAVP had a shortened survival in vivo. Nucleotide sequence analysis revealed a T-to-A transition at nucleotide 2451 on both alleles. This transition results in a substitution of Gln for His at amino acid 54 in the mature subunit of von Willebrand factor.

Factor VIII-associated antigen in human lymphatic endothelium.

PubMed

Nagle, R B; Witte, M H; Martinez, A P; Witte, C L; Hendrix, M J; Way, D; Reed, K

1987-03-01

Lymphatic vascular endothelium both on tissue section and in culture exhibits positivity for Factor VIII-associated antigen although staining is generally less intense and more spotty than in comparable blood vascular endothelium. Lymphatic endothelium also exhibits Weibel-Palade bodies. Neither marker, therefore, reliably distinguishes blood vascular endothelium from lymphatic endothelium.

Risk factors for nosocomial pneumonia. Focus on prophylaxis.

PubMed

Fleming, C A; Balaguera, H U; Craven, D E

2001-11-01

Despite an increased understanding of the pathogenesis of NP and advances in diagnosis and treatment, the risk, cost, morbidity, and mortality of NP remain unacceptably high. This article has identified strategic areas for primary and secondary prophylaxis that are simple and cost-effective. Realizing that the pathogenesis of NP requires bacterial colonization and the subsequent entry of these bacteria into the lower respiratory tree helps highlight the role of cross-infection and the importance of standard infection control procedures. Similarly the role of sedation and devices as risk factors can be reduced by minimizing the duration and intensity of sedation and length of exposure to invasive devices. Additional low-cost interventions that have been shown to be effective in preventing NP are the positioning of patients in a semirecumbent position and the appropriate use of enteral feeding, antibiotics, and selected medical devices. Prophylaxis of NP and VAP is carried out best by a multidisciplinary management team comprised of physicians (critical care, pulmonary medicine, infectious diseases, and primary care), critical care and infection control nurses, and respiratory therapists, even though this approach may result in decreased professional autonomy and freedom. This group should review the current guidelines, pathways, and standards for short-term and long-term prophylaxis of NP and VAP, then integrate them into and monitor their use for routine patient care. The risk factors and prophylaxis strategies for NP discussed in this article apply primarily to patients in acute care facilities, but also are relevant to alternative health care settings as well as the care of ill patients in ambulatory settings. The routine use of effective team policies for prophylaxis needs to be monitored by the Joint Commission for the Accreditation of Health Care or other agencies. Research to delineate the most effective and feasible strategies for prophylaxis NP has been

Nattokinase decreases plasma levels of fibrinogen, factor VII, and factor VIII in human subjects.

PubMed

Hsia, Chien-Hsun; Shen, Ming-Ching; Lin, Jen-Shiou; Wen, Yao-Ke; Hwang, Kai-Lin; Cham, Thau-Ming; Yang, Nae-Cherng

2009-03-01

Nattokinase, a serine proteinase from Bacillus subtilis, is considered to be one of the most active functional ingredients found in natto. In this study, we hypothesized that nattokinase could reduce certain factors of blood clotting and lipids that are associated with an increase risk for cardiovascular disease (CVD). Thus, an open-label, self-controlled clinical trial was conducted on subjects of the following groups: healthy volunteers (Healthy Group), patients with cardiovascular risk factors (Cardiovascular Group), and patients undergoing dialysis (Dialysis Group). All subjects ingested 2 capsules of nattokinase (2000 fibrinolysis units per capsule) daily orally for 2 months. The laboratory measurements were performed on the screening visit and, subsequently, regularly after the initiation of the study. The intent-to-treat analysis was performed on all 45 enrolled subjects. By use of mixed model analysis, a significant time effect, but not group effect, was observed in the change from baseline of fibrinogen (P = .003), factor VII (P < .001), and factor VIII (P < .001), suggesting that the plasma levels of the 3 coagulation factors continuously declined during intake; also, the extents of decrease were similar between groups. After 2 months of administration, fibrinogen, factor VII, and factor VIII decreased 9%, 14%, and 17%, respectively, for the Healthy Group; 7%, 13%, and 19%, respectively, for the Cardiovascular Group; and 10%, 7%, and 19%, respectively, for the Dialysis Group, whereas blood lipids were unaffected by nattokinase. No significant changes of uric acid or notable adverse events were observed in any of the subjects. In summary, this study showed that oral administration of nattokinase could be considered as a CVD nutraceutical by decreasing plasma levels of fibrinogen, factor VII, and factor VIII.

A close insight to factor VIII inhibitor in the congenital hemophilia A.

PubMed

Tabriznia-Tabrizi, Shamsoreza; Gholampour, Marzie; Mansouritorghabeh, Hassan

2016-09-01

Hemophilia A (HA) has an X-linked pattern of inheritance and is the most common of the hemorrhagic disorders. HA is caused by a decreased or deficiency of the functional clotting factor VIII (FVIII) and effects 1 in 5000-10,000 male births. The common treatment for hemophilia is replacement therapy by plasma-derived or recombinant FVIII. Approximately 20-30% of people with a severe type of HA develop an inhibitor and this phenomenon is the main challenge in the management of these patients. Genetic factors and environmental determinants contribute to inhibitor development. Here, the roles of various genetic and environmental factors such as the type of FVIII concentrate used, the number of exposure days, and peak treatment time will be discussed in detail. It seems this information is helpful for hematologists. A literature review was done in January 2016 on PubMed and Scopus using the following keywords:' h(a)emophilia A & factor VIII inhibitor', 'h(a)emophilia A & factor VIII alloantibody', 'h(a)emophilia A & inhibitor'. There was no time limitation; however, there was an English language limitation placed on the articles selected. Expert commentary: Influential genetic and environmental factors in developing inhibitors have been discussed. Most of the risk factors are related to previously untreated patients with hemophili.

Population pharmacokinetics of recombinant coagulation factor VIII-SingleChain in patients with severe hemophilia A.

PubMed

Zhang, Y; Roberts, J; Tortorici, M; Veldman, A; St Ledger, K; Feussner, A; Sidhu, J

2017-06-01

Essentials rVIII-SingleChain is a unique recombinant factor VIII (FVIII) molecule. A population pharmacokinetic model was based on FVIII activity of severe hemophilia A patients. The model was used to simulate factor VIII activity-time profiles for various dosing scenarios. The model supports prolonged dosing of rVIII-SingleChain with intervals of up to twice per week. Background Single-chain recombinant coagulation factor VIII (rVIII-SingleChain) is a unique recombinant coagulation factor VIII molecule. Objectives To: (i) characterize the population pharmacokinetics (PK) of rVIII-SingleChain in patients with severe hemophilia A; (ii) identify correlates of variability in rVIII-SingleChain PK; and (iii) simulate various dosing scenarios of rVIII-SingleChain. Patients/Methods A population PK model was developed, based on FVIII activity levels of 130 patients with severe hemophilia A (n = 91 for ≥ 12-65 years; n = 39 for < 12 years) who had participated in a single-dose PK investigation with rVIII-SingleChain 50 IU kg -1 . PK sampling was performed for up to 96 h. Results A two-compartment population PK model with first-order elimination adequately described FVIII activity. Body weight and predose level of von Willebrand factor were significant covariates on clearance, and body weight was a significant covariate on the central distribution volume. Simulations using the model with various dosing scenarios estimated that > 85% and > 93% of patients were predicted to maintain FVIII activity level above 1 IU dL -1 , at all times with three-times-weekly dosing (given on days 0, 2, and 4.5) at the lowest (20 IU kg -1 ) and highest (50 IU kg -1 ) doses, respectively. For twice weekly dosing (days 0 and 3.5) of 50 IU kg -1 rVIII-SingleChain, 62-80% of patients across all ages were predicted to maintain a FVIII activity level above 1 IU dL -1 at day 7. Conclusions The population PK model adequately characterized rVIII-SingleChain PK, and the model

Factor VIII inhibitor in a patient with mild haemophilia A and an Asn618-->Ser mutation responsive to immune tolerance induction and cyclophosphamide.

PubMed

Vlot, André J; Wittebol, Shulamiet; Strengers, Paul F W; Turenhout, Ellen A M; Voorberg, Jan; van den Berg, H Marijke; Mauser-Bunschoten, Eveline P

2002-04-01

We describe a patient with mild haemophilia A (original value of factor VIII activity 0.30 U/ml) who developed an inhibitor (36.1 Bethesda U/ml) which cross-reacted with his endogenous factor VIII. This caused a decline in basal factor VIII level (< 0.01 U/ml) and severe haemorrhagic events. Treatment to induce immune tolerance was started with factor VIII/von Willebrand factor (VWF) concentrates, but inhibitor levels increased progressively and the patient suffered serious bleeding. Cyclophosphamide was administered and, after 8 months treatment, factor VIII levels increased to 0.20 U/ml and the inhibitor could no longer be detected. Screening of his factor VIII gene revealed a missense mutation in exon 13 that predicts substitution of Asn618-->Ser in the A2 domain of factor VIII. Immunoprecipitation analysis showed that the antibodies present in the patient's plasma reacted with metabolically labelled A2 domain and, to a lesser extent, with factor VIII light chain. Inhibitory antibodies were completely neutralized by recombinant A2 domain, whereas no neutralization was observed after the addition of factor VIII light chain (A3-C1-C2) and C2 domain. More detailed analysis showed that the majority of inhibitory antibodies were directed against residues Arg484-Ile508, a previously identified binding site for factor VIII inhibitors. Our findings suggest that immune tolerance therapy and cyclophosphamide were successful in eradicating inhibitory antibodies against a common epitope on factor VIII.

Is prophylaxis required for delivery in women with factor VII deficiency?

PubMed Central

Baumann Kreuziger, Lisa M.; Morton, Colleen T.; Reding, Mark T.

2013-01-01

Introduction Factor VII (fVII) deficiency is a rare congenital bleeding disorder in which fVII activity level and bleeding tendency do not completely correlate. Pregnancy and delivery present a significant hemostatic challenge to women with fVII deficiency. Treatment with recombinant factor VIIa (rfVIIa) carries a thrombotic risk and the literature is unclear whether prophylaxis is necessary prior to delivery. Aim To define management, hemorrhagic and thrombotic complications of pregnant women with fVII deficiency through a systematic review. Methods Medical databases (PubMed, MEDLINE, CINAHL, Academic Search Premier, Cochrane Library, Web of Science and Scopus) were searched using “factor VII deficiency” and “pregnancy” or “surgery.” Overall 34 articles, 4 abstracts, and 3 institutional cases were reviewed. Results Literature from 1953–2011 reported 94 live births from 62 women with fVII deficiency. The median fVII activity was 5.5%. Hemostatic prophylaxis was used in 32% of deliveries. Without prophylaxis, 40 vaginal deliveries and 16 cesarean sections were completed. The odds of receiving prophylaxis were 2.9 times higher in women undergoing cesarean section compared to vaginal delivery. Post-partum hemorrhage occurred in 10% of deliveries with prophylaxis and 13% of deliveries without prophylaxis. The fVII level did not significantly differ between women who did and did not receive prophylaxis. Conclusion We present the only systematic review of the management of pregnancy in fVII deficient women. No difference in post-partum hemorrhage was seen in deliveries with and without prophylaxis. Therefore we recommend that rfVIIa be available in the case of hemorrhage or surgical intervention, but not as mandatory prophylaxis. PMID:23607277

Is prophylaxis required for delivery in women with factor VII deficiency?

PubMed

Baumann Kreuziger, L M; Morton, Colleen T; Reding, Mark T

2013-11-01

Factor VII (fVII) deficiency is a rare congenital bleeding disorder in which fVII activity level and bleeding tendency do not completely correlate. Pregnancy and delivery present a significant haemostatic challenge to women with fVII deficiency. Treatment with recombinant factor VIIa (rfVIIa) carries a thrombotic risk and the literature is not clear whether prophylaxis is necessary prior to delivery. The aim of this study was to define management, haemorrhagic and thrombotic complications of pregnant women with fVII deficiency through a systematic review. Medical databases (PubMed, MEDLINE, CINAHL, Academic Search Premier, Cochrane Library, Web of Science and Scopus) were searched using "factor VII deficiency" and "pregnancy" or "surgery." Overall 34 articles, four abstracts, and three institutional cases were reviewed. Literature from 1953 to 2011 reported 94 live births from 62 women with fVII deficiency. The median fVII activity was 5.5%. Haemostatic prophylaxis was used in 32% of deliveries. Without prophylaxis, 40 vaginal deliveries and 16 caesarean sections were completed. The odds of receiving prophylaxis were 2.9 times higher in women undergoing caesarean section compared to vaginal delivery. Post-partum haemorrhage occurred in 10% of deliveries with prophylaxis and 13% of deliveries without prophylaxis. The fVII level did not significantly differ between women who did and did not receive prophylaxis. We present the only systematic review of the management of pregnancy in fVII deficient women. No difference in post-partum haemorrhage was seen in deliveries with and without prophylaxis. Therefore, we recommend that rfVIIa be available in the case of haemorrhage or surgical intervention, but not as mandatory prophylaxis. © 2013 John Wiley & Sons Ltd.

Report of a factor VIII inhibitor in a patient with autoimmune lymphoproliferative syndrome.

PubMed

Fang, B S; Sneller, M C; Straus, S E; Frenkel, L; Dale, J K; Rick, M E

2000-07-01

The occurrence of factor VIII inhibitors in non-hemophilic patients is a rare event with a potentially lethal outcome. Despite its infrequent occurrence, the association of this inhibitor with multiple autoimmune diseases is well recognized. We report the case of a patient with the recently described autoimmune lymphoproliferative syndrome (ALPS) who developed an inhibitor to factor VIII. ALPS is a disease characterized by defective lymphocyte apoptosis due to inherited mutations in genes that regulate apoptosis, with the resulting enlargement of lymphoid organs and a variety of autoimmune manifestations. Published 2000 Wiley-Liss, Inc.

Factor VIII levels and the risk of pre-eclampsia, HELLP syndrome, pregnancy related hypertension and severe intrauterine growth retardation.

PubMed

Witsenburg, C P J; Rosendaal, F R; Middeldorp, J M; Van der Meer, F J M; Scherjon, S A

2005-01-01

Recently, acquired as well as genetic prothrombotic factors are associated with thrombotic events. These factors have also been related to conditions of uteroplacental insufficiency such as pre-eclampsia, HELLP syndrome and severe intrauterine growth restriction (IUGR). The aim of this study was to determine whether elevated factor VIII levels are associated with uteroplacental insufficiency, in particular pre-eclampsia, HELLP syndrome or pregnancy-induced hypertension and intrauterine growth retardation. Plasma samples of 75 women with a history of pregnancy complicated by pre-eclampsia, HELLP syndrome, pregnancy induced hypertension or intrauterine growth restriction were tested for factor VIII:C (FVIII:C) levels at a minimum of 10 weeks post-partum. Laboratory results were compared to factor VIII:C levels found in a healthy control group of 272 women. Mean factor VIII:C levels were similar at 123 IU/dl in both the patient group and the controls. In a logistic regression model, after adjusting for age and blood group, no effect of factor VIII:C levels on the risk of pregnancy complications was observed, with the exception of IUGR with (OR 2.9, CI 1.0-8.7) or without hypertension (OR 2.0, CI 0.7-6.4). If the elevated level of factor VIII would be the sole factor responsible for the increased risk observed, one would expect to find an effect of blood group on risk as well (blood group being an important determinant of FVIII:C). While no such effect could be shown a causal relationship between elevated levels of factor VIII and conditions of uteroplacental insufficiency such as pre-eclampsia, HELLP syndrome, pregnancy-induced hypertension and IUGR is not very likely.

Studies of Factors V and VIII:C in an animal model of disseminated intravascular coagulation.

PubMed Central

Giles, A R; Nesheim, M E; Mann, K G

1984-01-01

An experimental animal model of disseminated intravascular coagulation (DIC) induced by the co-infusion of coagulant-active phospholipid and activated Factor X (Factor Xa) is described. The infusion of Factor Xa at a dose of 6.6 X 10(-12) mol/kg with phosphatidylcholine/phosphatidylserine (PCPS) lipid vesicles at a dose of 4.0 X 10(-8) mol/kg was associated with significant falls in the levels of fibrinogen and Factors V and VIII, and a bleeding diathesis developed. Assays of Factors V and VIII were performed by a one-stage prothrombin time and activated partial thrombin time system, respectively. In additional experiments, the effect of the same dose combination of Factor Xa/PCPS on Factor V kinetics was studied by preinfusing 125I-labeled Factor V. After Factor Xa/PCPS infusion, Factors VIII and V were reduced at 2 min by 90 and 50% of the preinfusion levels, respectively, and at 1 h by 80 and 75%, respectively. During the same period, there was little change in the total circulating radioactivity. Autoradiography indicated small but detectable levels of circulating proteolytic products of Factor V that comigrated with peptides obtained by the incubation of Factor V with Factor Xa and activated protein C. The majority of radioactivity remained associated with the intact single-chain precursor Factor V. These observations suggested maintenance of the precursor pool after the onset of DIC. This was confirmed by performing two-stage assays of Factors V and VIII, whereby each was completely converted to the active cofactor, i.e., Va and VIII:Ca, by preincubation of the test sample with thrombin before assaying in a one-stage system as before. The Factor V levels assayed by the two-stage procedure did not change appreciably over 1 h. The Factor VIII levels fell but corrected within 1 h at a time when the level measured by a one-stage assay remained depressed. These results indicate that in the dog, infusion of Factor Xa/PCPS induces changes characteristic of DIC, and

Differentiation of embryonic stem cells into hepatocytes that coexpress coagulation factors VIII and IX.

PubMed

Cao, Jun; Shang, Chang-zhen; Lü, Li-hong; Qiu, De-chuan; Ren, Meng; Chen, Ya-jin; Min, Jun

2010-11-01

To establish an efficient culture system to support embryonic stem (ES) cell differentiation into hepatocytes that coexpress F-VIII and F-IX. Mouse E14 ES cells were cultured in differentiation medium containing sodium butyrate (SB), basic fibroblast growth factor (bFGF), and/or bone morphogenetic protein 4 (BMP4) to induce the differentiation of endoderm cells and hepatic progenitor cells. Hepatocyte growth factor, oncostatin M, and dexamethasone were then used to induce the maturation of ES cell-derived hepatocytes. The mRNA expression levels of endoderm-specific genes and hepatocyte-specific genes, including the levels of F-VIII and F-IX, were detected by RT-PCR and real-time PCR during various stages of differentiation. Protein expression was examined by immunofluorescence and Western blot. At the final stage of differentiation, flow cytometry was performed to determine the percentage of cells coexpressing F-VIII and F-IX, and ELISA was used to detect the levels of F-VIII and F-IX protein secreted into the culture medium. The expression of endoderm-specific and hepatocyte-specific markers was upregulated to highest level in response to the combination of SB, bFGF, and BMP4. Treatment with the three inducers during hepatic progenitor differentiation significantly enhanced the mRNA and protein levels of F-VIII and F-IX in ES cell-derived hepatocytes. More importantly, F-VIII and F-IX were coexpressed with high efficiency at the final stage of differentiation, and they were also secreted into the culture medium. We have established a novel in vitro differentiation protocol for ES-derived hepatocytes that coexpress F-VIII and F-IX that may provide a foundation for stem cell replacement therapy for hemophilia.

Quantitative immunohistochemistry of factor VIII-related antigen in breast carcinoma: a comparison of computer-assisted image analysis with established counting methods.

PubMed

Kohlberger, P D; Obermair, A; Sliutz, G; Heinzl, H; Koelbl, H; Breitenecker, G; Gitsch, G; Kainz, C

1996-06-01

Microvessel density in the area of the most intense neovascularization in invasive breast carcinoma is reported to be an independent prognostic factor. The established method of enumeration of microvessel density is to count the vessels using an ocular raster (counted microvessel density [CMVD]). The vessels were detected by staining endothelial cells using Factor VIII-related antigen. The aim of the study was to compare the CMVD results with the percentage of factor VIII-related antigen-stained area using computer-assisted image analysis. A true color red-green-blue (RGB) image analyzer based on a morphologically reduced instruction set computer processor was used to evaluate the area of stained endothelial cells. Sixty invasive breast carcinomas were included in the analysis. There was no significant correlation between the CMVD and the percentage of factor VIII-related antigen-stained area (Spearman correlation coefficient = 0.24, confidence interval = 0.02-0.46). Although high CMVD was significantly correlated with poorer recurrence free survival (P = .024), percentage of factor VIII-related antigen-stained area showed no prognostic value. Counted microvessel density and percentage of factor VIII-related antigen-stained area showed a highly significant correlation with vessel invasion (P = .0001 and P = .02, respectively). There was no correlation between CMVD and percentage of factor VIII-related antigen-stained area with other prognostic factors. In contrast to the CMVD within malignant tissue, the percentage of factor VIII-related antigen-stained area is not suitable as an indicator of prognosis in breast cancer patients.

Efficacy and safety of BAY 81-8973, a full-length recombinant factor VIII: results from the LEOPOLD I trial.

PubMed

Saxena, K; Lalezari, S; Oldenburg, J; Tseneklidou-Stoeter, D; Beckmann, H; Yoon, M; Maas Enriquez, M

2016-09-01

BAY 81-8973 (Kovaltry(®) ) is a full-length, unmodified recombinant human factor VIII (FVIII) with the same amino acid sequence as sucrose-formulated recombinant FVIII and is produced using additional advanced manufacturing technologies. To demonstrate efficacy and safety of BAY 81-8973 for treatment of bleeds and as prophylaxis based on two different potency assignments. In LEOPOLD I (ClinicalTrials.gov identifier, NCT01029340), males aged 12-65 years with severe haemophilia A and ≥150 exposure days received BAY 81-8973 20-50 IU kg(-1) two or three times per week for 12 months. Potency was based on chromogenic substrate assay per European Pharmacopoeia and label adjusted to mimic one-stage assay potency. Patients were randomized for potency sequence and crossed over potency groups after 6 months, followed by an optional 12-month extension. Primary efficacy endpoint was annualized bleeding rate (ABR). Patients also received BAY 81-8973 during major surgeries. Sixty-two patients received BAY 81-8973 prophylaxis and were included in the analysis. Median ABR was 1.0 (quartile 1, 0; quartile 3, 5.1) without clinically relevant differences between potency periods. Median ABR was similar for twice-weekly vs. three times-weekly dosing (1.0 vs. 2.0). Haemostasis was maintained during 12 major surgeries. Treatment-related adverse event (AE) incidence was ≤7% overall; no patient developed inhibitors. One patient with risk factors for cardiovascular disease developed a myocardial infarction. BAY 81-8973 was efficacious in preventing and treating bleeding episodes, irrespective of the potency assignment method, with few treatment-related AEs. Caution should be used when treating older patients with cardiovascular risk factors. © 2016 Bayer. Haemophilia Published by John Wiley & Sons Ltd.

A post-marketing safety and efficacy assessment of a monoclonal antibody purified high-purity factor VIII concentrate.

PubMed

Hay, C R; Lee, C A; Savidge, G

1996-01-01

The identification of infrequent side-effects of clotting factor concentrates, undetected by clinical trials, is facilitated by post-marketing surveillance. We present a post-marketing surveillance study in which 97 patients with haemophilia A, attending three haemophilia centres, were treated over a median follow-up period of 284 days (range 1-1074), and a total follow-up period of 30,080 days, with a pasteurized immunoaffinity purified factor VIII concentrate (Monoclate-P, Armour, Collegeville, USA). 5216 infusions, using 10,527,000 units of Monoclate-P, were carried out, mostly for routine haemarthroses or prophylaxis. No new inhibitors were observed during the study. At the start of the study 60/97 were HIV seropositive, 67/97 HBs antibody positive, 12 HbsAb negative and the remainder HBsAb positive before the study period. 13/14 tested were HAV seropositive at the beginning of the study. One patient became HAV seropositive during the study period, an infection thought to be community acquired. No other seroconversions were observed. Only one mild transfusion reaction was observed. This study confirms the safety and efficacy of Monoclate-P. Post-marketing surveillance or nationally organized pharmaco-vigilance should be practiced more widely to enable identification of low-frequency side-effects of treatment.

Home therapy with continuous infusion of factor VIII after minor surgery or serious haemorrhage.

PubMed

Varon, D; Schulman, S; Bashari, D; Martinowitz, U

1996-10-01

Administration of factor VIII (F VIII) concentrates by continuous infusion is now routinely used at several haemophilia centers but almost exclusively for hospitalized patients. We evaluated various aspects of home therapy with continuous infusion of an immunoaffinity purified F VIII concentrate (Monoclate P®, Armour) in patients who would normally have been treated with high doses in bolus injections or with continuous infusion as in-patients. Twenty haemophilia A patients, eight after minor surgery and 12 for serious haemorrhage, received continuous infusion with undiluted F VIII by a minipump for a mean of 0.9 days in the hospital, followed by 3.3 days at home. Infusion bags were exchanged every 2.5 days. No haemorrhagic complications occurred, and five haemorrhages that had been resistant to treatment with bolus injections responded promptly to the continuous infusion. There were no technical problems and patient compliance and acceptance was good. We find this mode of therapy safe, efficacious and convenient for the patients as well as for the staff.

Hemorrhage and blood loss-induced anemia associated with an acquired coagulation factor VIII inhibitor in a Thoroughbred mare.

PubMed

Winfield, Laramie S; Brooks, Marjory B

2014-03-15

A 23-year-old Thoroughbred mare was evaluated because of a coagulopathy causing hemoperitoneum, hematomas, and signs of blood loss-induced anemia. The mare had tachycardia, pallor, hypoperfusion, and a large mass in the right flank. The mass was further characterized ultrasonographically as an extensive hematoma in the body wall with associated hemoabdomen. Coagulation testing revealed persistent, specific prolongation of the activated partial thromboplastin time (> 100 seconds; reference interval, 24 to 44 seconds) attributable to severe factor VIII deficiency (12%; reference interval, 50% to 200%). On the basis of the horse's age, lack of previous signs of a bleeding diathesis, and subsequent quantification of plasma factor VIII inhibitory activity (Bethesda assay titer, 2.7 Bethesda units/mL), acquired hemophilia A was diagnosed. The medical history did not reveal risk factors or underlying diseases; thus, the development of inhibitory antibodies against factor VIII was considered to be idiopathic. The mare was treated with 2 transfusions of fresh whole blood and fresh-frozen plasma. Immunosuppressive treatment consisting of dexamethasone and azathioprine was initiated. Factor VIII deficiency and signs of coagulopathy resolved, and the inhibitory antibody titer decreased. The mare remained healthy with no relapse for at least 1 year after treatment. Horses may develop inhibitory antibodies against factor VIII that cause acquired hemophilia A. A treatment strategy combining transfusions of whole blood and fresh-frozen plasma and administration of immunosuppressive agents was effective and induced sustained remission for at least 1 year in the mare described here.

Prevalence of the intron 22 inversion of the factor VIII gene and inhibitor development in Polish patients with severe hemophilia A.

PubMed

Sawecka, Jadwiga; Skulimowska, Joanna; Windyga, Jerzy; Lopaciuk, Stanisław; Kościelak, Jerzy

2005-01-01

Patients with severe hemophilia A often develop inhibitors (antibodies) against transfused factor VIII. One hundred thirteen Polish patients with severe hemophilia A, who had been treated on demand with cryoprecipitate until 1992 and exclusively with factor VIII concentrates after 1995, were examined for intron 22 inversion by Southern blotting and the presence and magnitude of inhibitor activity in blood as determined by the Bethesda assay. The patients' ages ranged 4--67 years (mean: 33.7+/-12.4 years, median: 32 years). The number of patients with the inversion amounted to 57, while in 56 patients the mutation types were unknown; 47 patients had a distal and 10 patients a proximal type of inversion. Thirteen patients with inversions (22.8%) were found to have inhibitor in their blood. Most patients (14 out of 15) who developed inhibitors in the course of cryoprecipitate therapy were high responders. Conversely, 4 of 5 patients treated between 1992 and 1995 with both cryoprecipitate and intermediate-purity factor VIII concentrates were low responders. One multitransfused patient who had remained inhibitor-free on cryoprecipitate therapy developed inhibitor after receiving a large dose of factor VIII concentrate during surgery. None of these 5 patients developed inhibitors during their 12--40 years of treatment with cryoprecipitate, suggesting that it was less immunogenic than factor VIII concentrates. The prevalence of the intron 22 inversion mutation of the factor VIII gene in Polish hemophiliacs is similar to that in other European countries. Treatment regimens with either cryoprecipitate or virus-inactivated plasma-derived factor VIII concentrates may affect inhibitor formation in hemophilia A patients.

Structure of the human factor VIII C2 domain in complex with the 3E6 inhibitory antibody

DOE PAGES

Wuerth, Michelle E.; Cragerud, Rebecca K.; Spiegel, P. Clint

2015-11-24

Blood coagulation factor VIII is a glycoprotein cofactor that is essential for the intrinsic pathway of the blood coagulation cascade. Inhibitory antibodies arise either spontaneously or in response to therapeutic infusion of functional factor VIII into hemophilia A patients, many of which are specific to the factor VIII C2 domain. The immune response is largely parsed into “classical” and “non-classical” inhibitory antibodies, which bind to opposing faces cooperatively. In this study, the 2.61 Å resolution structure of the C2 domain in complex with the antigen-binding fragment of the 3E6 classical inhibitory antibody is reported. The binding interface is largely conservedmore » when aligned with the previously determined structure of the C2 domain in complex with two antibodies simultaneously. Further inspection of the B factors for the C2 domain in various X-ray crystal structures indicates that 3E6 antibody binding decreases the thermal motion behavior of surface loops in the C2 domain on the opposing face, thereby suggesting that cooperative antibody binding is a dynamic effect. Furthermore, understanding the structural nature of the immune response to factor VIII following hemophilia A treatment will help lead to the development of better therapeutic reagents.« less

Recombinant factor VIII Fc fusion protein for the prevention and treatment of bleeding in children with severe hemophilia A.

PubMed

Young, G; Mahlangu, J; Kulkarni, R; Nolan, B; Liesner, R; Pasi, J; Barnes, C; Neelakantan, S; Gambino, G; Cristiano, L M; Pierce, G F; Allen, G

2015-06-01

Prophylactic factor replacement, which prevents hemarthroses and thereby reduces the musculoskeletal disease burden in children with hemophilia A, requires frequent intravenous infusions (three to four times weekly). Kids A-LONG was a phase 3 open-label study evaluating the safety, efficacy and pharmacokinetics of a longer-acting factor, recombinant factor VIII Fc fusion protein (rFVIIIFc), in previously treated children with severe hemophilia A (endogenous FVIII level of < 1 IU dL(-1) [< 1%]). The study enrolled 71 subjects. The starting rFVIIIFc regimen was twice-weekly prophylaxis (Day 1, 25 IU kg(-1) ; Day 4, 50 IU kg(-1) ); dose (≤ 80 IU kg(-1) ) and dosing interval (≥ 2 days) were adjusted as needed. A subset of subjects had sequential pharmacokinetic evaluations of FVIII and rFVIIIFc. The primary endpoint was development of inhibitors (neutralizing antibodies). Secondary endpoints included pharmacokinetics, annualized bleeding rate (ABR), and number of infusions required to control a bleed. No subject developed an inhibitor to rFVIIIFc. Adverse events were typical of a pediatric hemophilic population. The rFVIIIFc half-life was prolonged relative to that of FVIII, consistent with observations in adults and adolescents. The median ABR was 1.96 overall, and 0.00 for spontaneous bleeds; 46.4% of subjects reported no bleeding episodes on study. Ninety-three per cent of bleeding episodes were controlled with one to two infusions. The median average weekly rFVIIIFc prophylactic dose was 88.11 IU kg(-1) . At study end, 62 of 69 subjects (90%) were infusing twice weekly. Among subjects who had been previously receiving FVIII prophylaxis, 74% reduced their dosing frequency with rFVIIIFc. Twice-weekly infusions with rFVIIIFc were well tolerated and yielded low bleeding rates in children with severe hemophilia A. © 2015 The Authors. Journal of Thrombosis and Haemostasis published by Wiley Periodicals, Inc. on behalf of International Society on Thrombosis and

Physical activity in individuals with haemophilia and experience with recombinant factor VIII Fc fusion protein and recombinant factor IX Fc fusion protein for the treatment of active patients: a literature review and case reports.

PubMed

Wang, Michael; Álvarez-Román, María Teresa; Chowdary, Pratima; Quon, Doris V; Schafer, Kim

2016-10-01

The World Federation of Hemophilia and the National Hemophilia Foundation encourage people with haemophilia (PWH) to participate in routine physical activity. The benefits of physical activity for PWH include improvements in joint, bone, and muscle health. Accordingly, a number of studies suggest that levels of physical activity among PWH are similar to those of their healthy peers, especially among individuals who began prophylaxis at an early age (≤3 years). Importantly, several studies found either no increased risk or only a transient increase in risk of bleeding with more intensive physical activity compared with less intensive physical activity. Data on optimal prophylaxis regimens for PWH who participate in physical/sporting activities; however, remain sparse. Long-acting recombinant factor VIII Fc fusion protein (rFVIIIFc) and recombinant factor IX Fc fusion protein (rFIXFc) demonstrated efficacy for the prevention and treatment of bleeding episodes in Phase 3 clinical trials of participants with haemophilia A and B, respectively, with most individuals able to maintain or increase their physical activities. This manuscript reviews the current literature that describes physical activity in PWH. Additionally, case studies are presented to provide supplemental information to clinicians illustrating the use of rFVIIIFc and rFIXFc in physically active patients with haemophilia A and B, respectively. These case reports demonstrate that it is possible for patients to be physically active and maintain good control of their haemophilia with extended interval prophylactic dosing using rFVIIIFc or rFIXFc.

Physical activity in individuals with haemophilia and experience with recombinant factor VIII Fc fusion protein and recombinant factor IX Fc fusion protein for the treatment of active patients: a literature review and case reports

PubMed Central

Wang, Michael; Álvarez-Román, María Teresa; Chowdary, Pratima; Quon, Doris V.; Schafer, Kim

2016-01-01

The World Federation of Hemophilia and the National Hemophilia Foundation encourage people with haemophilia (PWH) to participate in routine physical activity. The benefits of physical activity for PWH include improvements in joint, bone, and muscle health. Accordingly, a number of studies suggest that levels of physical activity among PWH are similar to those of their healthy peers, especially among individuals who began prophylaxis at an early age (≤3 years). Importantly, several studies found either no increased risk or only a transient increase in risk of bleeding with more intensive physical activity compared with less intensive physical activity. Data on optimal prophylaxis regimens for PWH who participate in physical/sporting activities; however, remain sparse. Long-acting recombinant factor VIII Fc fusion protein (rFVIIIFc) and recombinant factor IX Fc fusion protein (rFIXFc) demonstrated efficacy for the prevention and treatment of bleeding episodes in Phase 3 clinical trials of participants with haemophilia A and B, respectively, with most individuals able to maintain or increase their physical activities. This manuscript reviews the current literature that describes physical activity in PWH. Additionally, case studies are presented to provide supplemental information to clinicians illustrating the use of rFVIIIFc and rFIXFc in physically active patients with haemophilia A and B, respectively. These case reports demonstrate that it is possible for patients to be physically active and maintain good control of their haemophilia with extended interval prophylactic dosing using rFVIIIFc or rFIXFc. PMID:27116081

Severe Hemophilia A in a Male Old English Sheep Dog with a C→T Transition that Created a Premature Stop Codon in Factor VIII

PubMed Central

Lozier, Jay N; Kloos, Mark T; Merricks, Elizabeth P; Lemoine, Nathaly; Whitford, Margaret H; Raymer, Robin A; Bellinger, Dwight A; Nichols, Timothy C

2016-01-01

Animals with hemophilia are models for gene therapy, factor replacement, and inhibitor development in humans. We have actively sought dogs with severe hemophilia A that have novel factor VIII mutations unlike the previously described factor VIII intron 22 inversion. A male Old English Sheepdog with recurrent soft-tissue hemorrhage and hemarthrosis was diagnosed with severe hemophilia A (factor VIII activity less than 1% of normal). We purified genomic DNA from this dog and ruled out the common intron 22 inversion; we then sequenced all 26 exons. Comparing the results with the normal canine factor VIII sequence revealed a C→T transition in exon 12 of the factor VIII gene that created a premature stop codon at amino acid 577 in the A2 domain of the protein. In addition, 2 previously described polymorphisms that do not cause hemophilia were present at amino acids 909 and 1184. The hemophilia mutation creates a new TaqI site that facilitates rapid genotyping of affected offspring by PCR and restriction endonuclease analyses. This mutation is analogous to the previously described human factor VIII mutation at Arg583, which likewise is a CpG dinucleotide transition causing a premature stop codon in exon 12. Thus far, despite extensive treatment with factor VIII, this dog has not developed neutralizing antibodies (‘inhibitors’) to the protein. This novel mutation in a dog gives rise to severe hemophilia A analogous to a mutation seen in humans. This model will be useful for studies of the treatment of hemophilia. PMID:27780008

Clotting factor VIII (FVIII) and thrombin generation in camel plasma: A comparative study with humans

PubMed Central

Abdel Gader, Abdel Galil M.; Al Momen, Abdul Karim M.; Alhaider, Abdulqader; Brooks, Marjory B.; Catalfamo, James L.; Al Haidary, Ahmed A.; Hussain, Mansour F.

2013-01-01

The objective of this study was to characterize the highly elevated levels of clotting factor VIII (FVIII) in camel plasma. Whole blood was collected from healthy camels and factor VIII clotting activity (FVIII:C) assays were conducted using both the clotting and the chromogenic techniques. The anticoagulant citrate phosphate dextrose adenine (CPDA) produced the highest harvest of FVIII:C, the level of plasma factor VIII, compared to heparin:saline and heparin:CPDA anticoagulants. Camel FVIII can be concentrated 2 to 3 times in cryoprecipitate. There was a significant loss of camel FVIII when comparing levels of FVIII in camel plasma after 1 h of incubation at 37°C (533%), 40°C (364%), and 50°C (223%). Thrombin generation of camel plasma is comparable to that of human plasma. It was concluded that camel plasma contains very elevated levels of FVIII:C, approaching 8 times the levels in human plasma, and that these elevated levels could not be attributed to excessive thrombin generation. Unlike human FVIII:C, camel FVIII:C is remarkably heat stable. Taken together, these unique features of camel FVIII could be part of the physiological adaptation of hemostasis of the Arabian camel in order to survive in the hot desert environment. PMID:24082408

Controlled, cross-sectional MRI evaluation of joint status in severe haemophilia A patients treated with prophylaxis vs. on demand

PubMed Central

Oldenburg, J; Zimmermann, R; Katsarou, O; Theodossiades, G; Zanon, E; Niemann, B; Kellermann, E; Lundin, B

2015-01-01

In patients with haemophilia A, factor VIII (FVIII) prophylaxis reduces bleeding frequency and joint damage compared with on-demand therapy. To assess the effect of prophylaxis initiation age, magnetic resonance imaging (MRI) was used to evaluate bone and cartilage damage in patients with severe haemophilia A. In this cross-sectional, multinational investigation, patients aged 12–35 years were assigned to 1 of 5 groups: primary prophylaxis started at age <2 years (group 1); secondary prophylaxis started at age 2 to <6 years (group 2), 6 to <12 years (group 3), or 12−18 years (group 4); or on-demand treatment (group 5). Joint status at ankles and knees was assessed using Compatible Additive MRI scoring (maximum and mean ankle; maximum and mean of all 4 joints) and Gilbert scores in the per-protocol population (n = 118). All prophylaxis groups had better MRI joint scores than the on-demand group. MRI scores generally increased with current patient age and later start of prophylaxis. Ankles were the most affected joints. In group 1 patients currently aged 27−35 years, the median of maximum ankle scores was 0.0; corresponding values in groups 4 and 5 were 17.0 and 18.0, respectively [medians of mean index joint scores: 0.0 (group 1), 8.1 (group 2) and 13.8 (group 4)]. Gilbert scores revealed outcomes less pronounced than MRI scores. MRI scores identified pathologic joint status with high sensitivity. Prophylaxis groups had lower annualized joint bleeds and MRI scores vs. the on-demand group. Primary prophylaxis demonstrated protective effects against joint deterioration compared with secondary prophylaxis. PMID:25470205

The new albumin-free recombinant factor VIII concentrates for treatment of hemophilia: do they represent an actual incremental improvement?

PubMed

Josephson, Cassandra D; Abshire, Thomas

2004-07-01

The goal of eliminating the low levels of infectious disease risk from hemophilia treatment has resulted in the development of multiple generations of recombinant factor VIII (rFVIII) products. The ideal product should be devoid of human and animal proteins, which may transmit infectious agents. These products should also maintain molecular integrity, hemostatic efficacy, similar immunogenicity, and acceptable side effect profiles as compared to plasma-derived factor VIII. Currently available first-, second-, and third-generation rFVIII products include Recombinate; Kogenate FS/Helixate FS and ReFacto; and Advate, respectively. During the evolution of rFVIII products, either full-length or B-domain-deleted factor VIII were transfected into immortalized cell lines. The B-domain-deleted product, ReFacto, has resulted in an additional method to monitor factor VIII levels. The third-generation products offer the theoretical advantage of being produced without human and/or animal proteins. Upon initial introduction into the marketplace, the newer products have a higher cost. However, when analyzing historical trends, the prices of these products are almost equivalent to first-generation products within 3 years of licensure. Thus, the initial cost of the product may be a minimal issue in the medical decision process when selecting rFVIII replacement therapy.

Establishment of the 2nd Korean national biological reference standard for blood coagulation factor VIII:C concentrate.

PubMed

Lee, Naery; Seo, Ji Suk; Kim, Jae Ok; Ban, Sang Ja

2017-05-01

Since the 1st Korean national biological reference standard for factor (F)VIII concentrate, established in 2001, has shown declining potency, we conducted this study to replace this standard with a 2nd Korean national biological reference standard for blood coagulation FVIII concentrate. The candidate materials for the 2nd standard were prepared in 8000 vials with 10 IU/ml of target potency, according to the approved manufacturing process of blood coagulation Factor VIII:C Monoclonal Antibody-purified, Freeze-dried Human Blood Coagulation Factor VIII:C. Potency was evaluated by one-stage clotting and chromogenic methods and the stability was confirmed to meet the specifications during a period of 73 months. Since the potencies obtained by the two methods differed significantly (P < 0.015), the values were determined separately according to the geometric means (8.9 and 7.4 IU/vial, respectively). The geometric coefficients of interlaboratory variability were 3.4% and 7.6% by the one-stage clotting and chromogenic assays, respectively. Copyright © 2017 International Alliance for Biological Standardization. Published by Elsevier Ltd. All rights reserved.

Benefits of prophylaxis versus on-demand treatment in adolescents and adults with severe haemophilia A: the POTTER study.

PubMed

Tagliaferri, Annarita; Feola, Giulio; Molinari, Angelo Claudio; Santoro, Cristina; Rivolta, Gianna Franca; Cultrera, Dorina Bianca; Gagliano, Fabio; Zanon, Ezio; Mancuso, Maria Elisa; Valdré, Lelia; Mameli, Luciana; Amoresano, Susanna; Mathew, Prasad; Coppola, Antonio

2015-07-01

Rigorous evidence is lacking on long-term outcomes of factor VIII (FVIII) prophylaxis initiated in adolescent or adult patients with severe haemophilia A. The prospective, open-label Prophylaxis versus On-demand Therapy Through Economic Report (POTTER) study (ClinicalTrials.gov NCT01159587) compared long-term late secondary prophylaxis (recombinant FVIII-FS 20-30 IU/kg thrice weekly) with on-demand treatment in patients aged 12 to 55 years with severe haemophilia A. The annual number of joint bleeding episodes (primary endpoint), total bleeding episodes, orthopaedic and radiologic (Pettersson) scores, health-related quality of life (HRQoL), pharmacoeconomic impact, and safety were evaluated over a > 5-year period (2004-2010). Fifty-eight patients were enrolled at 11 centres in Italy; 53 (27 prophylaxis, 26 on demand) were evaluated and stratified into 2 age subgroups (12-25 and 26-55 years). Patients receiving prophylaxis experienced a significantly lower number of joint bleeding episodes vs the on-demand group (annualised bleeding rate, 1.97 vs 16.80 and 2.46 vs 16.71 in younger and older patients, respectively; p=0.0043). Results were similar for total bleeding episodes. Prophylaxis was associated with significantly fewer target joints (p< 0.001), better orthopaedic (p=0.0019) and Pettersson (p=0.0177) scores, better HRQoL, and fewer days of everyday activities lost (p< 0.0001) but required significantly higher FVIII product consumption. The POTTER study is the first prospective, controlled trial documenting long-term benefits of late secondary prophylaxis in adolescents and adults with severe haemophilia A. The benefits of reduced bleeding frequency, improved joint status, and HRQoL may offset the higher FVIII consumption and costs.

von Willebrand factor and factor VIII are independently required to form stable occlusive thrombi in injured veins

PubMed Central

Chauhan, Anil K.; Kisucka, Janka; Lamb, Colin B.; Bergmeier, Wolfgang

2007-01-01

von Willebrand factor (VWF) protects factor VIII (FVIII) from proteolysis and mediates the initial contact of platelets with the injured vessel wall, thus playing an important role in hemostasis and thrombosis. VWF is crucial for the formation of occlusive thrombi at arterial shear rates. However, with only a few conflicting studies published, the role of VWF in venous thrombosis is still unclear. Using gene-targeted mice, we show that in ferric chloride–injured veins platelet adhesion to subendothelium is decreased and thrombus growth is impaired in VWF−/− mice when compared with wild type (WT). We also observed increased embolization in the VWF−/− mice, which was due to lower FVIII levels in these mice as recombinant factor VIII (r-FVIII) restored thrombus stability. Despite normalization of blood clotting time and thrombus stability after r-FVIII infusion, the VWF−/− venules did not occlude. Transgenic platelets lacking the VWF receptor GPIbα extracellular domain showed decreased adhesion to injured veins. But, after a delay, all the injured venules occluded in these transgenic mice. Thus, VWF likely uses other adhesion receptors besides GPIbα in thrombus growth under venous shear conditions. Our studies document crucial roles for VWF and FVIII in experimental thrombosis under venous flow conditions in vivo. PMID:17119108

Tailored frequency-escalated primary prophylaxis for severe haemophilia A: results of the 16-year Canadian Hemophilia Prophylaxis Study longitudinal cohort.

PubMed

Feldman, Brian M; Rivard, Georges E; Babyn, Paul; Wu, John K M; Steele, MacGregor; Poon, Man-Chiu; Card, Robert T; Israels, Sara J; Laferriere, Nicole; Gill, Kulwant; Chan, Anthony K; Carcao, Manuel; Klaassen, Robert J; Cloutier, Stephanie; Price, Victoria E; Dover, Saunya; Blanchette, Victor S

2018-06-01

Severe haemophilia A has high morbidity, and treatment, while effective, is very expensive. We report the 16-year follow-up of the Canadian Hemophilia Prophylaxis Study, which examined the effectiveness of tailored frequency-escalated primary prophylaxis with a focus on health outcomes within the domains of body structures and functions, and activities and participation (according to the WHO International Classification of Functioning, Disability and Health [WHO-ICF] framework) and a view to reducing consumption of costly clotting factor, which accounts for more than 90% of the cost of care of severe haemophilia. In this longitudinal study, boys with severe haemophilia A from 12 Canadian centres were enrolled at age 1·0-2·5 years. They were treated with standard half-life recombinant factor VIII (SHL-rFVIII), beginning as once-weekly prophylaxis with 50 IU/kg and escalating in frequency (with accompanying dose adjustments) in response to breakthrough bleeding as determined by the protocol. The primary endpoint for this analysis was joint health, as measured by the modified Colorado Child Physical Examination Scores (CCPES) at study end. All analyses were done by intention to treat. The trial is complete, and is registered with ClinicalTrials.gov, number NCT01085344. Between June 26, 1997, and Jan 30, 2007, 56 boys were enrolled. They were followed for a median of 10·2 years (to a maximum of 16·1 years). Median rFVIII usage was about 3600 IU/kg per year. The median end-of-study CCPES physical examination score was 1 (IQR 1-3; range 0-12) for the left ankle and 1 (1-2; 0-12) for the right ankle, with all other joints having a median score of 0. No treatment-related safety events occurred over the duration of the study, including central venous catheter infections. The median annualised index joint bleeding rate was 0·95 per year (IQR 0·44-1·35; range 0·00-13·43), but 17 (30%) patients had protocol-defined unacceptable breakthrough bleeding at some point

Prophylaxis in congenital factor VII deficiency: indications, efficacy and safety. Results from the Seven Treatment Evaluation Registry (STER).

PubMed

Napolitano, Mariasanta; Giansily-Blaizot, Muriel; Dolce, Alberto; Schved, Jean F; Auerswald, Guenter; Ingerslev, Jørgen; Bjerre, Jens; Altisent, Carmen; Charoenkwan, Pimlak; Michaels, Lisa; Chuansumrit, Ampaiwan; Di Minno, Giovanni; Caliskan, Umran; Mariani, Guglielmo

2013-04-01

Because of the very short half-life of factor VII, prophylaxis in factor VII deficiency is considered a difficult endeavor. The clinical efficacy and safety of prophylactic regimens, and indications for their use, were evaluated in factor VII-deficient patients in the Seven Treatment Evaluation Registry. Prophylaxis data (38 courses) were analyzed from 34 patients with severe factor VII deficiency (<1-45 years of age, 21 female). Severest phenotypes (central nervous system, gastrointestinal, joint bleeding episodes) were highly prevalent. Twenty-one patients received recombinant activated factor VII (24 courses), four received plasma-derived factor VII, and ten received fresh frozen plasma. Prophylactic schedules clustered into "frequent" courses (three times weekly, n=23) and "infrequent" courses (≤ 2 times weekly, n=15). Excluding courses for menorrhagia, "frequent" and "infrequent" courses produced 18/23 (78%) and 5/12 (41%) "excellent" outcomes, respectively; relative risk, 1.88; 95% confidence interval, 0.93-3.79; P=0.079. Long term prophylaxis lasted from 1 to >10 years. No thrombosis or new inhibitors occurred. In conclusion, a subset of patients with factor VII deficiency needed prophylaxis because of severe bleeding. Recombinant activated factor VII schedules based on "frequent" administrations (three times weekly) and a 90 μg/kg total weekly dose were effective. These data provide a rationale for long-term, safe prophylaxis in factor VII deficiency.

Long-term prophylaxis in severe factor VII deficiency.

PubMed

Siboni, S M; Biguzzi, E; Mistretta, C; Garagiola, I; Peyvandi, F

2015-11-01

The spectrum of bleeding problems in FVII deficiency is highly variable and FVII levels and causative genetic mutations correlate poorly with the bleeding risk. Long-term prophylaxis is generally initiated in order to prevent subsequent CNS bleeding after a first event or in patients with other major/ life threatening/ frequent bleeding symptoms as gastrointestinal bleeding or hemarthrosis. However few data are available in the literature regarding FVII prophylaxis and clinical decisions cannot be based on evidence. We report the data available in the literature on FVII prophylaxis and our personal experience regarding three patients affected by severe FVII deficiency. Specific papers on long-term prophylaxis in severe FVII deficiency were identified using the database, PUBMED. The most frequent indications for long-term prophylaxis were CNS bleeding (58%), hemartrosis (15%) and GI bleeding (9%). Patients were treated with various dosages and frequency. Prophylactic treatment with 10-30U/kg (pdFVII) or 20-30mcg/kg (rFVIIa) twice or three times/weeks was described to be effective. In the literature and in our experience, prophylaxis can be considered in patients with severe FVII deficiency and severe bleeding phenotype. A dose of 10-30U/kg (pdFVII) or 20-30 microg/kg (rFVIIa) twice or three times/week is usually administrated, but dose and frequency can be tailored based on the clinical follow-up of the patients. Since hemarthrosis is a frequent manifestation, a suggestion to improve the outcomes of patients with severe FVII deficiency is to monitor joint condition in order to identify early arthropathy that could be another indication to start secondary prophylaxis. © 2015 John Wiley & Sons Ltd.

COST-UTILITY ANALYSIS OF PRIMARY PROPHYLAXIS, COMPARED WITH ON-DEMAND TREATMENT, FOR PATIENTS WITH SEVERE HEMOPHILIA TYPE A IN COLOMBIA.

PubMed

Castro Jaramillo, Héctor Eduardo; Moreno Viscaya, Mabel; Mejia, Aurelio E

2016-01-01

This article presents a cost-utility analysis from the Colombian health system perspective comparing primary prophylaxis to on-demand treatment using exogenous clotting factor VIII (FVIII) for patients with severe hemophilia type A. We developed a Markov model to estimate expected costs and outcomes (measured as quality-adjusted life-years, QALYs) for each strategy. Transition probabilities were estimated using published studies; utility weights were obtained from a sample of Colombian patients with hemophilia and costs were gathered using local data. Both deterministic and probabilistic sensitivity analysis were performed to assess the robustness of results. The additional cost per QALY gained of primary prophylaxis compared with on-demand treatment was 105,081,022 Colombian pesos (COP) (55,204 USD), and thus not considered cost-effective according to a threshold of up to three times the current Colombian gross domestic product (GDP) per-capita. When primary prophylaxis was provided throughout life using recombinant FVIII (rFVIII), which is much costlier than FVIII, the additional cost per QALY gained reached 174,159,553 COP (91,494 USD). using a decision rule of up to three times the Colombian GDP per capita, primary prophylaxis (with either FVIII or rFVIII) would not be considered as cost-effective in this country. However, a final decision on providing or preventing patients from primary prophylaxis as a gold standard of care for severe hemophilia type A should also consider broader criteria than the incremental cost-effectiveness ratio results itself. Only a price reduction of exogenous FVIII of 50 percent or more would make primary prophylaxis cost-effective in this context.

Primary prophylaxis for children with severe congenital factor VII deficiency - Clinical and laboratory assessment.

PubMed

Kuperman, A A; Barg, A A; Fruchtman, Y; Shaoul, E; Rosenberg, N; Kenet, G; Livnat, T

2017-09-01

Severe congenital factor VII (FVII) deficiency is a rare bleeding disorder. Prophylaxis with replacement therapy has been suggested to patients, yet the most beneficial dosing regimens and therapy intervals are still to be defined. Due to the lack of evidence-based data, we hereby present our experience with long-term administration and monitoring primary prophylaxis in children with severe FVII deficiency and an extremely high bleeding risk. Four children with familial FVII deficiency, treated by prophylactic recombinant activated factor VII (rFVIIa), 15-30μg/kg/dose, given 2-3 times weekly since infancy, are discussed. Clinical follow up and monitoring laboratory assays, including thrombin generation, measured at various time points after prophylactic rFVIIa administration are presented. Among our treated patients neither FVII activity nor thrombin generation parameters (both already declined 24h post rFVIIa administration) were able to predict the impact of prophylaxis, and could not be used as surrogate markers in order to assess the most beneficial treatment frequency. However, the long clinical follow-up and comprehensive laboratory assessment performed, have shown that early primary prophylaxis as administered in our cohort was safe and effective. Copyright © 2016 Elsevier Inc. All rights reserved.

Innovative Approaches for Immune Tolerance to Factor VIII in the Treatment of Hemophilia A

PubMed Central

Sherman, Alexandra; Biswas, Moanaro; Herzog, Roland W.

2017-01-01

Hemophilia A (coagulation factor VIII deficiency) is a debilitating genetic disorder that is primarily treated with intravenous replacement therapy. Despite a variety of factor VIII protein formulations available, the risk of developing anti-dug antibodies (“inhibitors”) remains. Overall, 20–30% of patients with severe disease develop inhibitors. Current clinical immune tolerance induction protocols to eliminate inhibitors are not effective in all patients, and there are no prophylactic protocols to prevent the immune response. New experimental therapies, such as gene and cell therapies, show promising results in pre-clinical studies in animal models of hemophilia. Examples include hepatic gene transfer with viral vectors, genetically engineered regulatory T cells (Treg), in vivo Treg induction using immune modulatory drugs, and maternal antigen transfer. Furthermore, an oral tolerance protocol is being developed based on transgenic lettuce plants, which suppressed inhibitor formation in hemophilic mice and dogs. Hopefully, some of these innovative approaches will reduce the risk of and/or more effectively eliminate inhibitor formation in future treatment of hemophilia A. PMID:29225598

Efficacy of standard prophylaxis versus on-demand treatment with bayer's sucrose-formulated recombinant FVIII (rFVIII-FS) in Chinese children with severe hemophilia A.

PubMed

Zhao, Yongqiang; Xiao, Juan; Yang, Renchi; Wu, Runhui; Hu, Yu; Beckmann, Horst; Wu, Junde; Hou, Qingsong; Sun, Jing

2017-04-01

In China, care of patients with severe hemophilia primarily involves insufficient dosing of on-demand treatment and secondary low-dose prophylaxis (10 IU/kg 2× /wk). We sought to evaluate 3× /wk, standard-dose prophylaxis with sucrose-formulated recombinant factor VIII (rFVIII-FS; Bayer) compared with on-demand treatment in Chinese children with severe hemophilia A. Children and adolescents aged 2-16 years with severe hemophilia A, no inhibitors, and no prophylaxis for >6 consecutive months before study entry were eligible for this 24-week, interventional, sequential-treatment study. Patients received rFVIII-FS on demand for 12 weeks followed by a 12-week prophylaxis period (25 IU/kg 3× /wk). The primary efficacy endpoint was comparison of the annualized bleeding rate (ABR) of all bleeds in the prophylaxis versus on-demand phase. Additional variables included ABR of joint bleeds, school attendance/activity, daily activity, and hemophilia Joint Health Score (HJHS). Thirty patients (median age, 12 years) were treated and analyzed. Compared with on-demand treatment, prophylaxis reduced median (quartile [Q1; Q3]) ABR of all bleeds (57.5 [44.5; 73.9] vs 0 [0; 4.0]) and joint bleeds (34.5 [26.1; 56.5] vs 0 [0; 4.0]). Median (range) total HJHS improved after both the prophylaxis and on-demand phases (8.0 [0-48.0] and 11.0 [0-55.0], respectively) compared with baseline (16.0 [0-56.0]). School attendance/activity and daily activity improved with prophylaxis versus on demand. No inhibitors or treatment-related adverse events were reported. In this first prospective, standard-dose, secondary prophylaxis study in China, rFVIII-FS prophylaxis reduced bleeding and improved health outcomes versus on-demand treatment in children with severe hemophilia A.

Crystal Structure of the Bovine lactadherin C2 Domain, a Membrane Binding Motif, Shows Similarity of the C2 Domains of Factor V and Factor VIII

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lin,L.; Huai, Q.; Huang, M.

2007-01-01

Lactadherin, a glycoprotein secreted by a variety of cell types, contains two EGF domains and two C domains with sequence homology to the C domains of blood coagulation proteins factor V and factor VIII. Like these proteins, lactadherin binds to phosphatidylserine (PS)-containing membranes with high affinity. We determined the crystal structure of the bovine lactadherin C2 domain (residues 1 to 158) at 2.4 Angstroms. The lactadherin C2 structure is similar to the C2 domains of factors V and VIII (rmsd of C? atoms of 0.9 Angstroms and 1.2 Angstroms, and sequence identities of 43% and 38%, respectively). The lactadherin C2more » domain has a discoidin-like fold containing two ?-sheets of five and three antiparallel ?-strands packed against one another. The N and C termini are linked by a disulfide bridge between Cys1 and Cys158. One ?-turn and two loops containing solvent-exposed hydrophobic residues extend from the C2 domain ?-sandwich core. In analogy with the C2 domains of factors V and VIII, some or all of these solvent-exposed hydrophobic residues, Trp26, Leu28, Phe31, and Phe81, likely participate in membrane binding. The C2 domain of lactadherin may serve as a marker of cell surface phosphatidylserine exposure and may have potential as a unique anti-thrombotic agent.« less

Evaluation of B&W UO2/ThO2 VIII experimental core: criticality and thermal disadvantage factor analysis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Carlo Parisi; Emanuele Negrenti

2017-02-01

In the framework of the OECD/NEA International Reactor Physics Experiment (IRPHE) Project, an evaluation of core VIII of the Babcock & Wilcox (B&W) Spectral Shift Control Reactor (SSCR) critical experiment program was performed. The SSCR concept, moderated and cooled by a variable mixture of heavy and light water, envisaged changing of the thermal neutron spectrum during the operation to encourage breeding and to sustain the core criticality. Core VIII contained 2188 fuel rods with 93% enriched UO2-ThO2 fuel in a moderator mixture of heavy and light water. The criticality experiment and measurements of the thermal disadvantage factor were evaluated.

Factors associated with coverage of cotrimoxazole prophylaxis in HIV-exposed children in South Africa.

PubMed

Moodley, Dhayendre; Reddy, Leanne; Mahungo, Wisani; Masha, Rebotile

2013-01-01

The World Health Organisation and the Joint United Nations Programme in 2006 reaffirmed the earlier recommendation of 2000 that all HIV-exposed infants in resource-poor countries should commence cotrimoxazole (CTX) prophylaxis at 6-weeks of life. CTX prophylaxis should be continued until the child is confirmed HIV-uninfected and there is no further exposure to breastmilk transmission. We determined CTX coverage and explored factors associated with CTX administration in HIV-exposed infants at a primary health clinic in South Africa. In a cross-sectional study of HIV-exposed infants 6-18 months of age attending a child immunisation clinic, data from the current visit and previous visits related to CTX prophylaxis, feeding practice and infant HIV testing were extracted from the child's immunisation record. Further information related to the administration of CTX prophylaxis was obtained from an interview with the child's mother. One-third (33.0%) HIV-exposed infants had not initiated CTX at all and breastfed infants were more likely to have commenced CTX prophylaxis as compared to their non-breastfed counterparts (78.7% vs 63.4%) (p = 0.008). Availability of infant's HIV status was strongly associated with continuation or discontinuation of CTX after 6 months of age or after breastfeeding cessation. Maternal self-reports indicated that only 52.5% (95%CI 47.5-57.5) understood the reason for CTX prophylaxis, 126 (47%) did not dose during weekends; 55 (21%) dosed their infants 3 times a day and 70 (26%) dosed their infants twice daily. A third of HIV-exposed children attending a primary health care facility in this South African setting did not receive CTX prophylaxis. Not commencing CTX prophylaxis was strongly associated with infants not breastfeeding and unnecessary continued exposure to CTX in this paediatric population was due to limited availability of early infant diagnosis. Attendance at immunization clinics can be seen as missed opportunities for early

Factors Associated with Coverage of Cotrimoxazole Prophylaxis in HIV-Exposed Children in South Africa

PubMed Central

Moodley, Dhayendre; Reddy, Leanne; Mahungo, Wisani; Masha, Rebotile

2013-01-01

Background The World Health Organisation and the Joint United Nations Programme in 2006 reaffirmed the earlier recommendation of 2000 that all HIV-exposed infants in resource-poor countries should commence cotrimoxazole (CTX) prophylaxis at 6-weeks of life. CTX prophylaxis should be continued until the child is confirmed HIV-uninfected and there is no further exposure to breastmilk transmission. We determined CTX coverage and explored factors associated with CTX administration in HIV-exposed infants at a primary health clinic in South Africa. Methods In a cross-sectional study of HIV-exposed infants 6–18 months of age attending a child immunisation clinic, data from the current visit and previous visits related to CTX prophylaxis, feeding practice and infant HIV testing were extracted from the child's immunisation record. Further information related to the administration of CTX prophylaxis was obtained from an interview with the child's mother. Results One-third (33.0%) HIV-exposed infants had not initiated CTX at all and breastfed infants were more likely to have commenced CTX prophylaxis as compared to their non-breastfed counterparts (78.7% vs 63.4%) (p = 0.008). Availability of infant's HIV status was strongly associated with continuation or discontinuation of CTX after 6 months of age or after breastfeeding cessation. Maternal self-reports indicated that only 52.5% (95%CI 47.5–57.5) understood the reason for CTX prophylaxis, 126 (47%) did not dose during weekends; 55 (21%) dosed their infants 3 times a day and 70 (26%) dosed their infants twice daily. Conclusion A third of HIV-exposed children attending a primary health care facility in this South African setting did not receive CTX prophylaxis. Not commencing CTX prophylaxis was strongly associated with infants not breastfeeding and unnecessary continued exposure to CTX in this paediatric population was due to limited availability of early infant diagnosis. Attendance at immunization clinics can be

Continuous prophylaxis with recombinant factor IX Fc fusion protein and conventional recombinant factor IX products: comparisons of efficacy and weekly factor consumption.

PubMed

Iorio, Alfonso; Krishnan, Sangeeta; Myrén, Karl-Johan; Lethagen, Stefan; McCormick, Nora; Yermakov, Sander; Karner, Paul

2017-04-01

Continuous prophylaxis for patients with hemophilia B requires frequent injections that are burdensome and that may lead to suboptimal adherence and outcomes. Hence, therapies requiring less-frequent injections are needed. In the absence of head-to-head comparisons, this study compared the first extended-half-life-recombinant factor IX (rFIX) product-recombinant factor IX Fc fusion protein (rFIXFc)-with conventional rFIX products based on annualized bleed rates (ABRs) and factor consumption reported in studies of continuous prophylaxis. This study compared ABRs and weekly factor consumption rates in clinical studies of continuous prophylaxis treatment with rFIXFc and conventional rFIX products (identified by systematic literature review) in previously-treated adolescents and adults with moderate-to-severe hemophilia B. Meta-analysis was used to pool ABRs reported for conventional rFIX products for comparison. Comparisons of weekly factor consumption were based on the mean, reported or estimated from the mean dose per injection. Five conventional rFIX studies (injections 1 to >3 times/week) met the criteria for comparison with once-weekly rFIXFc reported by the B-LONG study. The pooled mean ABR for conventional rFIX was slightly higher than but comparable to rFIXFc (difference=0.71; p = 0.210). Weekly factor consumption was significantly lower with rFIXFc than in conventional rFIX studies (difference in means = 42.8-74.5 IU/kg/week [93-161%], p < 0.001). Comparisons of clinical study results suggest weekly injections with rFIXFc result in similar bleeding rates and significantly lower weekly factor consumption compared with more-frequently-injected conventional rFIX products. The real-world effectiveness of rFIXFc may be higher based on results from a model of the impact of simulated differences in adherence.

Incidence and Risk Factors for Leukopenia in Kidney Transplant Recipients Receiving Valganciclovir for Cytomegalovirus Prophylaxis.

PubMed

Liang, Xinyun; Famure, Olusegun; Li, Yanhong; Kim, S Joseph

2018-06-01

Valganciclovir is used not only for cytomegalovirus prophylaxis after kidney transplantation but can also induce leukopenia, thereby making patients more susceptible to other infections. The epidemiology of leukopenia in patients on valganciclovir remains poorly understood. To determine the incidence and risk factors for leukopenia in patients receiving valganciclovir for cytomegalovirus prophylaxis after kidney transplantation. In this single-center, retrospective, cohort study, we included kidney recipients transplanted from January 1, 2003, to December 31, 2010, to determine the incidence and risk factors for leukopenia in patients who received valganciclovir for cytomegalovirus prophylaxis. The Kaplan-Meier product limit method was used to graphically assess time to leukopenia, and risk factors were assessed using Cox proportional hazards models. A total of 542 kidney transplant recipients were included in the study cohort. The cumulative incidence of leukopenia at 6 months posttransplant was 39.3% (11.0% for neutropenia). Low baseline white blood cell count (hazard ratio [HR] 2.34 [95% confidence interval [CI], 1.37-4.00]) and high baseline body mass index (HR 1.05 [95% CI, 1.02-1.09]) were independently associated with an increased risk of leukopenia, while higher Cockcroft-Gault creatinine clearance (HR 0.87 [95% CI, 0.78-0.97]) was significantly associated with a decreased risk of leukopenia. These data suggest that recipient baseline white blood cell count, baseline body mass index, and kidney function are clinical predictors of new-onset leukopenia after kidney transplantation. Our results may inform the approach to cytomegalovirus prophylaxis to reduce the risk of valganciclovir-induced leukopenia in kidney transplant recipients.

Crystal Structure of the Bovine lactadherin C2 Domain, a Membrane Binding Motif, Shows Similarity to the C2 Domains of Factor V and Factor VIII

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lin,L.

2007-01-01

Lactadherin, a glycoprotein secreted by a variety of cell types, contains two EGF domains and two C domains with sequence homology to the C domains of blood coagulation proteins factor V and factor VIII. Like these proteins, lactadherin binds to phosphatidylserine (PS)-containing membranes with high affinity. We determined the crystal structure of the bovine lactadherin C2 domain (residues 1 to 158) at 2.4 {angstrom}. The lactadherin C2 structure is similar to the C2 domains of factors V and VIII (rmsd of C{sub {alpha}} atoms of 0.9 {angstrom} and 1.2 {angstrom}, and sequence identities of 43% and 38%, respectively). The lactadherinmore » C2 domain has a discoidin-like fold containing two {beta}-sheets of five and three antiparallel {beta}-strands packed against one another. The N and C termini are linked by a disulfide bridge between Cys1 and Cys158. One {beta}-turn and two loops containing solvent-exposed hydrophobic residues extend from the C2 domain {beta}-sandwich core. In analogy with the C2 domains of factors V and VIII, some or all of these solvent-exposed hydrophobic residues, Trp26, Leu28, Phe31, and Phe81, likely participate in membrane binding. The C2 domain of lactadherin may serve as a marker of cell surface phosphatidylserine exposure and may have potential as a unique anti-thrombotic agent.« less

Variation in baseline factor VIII concentration in a retrospective cohort of mild/moderate hemophilia A patients carrying identical F8 mutations.

PubMed

Loomans, J I; van Velzen, A S; Eckhardt, C L; Peters, M; Mäkipernaa, A; Holmstrom, M; Brons, P P; Dors, N; Haya, S; Voorberg, J; van der Bom, J G; Fijnvandraat, K

2017-02-01

Essentials Factor VIII levels vary in mild and moderate hemophilia A (MHA) patients with the same mutation. We aimed to estimate the variation and determinants of factor VIII levels among MHA patients. Age and genotype explain 59% of the observed inter-individual variation in factor VIII levels. Intra-individual variation accounted for 45% of the variation in the three largest mutation groups. Background The bleeding phenotype in patients with mild/moderate hemophilia A (MHA) is inversely associated with the residual plasma concentration of factor VIII (FVIII:C). Within a group of patients with the same F8 missense mutation, baseline FVIII:C may vary, because, in healthy individuals, von Willebrand factor (VWF) levels, ABO blood group and age are also known to influence baseline FVIII:C. Our understanding of the pathophysiologic process of the causative genetic event leading to reduced baseline FVIII:C in MHA patients is still limited. Objectives To estimate the variation and determinants of baseline FVIII:C among MHA patients with the same F8 missense mutation. Methods Three hundred and forty-six patients carrying mutations that were present in at least 10 patients in the cohort were selected from the INSIGHT and the RISE studies, which are cohort studies including data of 3534 MHA patients from Europe, Canada, and Australia. Baseline FVIII:C was measured with a one-stage clotting assay. We used Levene's test, univariate and multivariate linear regression, and mixed-model analyses. Results For 59% of patients, the observed variation in baseline FVIII:C was explained by age and genotype. Compared to FVIII:C in patients with Arg612Cys, FVIII:C was significantly different in patients with eight other F8 missense mutations. Intra-individual variation explained 45% of the observed variance in baseline FVIII:C among patients with the same mutation. Conclusion Our results indicate that baseline FVIII:C levels are not exclusively determined by F8 genotype in MHA patients

Characterization of factor VIII pharmaceutical preparations by means of MudPIT proteomic approach.

PubMed

Basilico, Fabrizio; Nardini, Ilaria; Mori, Filippo; Brambilla, Elena; Benazzi, Louise; De Palma, Antonella; Rosti, Enrico; Farina, Claudio; Mauri, PierLuigi

2010-09-21

For a good clinical outcome of Haemophilia A substitutive therapy a detailed characterization of factor VIII (FVIII) concentrates is required, in order to disclose the eventual relations between differently composed concentrates and their biological effects. This preliminary work could be a first step towards a deep structural characterization of FVIII concentrates, using the fast and simply manageable MudPIT technology, which enables the identification and characterization of protein mixtures taking advantage of both the high separation capacity of two-dimensional chromatography and the powerful peptide characterization ability of tandem mass spectrometry. The aim of this study was to evaluate the suitability of for the characterization of FVIII molecule in complex mixtures such its commercial concentrates, both plasma-derived and recombinant, and for the determination of the protein composition of different FVIII preparations. By means of Multidimensional Protein Identification Technology (MudPIT) it was possible to assess the presence of factor VIII in its preparations and to identify most of the contaminant proteins without gel separation. In particular, 125 and 42 proteins were identified in plasma-derived and recombinant concentrates, respectively. Concerning investigation of FVIII, 24 different peptides were identified in plasma-derived corresponding to 7, 29, 27, 19 and 67 of percentage coverage for A1, A2, A3, C1 and C2 domains, respectively. About its multimeric carrier von Willebrand factor (VWF), we have sequenced 42% of domain interacting with A3 and C2 domains of FVIII. Finally, it has been observed that normalized parameters, such as total peptide hits obtained by SEQUEST may be used for evaluation of the relative abundance of FVIII in different preparations. Copyright 2010 Elsevier B.V. All rights reserved.

Estimates of utility weights in hemophilia: implications for cost-utility analysis of clotting factor prophylaxis

PubMed Central

Grosse, Scott D; Chaugule, Shraddha S; Hay, Joel W

2015-01-01

Estimates of preference-weighted health outcomes or health state utilities are needed to assess improvements in health in terms of quality-adjusted life-years. Gains in quality-adjusted life-years are used to assess the cost–effectiveness of prophylactic use of clotting factor compared with on-demand treatment among people with hemophilia, a congenital bleeding disorder. Published estimates of health utilities for people with hemophilia vary, contributing to uncertainty in the estimates of cost–effectiveness of prophylaxis. Challenges in estimating utility weights for the purpose of evaluating hemophilia treatment include selection bias in observational data, difficulty in adjusting for predictors of health-related quality of life and lack of preference-based data comparing adults with lifetime or primary prophylaxis versus no prophylaxis living within the same country and healthcare system. PMID:25585817

[Case of cerebral venous thrombosis due to graves' disease with increased factor VIII activity].

PubMed

Kasuga, Kensaku; Naruse, Satoshi; Umeda, Maiko; Tanaka, Midori; Fujita, Nobuya

2006-04-01

A 39 year-old man was admitted to our hospital because of severe headache with fever continuing over two weeks. Three days after admission he developed aphasia and right hemiparesis, when his CT revealed subarachnoid hemorrhage at the left sylvian fissure. He was diagnosed as suffering from cerebral venous thrombosis because empty delta sign was positive on the enhanced brain CT. Suprasagittal sinus and bilateral transverse sinuses were not detected on the cerebral angiography. He was also diagnosed as having Graves' disease for the first time on the basis of free T3 13.56 pg/ml, free T4 4.65 ng/dl, TSH < 0.01 IU/ml, anti-TSH receptor antibody 4.3 IU/l, and thyroid stimulating antibody 224%. On the examination, homocystine and activities of antithrombin III, protein C, and protein S were normal. Antinculear, anti-DNA, anti-Sm, anticardiolipin beta2GP-I antibodies, and PR3ANCA were negative. Factor VIII activity, however, markedly increased over 300%, which has been known to increase in the cases of hyperthyroidism. He recovered well after the treatment with thiamazole in addition to warfarin followed by intravenous heparin. There are only six cases of cerebral venous thrombosis due to hyperthyroidism with increased factor VIII level. All of those cases were female, and 5 of them were taking oral contraceptives. This is a first Japanese male case.

Cerebral venous thrombosis associated with thyrotoxicosis, the use of desmopressin and elevated factor VIII/von Willebrand factor.

PubMed

Waheed, Waqar; Aljerdi, Salman; Decker, Barbara; Cushman, Mary; Hamill, Robert W

2016-08-08

Cerebral venous thrombosis (CVT) is an uncommon disorder associated with diverse processes. We report a patient who, while receiving desmopressin and contraceptive pills (OCP), developed straight sinus thrombosis. Clinical assessment and laboratory investigations revealed untreated hyperthyroidism and a hypercoagulable state, characterised by high levels of von Willebrand factor, factor VIII coagulant activity and IgM cardiolipin antibody. The clinical picture improved with anticoagulation, treatment of hyperthyroidism and discontinuation of OCP and desmopressin. To the best of our knowledge, the association between the use of oral desmopressin and CVT has not been described. The multiple risk factors present in our case were probably additive in increasing the risk of CVT. Although this case represents a rare occurrence, practitioners should be alerted to the possible associations of desmopressin, oral contraceptives and Graves' disease with venous thrombosis. 2016 BMJ Publishing Group Ltd.

Recombinant to modified factor VIII and factor IX - chromogenic and one-stage assays issues.

PubMed

Kitchen, S; Kershaw, G; Tiefenbacher, S

2016-07-01

The recent development of modified recombinant factor VIII (FVIII) and factor IX (FIX) therapeutic products with extended half-lives will create challenges for the haemostasis laboratory in obtaining recovery estimates of these products in clinical samples using existing assays. The new long-acting therapeutic concentrates contain molecular modifications of Fc fusion, site-specific of polyethylene glycol or albumin fusion. The optimum methods for monitoring each new product will need to be assessed individually and laboratories should select an assay which gives similar results to the assay used to assign potency to the product in question. For some extended half-life FVIII and FIX products some one stage assays are entirely unsuitable for monitoring purposes. For most products and assay reagents studied so far, and reviewed in this manuscript, chromogenic FVIII or FIX assays can be safely used with conventional plasma standards. If one stage assays are used then they should be performed using carefully selected reagents/methods which have been shown to recover activity close to the labelled potency for the specific product being monitored. © 2016 John Wiley & Sons Ltd.

A comparison of traditional vs. Canadian tailored prophylaxis dosing of prophylactic factor infusions in children with haemophilia A and B in a single hemophilia treatment center.

PubMed

Dodd, C; Watts, R G

2012-07-01

Prophylactic infusion of clotting factor concentrates is a developing standard of care for individuals with haemophilia. The ideal schedule and techniques of prophylactic infusions remain incompletely defined. Our aim was to determine the optimal techniques and schedules for factor prophylaxis in paediatric patients. A retrospective electronic medical record review of all children treated with prophylactic factor infusions in a single Haemophilia Treatment Center was conducted. Comparison of traditional vs. Canadian dosing regimens and primary vs. secondary prophylaxis was made. Failure of prophylaxis was defined as the first serious bleed. A total of 58 children were identified for review. Five cases were excluded (four due to high titre inhibitors and one due to repeated non-compliance), thus there were 53 total cases: 46 with severe haemophilia, 2 with moderate haemophilia, 5 with mild haemophilia, 44 with haemophilia A and 9 with haemophilia B; 32 Traditional dosing and 21 Canadian dosing regimens. Patients on primary prophylaxis had a decreased failure rate (25%) compared to children treated with secondary prophylaxis (67%) regardless of technique of prophylaxis. When compared to a 'Traditional' factor prophylaxis schedule, the 'Canadian' tailored prophylaxis protocol was comparable with the exception of a decreased use of implanted venous devices in the 'Canadian' group. Ongoing bleeding (primarily joint bleeds) occurs with all prophylactic regimens. The lowest incidence of treatment failure was noted in children who began primary prophylaxis at a young age and before initial joint bleeds. Primary prophylaxis is superior to secondary prophylaxis regardless of dosing regimen. Traditional and Canadian dosing regimens were equivalent in outcome when measured over several years of follow-up. © 2012 Blackwell Publishing Ltd.

Cytomegalovirus prophylaxis in seropositive renal transplant recipients receiving thymoglobulin induction therapy: outcome and risk factors for late CMV disease.

PubMed

Reusing, Jose O; Feitosa, Emanoela B; Agena, Fabiana; Pierroti, Lígia C; Azevedo, Luiz S F; Kotton, Camille N; David-Neto, Elias

2018-05-29

Anti-thymocyte globulin (ATG) therapy is a risk factor for CMV disease in renal transplant (RTx) recipients and therefore antiviral prophylaxis is commonly used. We evaluated the outcome of our current policy of 90 days of CMV prophylaxis in seropositive recipients given ATG and the risk factors for the occurrence of CMV disease after prophylaxis. We studied a retrospective cohort of 423 RTx (2010-2014) CMV-seropositive adults given ATG induction therapy. 54 (13%) patients developed cytomegalovirus (CMV) disease at a median of 163 days after transplant, of which 29 (54%) had viral syndrome and 25 (46%) had invasive disease. Median prophylaxis time (94 days) and immunosuppressive drugs were similar between groups (CMV vs no-CMV). Those with CMV disease had more deceased donors and higher donor age, lower lymphocyte count, and lower median eGFR at day 90. Multivariable logistic regression analysis at day 90 and 180 found that eGFR ≤ 40 ml/min/1.73 m 2 (but not acute rejection) was associated with late CMV disease. In a separate validation cohort of 124 patients with 8% late CMV disease, eGFR ≤ 45 and lymphocyte count ≤ 800 cells/mm 3 at the end of prophylaxis remained predictive of late CMV disease occurrence. These data indicate that antiviral prophylaxis adequately prevented CMV in seropositive recipients given ATG, but late disease still occurred. Low eGFR and low lymphocyte count at the end of prophylaxis may help identify patients at higher risk of CMV disease. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Granulocyte colony-stimulating factors for febrile neutropenia prophylaxis following chemotherapy: systematic review and meta-analysis

PubMed Central

2011-01-01

Background Febrile neutropenia (FN) occurs following myelosuppressive chemotherapy and is associated with morbidity, mortality, costs, and chemotherapy reductions and delays. Granulocyte colony-stimulating factors (G-CSFs) stimulate neutrophil production and may reduce FN incidence when given prophylactically following chemotherapy. Methods A systematic review and meta-analysis assessed the effectiveness of G-CSFs (pegfilgrastim, filgrastim or lenograstim) in reducing FN incidence in adults undergoing chemotherapy for solid tumours or lymphoma. G-CSFs were compared with no primary G-CSF prophylaxis and with one another. Nine databases were searched in December 2009. Meta-analysis used a random effects model due to heterogeneity. Results Twenty studies compared primary G-CSF prophylaxis with no primary G-CSF prophylaxis: five studies of pegfilgrastim; ten of filgrastim; and five of lenograstim. All three G-CSFs significantly reduced FN incidence, with relative risks of 0.30 (95% CI: 0.14 to 0.65) for pegfilgrastim, 0.57 (95% CI: 0.48 to 0.69) for filgrastim, and 0.62 (95% CI: 0.44 to 0.88) for lenograstim. Overall, the relative risk of FN for any primary G-CSF prophylaxis versus no primary G-CSF prophylaxis was 0.51 (95% CI: 0.41 to 0.62). In terms of comparisons between different G-CSFs, five studies compared pegfilgrastim with filgrastim. FN incidence was significantly lower for pegfilgrastim than filgrastim, with a relative risk of 0.66 (95% CI: 0.44 to 0.98). Conclusions Primary prophylaxis with G-CSFs significantly reduces FN incidence in adults undergoing chemotherapy for solid tumours or lymphoma. Pegfilgrastim reduces FN incidence to a significantly greater extent than filgrastim. PMID:21943360

Factor VIII organisation on nanodiscs with different lipid composition.

PubMed

Grushin, Kirill; Miller, Jaimy; Dalm, Daniela; Stoilova-McPhie, Svetla

2015-04-01

Nanodiscs (ND) are lipid bilayer membrane patches held by amphiphilic scaffolding proteins (MSP) of ~10 nm in diameter. Nanodiscs have been developed as lipid nanoplatforms for structural and functional studies of membrane and membrane associated proteins. Their size and monodispersity have rendered them unique for electron microscopy (EM) and single particle analysis studies of proteins and complexes either spanning or associated to the ND membrane. Binding of blood coagulation factors and complexes, such as the Factor VIII (FVIII) and the Factor VIIIa - Factor IXa (intrinsic tenase) complex to the negatively charged activated platelet membrane is required for normal haemostasis. In this study we present our work on optimising ND, specifically designed to bind FVIII at close to physiological conditions. The binding of FVIII to the negatively charged ND rich in phosphatidylserine (PS) was followed by electron microscopy at three different PS compositions and two different membrane scaffolding protein (MSP1D1) to lipid ratios. Our results show that the ND with highest PS content (80 %) and lowest MSP1D1 to lipid ratio (1:47) are the most suitable for structure determination of the membrane-bound FVIII by single particle EM. Our preliminary FVIII 3D reconstruction as bound to PS containing ND demonstrates the suitability of the optimised ND for structural studies by EM. Further assembly of the activated FVIII form (FVIIIa) and the whole FVIIIa-FIXa complex on ND, followed by EM and single particle reconstruction will help to identify the protein-protein and protein-membrane interfaces critical for the intrinsic tenase complex assembly and function.

Attitudes toward infection prophylaxis in pediatric oncology: a qualitative approach.

PubMed

Diorio, Caroline; Tomlinson, Deborah; Boydell, Katherine M; Regier, Dean A; Ethier, Marie-Chantal; Alli, Amanda; Alexander, Sarah; Gassas, Adam; Taylor, Jonathan; Kellow, Charis; Mills, Denise; Sung, Lillian

2012-01-01

The risks and benefits of infection prophylaxis are uncertain in children with cancer and thus, preferences should be considered in decision making. The purpose of this report was to describe the attitudes of parents, children and healthcare professionals to infection prophylaxis in pediatric oncology. THE STUDY WAS COMPLETED IN THREE PHASES: 1) An initial qualitative pilot to identify the main attributes influencing the decision to use infection prophylaxis, which were then incorporated into a discrete choice experiment; 2) A think aloud during the discrete choice experiment in which preferences for infection prophylaxis were elicited quantitatively; and 3) In-depth follow up interviews. Interviews were recorded verbatim and analyzed using an iterative, thematic analysis. Final themes were selected using a consensus approach. A total of 35 parents, 22 children and 28 healthcare professionals participated. All three groups suggested that the most important factor influencing their decision making was the effect of prophylaxis on reducing the chance of death. Themes of importance to the three groups included antimicrobial resistance, side effects of medications, the financial impact of outpatient prophylaxis and the route and schedule of administration. Effect of prophylaxis on risk of death was a key factor in decision making. Other identified factors were antimicrobial resistance, side effects of medication, financial impact and administration details. Better understanding of factors driving decision making for infection prophylaxis will help facilitate future implementation of prophylactic regiments.

Correction of murine hemophilia A following nonmyeloablative transplantation of hematopoietic stem cells engineered to encode an enhanced human factor VIII variant using a safety-augmented retroviral vector

PubMed Central

Ramezani, Ali

2009-01-01

Insertional mutagenesis by retroviral vectors is a major impediment to the clinical application of hematopoietic stem cell gene transfer for the treatment of hematologic disorders. We recently developed an insulated self-inactivating gammaretroviral vector, RMSinOFB, which uses a novel enhancer-blocking element that significantly decreases genotoxicity of retroviral integration. In this study, we used the RMSinOFB vector to evaluate the efficacy of a newly bioengineered factor VIII (fVIII) variant (efVIII)—containing a combination of A1 domain point mutations (L303E/F309S) and an extended partial B domain for improved secretion plus A2 domain mutations (R484A/R489A/P492A) for reduced immunogenicity—toward successful treatment of murine hemophilia A. In cell lines, efVIII was secreted at up to 6-fold higher levels than an L303E/F309S A1 domain–only fVIII variant (sfVIIIΔB). Most important, when compared with a conventional gammaretroviral vector expressing sfVIIIΔB, lower doses of RMSin-efVIII-OFB–transduced hematopoietic stem cells were needed to generate comparable curative fVIII levels in hemophilia A BALB/c mice after reduced-intensity total body irradiation or nonmyeloablative chemotherapy conditioning regimens. These data suggest that the safety-augmented RMSin-efVIII-OFB platform represents an encouraging step in the development of a clinically appropriate gene addition therapy for hemophilia A. PMID:19470695

Attitudes toward Infection Prophylaxis in Pediatric Oncology: A Qualitative Approach

PubMed Central

Diorio, Caroline; Tomlinson, Deborah; Boydell, Katherine M.; Regier, Dean A.; Ethier, Marie-Chantal; Alli, Amanda; Alexander, Sarah; Gassas, Adam; Taylor, Jonathan; Kellow, Charis; Mills, Denise; Sung, Lillian

2012-01-01

Background The risks and benefits of infection prophylaxis are uncertain in children with cancer and thus, preferences should be considered in decision making. The purpose of this report was to describe the attitudes of parents, children and healthcare professionals to infection prophylaxis in pediatric oncology. Methods The study was completed in three phases: 1) An initial qualitative pilot to identify the main attributes influencing the decision to use infection prophylaxis, which were then incorporated into a discrete choice experiment; 2) A think aloud during the discrete choice experiment in which preferences for infection prophylaxis were elicited quantitatively; and 3) In-depth follow up interviews. Interviews were recorded verbatim and analyzed using an iterative, thematic analysis. Final themes were selected using a consensus approach. Results A total of 35 parents, 22 children and 28 healthcare professionals participated. All three groups suggested that the most important factor influencing their decision making was the effect of prophylaxis on reducing the chance of death. Themes of importance to the three groups included antimicrobial resistance, side effects of medications, the financial impact of outpatient prophylaxis and the route and schedule of administration. Conclusion Effect of prophylaxis on risk of death was a key factor in decision making. Other identified factors were antimicrobial resistance, side effects of medication, financial impact and administration details. Better understanding of factors driving decision making for infection prophylaxis will help facilitate future implementation of prophylactic regiments. PMID:23112849

Factors associated with short-course antiretroviral prophylaxis (dual therapy) adherence for PMTCT in Nkangala district, South Africa.

PubMed

Peltzer, Karl; Sikwane, Elisa; Majaja, Mmapaseka

2011-09-01

To identify factors that influence adherence to short-course antiretroviral (ARV) prophylaxis by pregnant women and mothers participating in the HIV prevention of mother to child (PMTCT) programme. The sample interviewed included 139 HIV-positive antenatal women (mean gestational age 32 weeks; sexually transmitted diseases [STD] = 2.8, range 4-9 months) and 607 postnatal HIV-positive women, with either having an infant aged 1-10 weeks (30.8%), 11 weeks to 6 months (36.7%) or 7-12 months (32.5%) from Nkangala district, Mpumalanga province, South Africa. A large percentage of antenatal and postnatal women in this study initiated ARV prophylaxis for PMTCT or were on ARV (85.6% and 98%, respectively). Sixty-one per cent of antenatal and 85.9% of postnatal women reported complete adherence to the appropriate medication schedule in the 4 days preceding the interview or prior to delivery. In multivariate analysis, it was found that women with higher HIV status disclosure and less discrimination were better in maternal AZT adherence, women with higher male involvement were better in maternal and infant nevirapine adherence. Adherence to maternal and infant dual therapy prophylaxis was found to be less than optimal. Community factors (discrimination, HIV disclosure, male involvement) contribute to adherence to short-course ARV prophylaxis in this largely rural setting in South Africa. © 2011 The Author(s)/Acta Paediatrica © 2011 Foundation Acta Paediatrica.

Evaluation of the biological differences of canine and human factor VIII in gene delivery: Implications in human hemophilia treatment

USDA-ARS?s Scientific Manuscript database

The canine is the most important large animal model for testing novel hemophilia A(HA) treatment. It is often necessary to use canine factor VIII (cFIII) gene or protein for the evaluation of HA treatment in the canine model. However, the different biological properties between cFVIII and human FVII...

Cost-effectiveness analysis of late prophylaxis vs. on-demand treatment for severe haemophilia A in Italy.

PubMed

Coppola, A; D'Ausilio, A; Aiello, A; Amoresano, S; Toumi, M; Mathew, P; Tagliaferri, A

2017-05-01

Long-term regular administrations of factor VIII (FVIII) concentrate (prophylaxis) initiated at an early age prevents bleeding in patients with severe haemophilia A (HA). The 5-year prospective Italian POTTER study provided evidence of benefits in adolescents and adults of late prophylaxis (LP) vs. on-demand therapy (OD) in reducing bleeding episodes and joint morbidity and improving quality of life; however, costs were increased. The aim of this study was to determine the cost-effectiveness of LP vs. OD with sucrose-formulated recombinant FVIII in adolescents and adults with severe HA in Italy. A Markov model evaluated lifetime cost-effectiveness of LP vs. OD in patients with severe HA in Italy, from both the healthcare and societal perspectives. Clinical input parameters were taken from the POTTER study and published literature. Health utility values were assigned to each health state as measured by the joint disease severity Pettersson score. Costs were expressed in Euro (€) 2014, including drug and other medical costs. Sensitivity analyses were performed considering societal perspective (including productivity lost) and varying relative risk of bleeding episodes between regimens. Clinical outcomes and costs were discounted at 6% according to previous studies. Lifetime incremental discounted quality-adjusted life-years (QALYs) were +4.26, whereas incremental discounted costs were +€229,694 from a healthcare perspective, with estimated incremental cost-effectiveness ratios (ICERs) equal to €53,978/QALY. Sensitivity analyses confirmed the base-case results showing lower ICERs with the societal perspective. Late prophylaxis vs. on-demand therapy results in a cost-effective approach with ICERs falling below the threshold considered acceptable in Italy. © 2017 John Wiley & Sons Ltd.

Effects of secondary prophylaxis started in adolescent and adult haemophiliacs.

PubMed

Tagliaferri, A; Franchini, M; Coppola, A; Rivolta, G F; Santoro, C; Rossetti, G; Feola, G; Zanon, E; Dragani, A; Iannaccaro, P; Radossi, P; Mannucci, P M

2008-09-01

While primary prophylaxis is a well-established and recommended method of care delivery for children with severe haemophilia, fewer studies have documented the benefits of secondary prophylaxis started in adolescence or adulthood. To evaluate the role of secondary prophylaxis started in adolescent and adult severe haemophiliacs, a retrospective observational cohort study was conducted in 10 Italian Centres that investigated 84 haemophiliacs who had bled frequently and had thus switched from on-demand to prophylactic treatment during adolescence (n = 30) or adulthood (n = 54). The consumption of clotting factor concentrates, the orthopaedic and radiological scores, quality of life and disease-related morbidity were compared before and after starting secondary prophylaxis. Prophylaxis reduced the mean annual number of total and joint bleeds (35.8 vs. 4.2 and 32.4 vs. 3.3; P < 0.01) and of days lost from work/school (34.6 vs. 3.0, P < 0.01). A statistically significant reduction in the orthopaedic score was observed during prophylaxis in adolescents, but not in the whole cohort. Patients used more factor concentrates with corresponding higher costs on prophylaxis, but experienced a better quality of life. With respect to on-demand treatment, higher factor consumption and cost of secondary prophylaxis were balanced by marked clinical benefits and greater well-being in this cohort of adolescent/adult haemophiliacs.

Future therapeutic directions for factor Xa inhibition in the prophylaxis and treatment of thrombotic disorders.

PubMed

Turpie, Alexander G G

2003-11-15

The targeted mechanism of factor Xa inhibition has been studied extensively, initially as prophylaxis for venous thromboembolism (VTE) in the orthopedic surgical setting. Future therapeutic directions for selective factor Xa inhibition in the management of other thrombotic diseases are discussed. Thromboembolic diseases can occur in the venous or arterial sides of the circulatory system. Factor Xa inhibition is a targeted approach to anticoagulation that resulted from significant advances in our understanding of the coagulation cascade. The factor Xa inhibitor fondaparinux has been studied extensively in the orthopedic surgical setting for the prophylaxis of VTE. Current investigations that are under way or completed evaluate the efficacy and safety of fondaparinux for the management of various thrombotic diseases. The future development of fondaparinux resides primarily in three therapeutic areas: prevention of VTE, treatment of VTE, and treatment of acute coronary syndromes. For the prevention of VTE, fondaparinux has been studied as extended prophylaxis following hip fracture surgery (PENTHIFRA Plus), for use in high-risk abdominal surgical patients (PEGASUS and APOLLO), and for use in medical patients (ARTEMIS). Studies evaluating fondaparinux for the treatment of VTE are part of the large MATISSE clinical program (MATISSE DVT and MATISSE PE). Fondaparinux was investigated in phase 2 studies for the treatment of acute coronary syndromes, including acute ST-segment myocardial infarction (PENTALYSE) and unstable angina (PENTUA). Encouraging data from these trials are the basis for phase 3 programs in this area (MICHELANGELO). The orthopedic prophylactic and nonorthopedic clinical programs for fondaparinux in the management of thrombosis support the concept that targeted inhibition of coagulation is an effective advance in antithrombotic therapy.

12 CFR 611.1137 - Title VIII service corporations.

Code of Federal Regulations, 2014 CFR

2014-01-01

... 12 Banks and Banking 7 2014-01-01 2014-01-01 false Title VIII service corporations. 611.1137... Corporations § 611.1137 Title VIII service corporations. (a) What is a title VIII service corporation? A title VIII service corporation is a service corporation organized for the purpose of exercising the...

12 CFR 611.1137 - Title VIII service corporations.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 12 Banks and Banking 6 2011-01-01 2011-01-01 false Title VIII service corporations. 611.1137... Organizations § 611.1137 Title VIII service corporations. (a) What is a title VIII service corporation? A title VIII service corporation is a service corporation organized for the purpose of exercising the...

12 CFR 611.1137 - Title VIII service corporations.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 12 Banks and Banking 7 2012-01-01 2012-01-01 false Title VIII service corporations. 611.1137... Organizations § 611.1137 Title VIII service corporations. (a) What is a title VIII service corporation? A title VIII service corporation is a service corporation organized for the purpose of exercising the...

12 CFR 611.1137 - Title VIII service corporations.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 12 Banks and Banking 7 2013-01-01 2013-01-01 false Title VIII service corporations. 611.1137... Organizations § 611.1137 Title VIII service corporations. (a) What is a title VIII service corporation? A title VIII service corporation is a service corporation organized for the purpose of exercising the...

Prolonged activity of a recombinant factor VIII-Fc fusion protein in hemophilia A mice and dogs

PubMed Central

Dumont, Jennifer A.; Liu, Tongyao; Low, Susan C.; Zhang, Xin; Kamphaus, George; Sakorafas, Paul; Fraley, Cara; Drager, Douglas; Reidy, Thomas; McCue, Justin; Franck, Helen W. G.; Merricks, Elizabeth P.; Nichols, Timothy C.; Bitonti, Alan J.; Pierce, Glenn F.

2012-01-01

Despite proven benefits, prophylactic treatment for hemophilia A is hampered by the short half-life of factor VIII. A recombinant factor VIII-Fc fusion protein (rFVIIIFc) was constructed to determine the potential for reduced frequency of dosing. rFVIIIFc has an ∼ 2-fold longer half-life than rFVIII in hemophilia A (HemA) mice and dogs. The extension of rFVIIIFc half-life requires interaction of Fc with the neonatal Fc receptor (FcRn). In FcRn knockout mice, the extension of rFVIIIFc half-life is abrogated, and is restored in human FcRn transgenic mice. The Fc fusion has no impact on FVIII-specific activity. rFVIIIFc has comparable acute efficacy as rFVIII in treating tail clip injury in HemA mice, and fully corrects whole blood clotting time (WBCT) in HemA dogs immediately after dosing. Furthermore, consistent with prolonged half-life, rFVIIIFc shows 2-fold longer prophylactic efficacy in protecting HemA mice from tail vein transection bleeding induced 24-48 hours after dosing. In HemA dogs, rFVIIIFc also sustains partial correction of WBCT 1.5- to 2-fold longer than rFVIII. rFVIIIFc was well tolerated in both species. Thus, the rescue of FVIII by Fc fusion to provide prolonged protection presents a novel pathway for FVIII catabolism, and warrants further investigation. PMID:22246033

A new method to determine wound age in early vital skin injuries: a probability scoring system using expression levels of Fibronectin, CD62p and Factor VIII in wound hemorrhage.

PubMed

van de Goot, Franklin R W; Korkmaz, H Ibrahim; Fronczek, Judith; Witte, Birgit I; Visser, Rob; Ulrich, Magda M W; Begieneman, Mark P V; Rozendaal, Lawrence; Krijnen, Paul A J; Niessen, Hans W M

2014-11-01

In forensic autopsies it is important to determine the age of early vital skin wounds as accurate as possible. In addition to inflammation, coagulation is also induced in vital wounds. Analysis of blood coagulation markers in wound hemorrhage could therefore be an important additional discriminating factor in wound age determination. The aim of this study was to develop a wound age probability scoring system, based on the immunohistochemical expression levels of Fibronectin, CD62p and Factor VIII in wound hemorrhage. Tissue samples of (A) non injured control skin (n=383), and samples of mechanically induced skin injuries of known wound age, (B) injuries inflicted shortly before death (up to a few minutes old) (n=382), and (C) injuries inflicted 15-30 min before death (n=42) were obtained at autopsy in order to validate wound age estimation. Tissue slides were stained for Fibronectin, CD62p and Factor VIII and were subsequently scored for staining intensity (IHC score) in wound hemorrhage (1=minor, 2=moderate, 3=strong positive). Finally, probability scores of these markers were calculated. In at most 14% of the non-injured control samples, hemorrhage was found, with mean±standard deviation IHC scores of 0.1±0.4, 0.2±0.4 and 0.2±0.5 for Fibronectin, CD62p, and Factor VIII, respectively. Expression of these markers significantly increased to mean IHC scores 1.4±0.8 (Fibronectin), 1.2±0.6 (CD62p), and 1.6±0.8 (Factor VIII) in wounds inflicted shortly before death (few minutes old) and to 2.6±0.5 (Fibronectin), 2.5±0.6 (CD62p), and 2.8±0.4 (Factor VIII) in 15-30 min old wounds. The probabilities that a wound was non vital in case of an IH score 0 were 87%, 88% and 90% for Fibronectin, CD62p, and Factor VIII, respectively. In case of an IHC score 1 or 2, the probabilities that a wound was a few minutes old were 82/90%, 82/83% and 72/93%. Finally, in case of an IHC score 3, the probabilities that a wound was 15-30 min old were 65%, 76% and 55%. Based on the

Burden of Chemotherapy-Induced Febrile Neutropenia Hospitalizations in US Clinical Practice, by Use and Patterns of Prophylaxis with Colony-Stimulating Factor.

PubMed

Weycker, Derek; Li, Xiaoyan; Tzivelekis, Spiros; Atwood, Mark; Garcia, Jacob; Li, Yanli; Reiner, Maureen; Lyman, Gary H

2017-02-01

Evidence suggests that many cancer chemotherapy patients who are candidates for colony-stimulating factor (CSF) prophylaxis do not receive it or receive it inconsistent with guidelines, and that such patients have a higher risk of febrile neutropenia hospitalization (FNH). Little is known about the number and consequences of FNH by use/patterns of CSF prophylaxis in US clinical practice. A retrospective cohort design and private healthcare claims data were employed. Study population comprised adults who received a chemotherapy course with a high-risk regimen, or an intermediate-risk regimen (if ≥1 FN risk factor present), for non-metastatic breast cancer or non-Hodgkin's lymphoma (NHL); each chemotherapy cycle within the course and each FNH episode within the cycles were identified. Consequences included mortality, inpatient days, and costs (US$2013) during FNH. Use (yes/no) and patterns (agent, administration day/duration) of CSF prophylaxis were evaluated within cycles in which FNH episodes occurred. Among all FNH episodes (n=6,355; 109 episodes per 1,000 patients), 41.3% (95% CI: 40.1-42.5) occurred among patients who did not receive CSF prophylaxis in that cycle, and 8.8% (8.1-9.5) occurred among those who received CSF prophylaxis on the same day as chemotherapy. Among FNH episodes occurring in patients who received daily CSF agents (2% of CSF use), 56.1% (44.1-68.0) received prophylaxis <7 days during the cycle. Results for FNH consequences were comparable. In this retrospective evaluation, one-half of FNH episodes, outcomes, and costs among cancer chemotherapy patients who were candidates for CSF prophylaxis occurred in those who either did not receive it or received it inconsistent with guidelines.

Bypassing agent prophylaxis in people with hemophilia A or B with inhibitors.

PubMed

Chai-Adisaksopha, Chatree; Nevitt, Sarah J; Simpson, Mindy L; Janbain, Maissaa; Konkle, Barbara A

2017-09-25

People with hemophilia A or B with inhibitors are at high risk of bleeding complications. Infusion of bypassing agents, such as recombinant activated FVII (rFVIIa) and plasma-derived activated prothrombin complex concentrate, are suggested as alternative therapies to factor VIII (haemophilia A) or IX (haemophilia B) for individuals who no longer respond to these treatments because they develop inhibitory antibodies. The ultimate goal of treatment is to preserve the individual's joints, otherwise destroyed by recurrent bleeds. To assess the effects of bypassing agent prophylaxis to prevent bleeding in people with hemophilia A or B and inhibitors. We searched for relevant studies from the Cystic Fibrosis and Genetic Disorders Group's Coagulopathies Trials Register, comprising of references identified from comprehensive electronic database searches and handsearches of relevant journals and abstract books of conference proceedings. We also searched trial registries (16 February 2017) and bibliographic references of retrieved studies were reviewed for potential articles to be included in the review.Date of the last search of the Cochrane Cystic Fibrosis and Genetic Disorders Coagulopathies Trials Register: 12 December 2016. We included randomized and quasi-randomized controlled studies (cross-over or parallel design) evaluating the effect of prophylaxis treatment with bypassing agents compared with on-demand treatment, or studies evaluating the effects of high-dose compared with low-dose prophylaxis in males of any age with hemophilia with inhibitors. Two authors independently selected studies and extracted data and assessed the risk of bias according to standard Cochrane criteria. They assessed the quality of the evidence using the GRADE criteria. We included four randomized studies (duration 7 to 15 months) involving 116 males. Risk of bias was judged to be high in two studies due to the open-label study design and in one study due to attrition bias.Two studies

Adherence to prophylaxis and quality of life in children and adolescents with severe haemophilia A.

PubMed

García-Dasí, M; Aznar, J A; Jiménez-Yuste, V; Altisent, C; Bonanad, S; Mingot, E; Lucía, F; Giménez, F; López, M Fernanda; Marco, P; Pérez, R; Fernández, M Á; Paloma, M J; Galmes, B; Herrero, S; García-Talavera, J A

2015-07-01

Treatment adherence in adolescents with chronic diseases is around 50%, and failure is more common in preventive therapy. In haemophilia, contradictory results are reported by the published studies. The objective of this study was to evaluate adherence with factor VIII (FVIII) prophylaxis in Spanish patients with severe haemophilia A between age 6 and 20 years. Data were collected retrosp-ectively in the previous 2 years. The primary endpoint was the absolute adherence index (AAI), and the endpoints were related to clinical status, age, prophylaxis regimen, responsibility for factor administration and quality of life (QoL), assessed by the Haemo-QoL questionnaires. A total of 78 patients from 14 Spanish hospitals were recruited. Adherence ranged between -64.4 and 66.7 (mean -3.08). No differences were observed between children and adolescents (7.11 vs. 6.39; P = 0.809). A statistically significant association (P < 0.010) between infra adherent group and target joint was found, as was a statistically significant difference (P < 0.010) between the number of bleeding episodes experienced by the adherent group (mean 1.4) and by infra adherents (mean 4.5). There was no significant difference between AAI and prophylactic regimen (6.35 vs. 6.96, P = 0.848), neither between AAI and the person responsible for factor administration (5.57 vs. 8.79, P = 0.326). The Haemo-QoL scores (8-12 years) were related to adherence level (P < 0.05). Adherence was approximately ideal and patients perceived a high QoL. Because of the repercussions for compliance, it is essential to work during puberty on emotional and self-acceptance aspects of the disease, as well as coping, and the patient's family, school and health team relationships. © 2015 John Wiley & Sons Ltd.

Purchasing factor concentrates in the 21st century through competitive tendering.

PubMed

Hay, C R M

2013-09-01

The increasing intensity of treatment, the widespread adoption of factor VIII and IX prophylaxis and increasing usage over the past decade have led to haemophilia becoming an almost uniquely expensive condition to treat. The average adult with severe haemophilia A in the UK used 250,000 IU of factor VIII in 2011/2012, at a cost in excess of £ 100,000 p.a. The cost to the end-user may be considerably higher than this for some US patients supplied by home care companies with high on-costs. This has led to a high level of administrative scrutiny of treatment and an imperative to procure clotting factor concentrates more efficiently and collectively. National procurement schemes have run successfully in various countries and will become commoner. The UK system of procurement is described. This system, following EU procurement rules, evaluated products technically and by price. The price of bioequivalent products was determined by reverse e-auction. Considerable cost reductions were achieved whilst retaining all suppliers and maintaining a degree of prescribing freedom. Elements of this system could be more widely applied. © 2013 John Wiley & Sons Ltd.

Human parvovirus B19 infection in hemophiliacs first infused with two high-purity, virally attenuated factor VIII concentrates.

PubMed

Azzi, A; Ciappi, S; Zakvrzewska, K; Morfini, M; Mariani, G; Mannucci, P M

1992-03-01

Human parvovirus B19 can be transmitted by coagulation factor concentrates and is highly resistant to virucidal methods. To evaluate whether the additional removal of virus by chromatographic methods during the manufacture of high-purity concentrates reduces the risk of B19 transmission, we have prospectively evaluated the rate of anti-B19 seroconversion in two groups of susceptible (anti-B19 negative) hemophiliacs infused with high-purity, heated (pasteurized) or solvent-detergent-treated factor VIII concentrates. Both products infected a relatively high proportion of patients (nine of 20).

Non-observance of guidelines for surgical antimicrobial prophylaxis and surgical-site infections.

PubMed

Lallemand, S; Thouverez, M; Bailly, P; Bertrand, X; Talon, D

2002-06-01

A prospective multicentre study was conducted to assess major aspects of surgical prophylaxis and to determine whether inappropriate antimicrobial prophylaxis was a factor associated (risk or protective factor) with surgical site infection (SSI). Surgical prophylaxis practices were assessed by analysing four variables: indication, antimicrobial agent, timing and duration. Univariate and multivariate analyses were carried out to identify predictors of SSI among patient-specific, operation-specific and antimicrobial prophylaxis-specific factors. The frequency of SSI was 2.7% (13 SSI in 474 observations). Total compliance of the prescription with guidelines was observed in 41.1% of cases (195 prescriptions). Of the 139 patients who received an inappropriate drug, 126 (90.6%) received a drug with a broader spectrum than the recommended drug. Prophylaxis was prolonged in 71 (87.7%) of the 81 patients who received prophylaxis for inappropriate lengths of time and 43 (61.4%) of the 70 patients who did not receive prophylaxis at the optimal moment were treated too late. Multivariate analysis clearly demonstrated that SSI was associated with multiple procedures (relative risk 8.5), short duration of prophylaxis (relative risk 12.7) and long-term therapy with antimicrobial agents during the previous year (relative risk 8.8). The ecological risk of the emergence of resistance associated with the frequent use of broad-spectrum antibiotics and prophylaxis for longer periods was not offset by individual benefit to the patients who received inappropriate prophylaxis.

Observation of patients with vesicoureteral reflux off antibiotic prophylaxis: physician bias on patient selection and risk factors for recurrent febrile urinary tract infection.

PubMed

Drzewiecki, Beth A; Thomas, John C; Pope, John C; Adams, Mark C; Brock, John W; Tanaka, Stacy T

2012-10-01

Observation off continuous antibiotic prophylaxis is an option for vesicoureteral reflux. We evaluated the characteristics of patients observed off continuous antibiotic prophylaxis and risk factors for febrile urinary tract infection. We identified children 1 to 18 years old with primary vesicoureteral reflux between January 1, 2010 and December 31, 2010. We excluded patients with prior surgical correction from analysis. We recorded age, gender, race/ethnicity, primary language, insurance carrier, age at vesicoureteral reflux diagnosis, initial presentation and vesicoureteral reflux severity. We quantified bladder and bowel dysfunction with a validated questionnaire if toilet trained. We compared patients off vs on continuous antibiotic prophylaxis with the chi-square test for categorical variables and the Mann-Whitney U test for continuous variables. We used a univariate Cox proportional hazards model to assess predictors of febrile urinary tract infection during observation off continuous antibiotic prophylaxis. Of 529 eligible patients 224 were observed off continuous antibiotic prophylaxis. Patients off continuous antibiotic prophylaxis tended to be older (p <0.001), to be older at diagnosis (p <0.001), to have an initial presentation other than febrile urinary tract infection (p = 0.05), to have nondilating vesicoureteral reflux on most recent cystogram (p <0.001) and to have lower bladder/bowel dysfunction scores if toilet trained (p <0.001). Of the patients off continuous antibiotic prophylaxis a febrile urinary tract infection developed in 19 (8.5%). Risk factors associated with febrile urinary tract infection included initial presentation of multiple febrile urinary tract infections (p = 0.03), older age at diagnosis (p = 0.03) and older age starting observation off continuous antibiotic prophylaxis (p = 0.0003). Criteria to select patients with vesicoureteral reflux for observation off continuous antibiotic prophylaxis remain poorly defined in the

[Detection of factor VIII intron 1 inversion in severe haemophilia A].

PubMed

Liang, Yan; Yan, Zhen-yu; Yan, Mei; Hua, Bao-lai; Xiao, Bai; Zhao, Yong-qiang; Liu, Jing-zhong

2009-06-01

Screening the intron 1 inversion of factor VIII (FVIII) in the population of severe haemophilia A(HA) in China and performing carrier detection and prenatal diagnosis. Using LD-PCR to detect intron 22 inversions and multiple-PCR within two tubes to intron 1 inversions in severe HA patients. Carrier detection and prenatal diagnosis were performed in affected families. Linkage analysis and DNA sequencing were used to verify these tests. One hundred and eighteen patients were seven diagnosed as intron 22 inversions and 7 were intron 1 inversions out of 247 severe HA patients. The prevalence of the intron 1 inversion in Chinese severe haemophilia A patients was 2.8% (7/247). Six women from family A and 2 from family B were diagnosed as carriers. One fetus from family A was affected fetus. Intron 1 inversion could be detected directly by multiple-PCR within two tubes. This method made the strategy more perfective in carrier and prenatal diagnosis of haemophilia A.

BAY 81-8973 safety and efficacy for prophylaxis and treatment of bleeds in previously treated children with severe haemophilia A: results of the LEOPOLD Kids Trial.

PubMed

Ljung, R; Kenet, G; Mancuso, M E; Kaleva, V; Rusen, L; Tseneklidou-Stoeter, D; Michaels, L A; Shah, A; Hong, W; Maas Enriquez, M

2016-05-01

BAY 81-8973, a full-length, unmodified, recombinant factor VIII (FVIII) in development for treatment of haemophilia A, has the same primary amino acid sequence as Bayer's sucrose-formulated recombinant FVIII but is produced with more advanced manufacturing technologies. To demonstrate safety and efficacy of BAY 81-8973 for prophylaxis and treatment of bleeds in previously treated children. In this phase III, multicentre, open-label, nonrandomized study, boys aged ≤12 years with severe haemophilia A and ≥50 exposure days (EDs) to FVIII products received prophylaxis with BAY 81-8973 25-50 IU kg(-1) ≥2 times weekly for ≥50 EDs. The efficacy endpoint was annualized number of total bleeds. Adverse events (AEs) and immunogenicity were assessed. Fifty-one patients were treated (age: <6 years, n = 25; 6-<12 years, n = 26) with a 2× per week (43%) or >2× per week (57%) regimen at study start. Median [quartile 1; quartile 3 (Q1; Q3)] annualized number of bleeds for the combined age groups was 1.90 (0; 6.02) for total bleeds, 0 (0; 2.01) for joint bleeds and 0 (0; 0) for spontaneous bleeds. Median (Q1; Q3) annualized number of total bleeds within 48 h of previous prophylaxis infusion was 1.88 (0; 3.97) for children aged <6 years and 0 (0; 1.96) for children aged 6-<12 years. No drug-related serious AEs or inhibitors were reported. Prophylaxis with BAY 81-8973 using individualized prophylaxis regimens of 2× per week, 3× per week and every-other-day infusions was efficacious in prevention and treatment of bleeds in children with severe haemophilia A. Treatment with BAY 81-8973 was well tolerated. © 2015 John Wiley & Sons Ltd.

Unravelling adherence to prophylaxis in haemophilia: a patients' perspective.

PubMed

Schrijvers, L H; Kars, M C; Beijlevelt-van der Zande, M; Peters, M; Schuurmans, M J; Fischer, K

2015-09-01

Given the lifelong therapy in haemophilia patients, insight in non-adherence behaviour from a patient perspective is important to understand patients' difficulties with the following treatment recommendations. The aim of this study was to clarify the process underlying adherence (behaviour) to prophylactic treatment, from a patients' perspective. To develop a grounded theory, a qualitative study using individual in-depth interviews was performed to understand experiences, perceptions and beliefs concerning adherence to prophylaxis. From two Dutch treatment centres, 21 adults with haemophilia using prophylaxis were interviewed. Patients were asked how they experience their task to administer prophylaxis and how they adhere to this. The interviews were transcribed, coded and analysed in an iterative process, leading to the development of the grounded theory. Adherence was determined by the position of prophylaxis in life. The position of prophylaxis was determined by the perception of prophylaxis and the ability to exert prophylaxis. Patients' perception was influenced by two main factors: acceptance of haemophilia and feeling/fearing symptoms. The ability to exert prophylaxis was influenced by understanding haemophilia and prophylaxis and planning/infusion skills. The combination of different perceptions and skills led to four main positions of prophylaxis in life: (i) prophylaxis integrated in life, (ii) prophylaxis according to doctors' advice, struggling with irregular situations, (iii) prophylaxis is too much to handle, (iv) prophylaxis is a confrontation with illness. The adherence level gradually decreased from position 1 to 4. This information can be used to design tailored interventions to promote adherence. © 2015 John Wiley & Sons Ltd.

[Assessment of venous thromboembolism risk in hospitalized medical patients. Concordance between PRETEMED guide and the recommendations of the viii conference of the American College of Chest Physicians].

PubMed

Gallardo Jiménez, Patricia; Guijarro Merino, Ricardo; Vallejo Herrera, Verónica; Sánchez Morales, David; Villalobos Sánchez, Aurora; Perelló González-Moreno, Juan Ignacio; Gómez-Huelgas, Ricardo

2012-11-03

The aim of this study is to evaluate the use of venous thromboembolism prophylaxis in hospitalized medical patients using 2 clinical practice guidelines and to analyze the agreement between them. Cross-sectional study of medical services in a third level hospital. We calculated the thromboembolic risk and the thromboprophylaxis adequacy by implementing the recommendations of viii conference of the American College of Chest Physicians (ACCP) and PRETEMED guide as well as their agreement. One hundred and twenty eight patients were included in the study. According to the PRETEMED guide, 34.4% of patients were low risk, 6.3% moderate and 59.4% high, with appropriate prophylaxis in 72.7% of patients (CI95%: 64.4-79.9), 18.8% (CI95%: 12.7-26.2) were undertreated and 8.6% (CI95%: 4.6-14.4) overtreated. According to ACCP recommendations, 50% of patients were low risk and 50% high, with appropriate prophylaxis in 74.2% of patients (CI95%: 66.1-81.2), 10.9% (CI95%: 6.4-17.3) were undertreated and 14.8% (CI95%: 9.4-21.8) overtreated. When PRETEMED risk was classified into low or moderate-high group versus ACCP risk low or high, the grade of concordance between both guides was 0.68 (CI95%: 0.56-0.81). When PRETEMED risk was classified into low-moderate or high group versus ACCP risk low or high, the grade of concordance between both guides was 0.81 (CI95%: 0.71-0.91). About a quarter of hospitalized medical patients did not receive adequate prophylaxis, showing an important room for improvement. PRETEMED guide and ACCP recommendations differ in risk assessment mainly because PRETEMED guide overestimates the risk of venous thromboembolism since it includes more risk factors. Copyright © 2011 Elsevier España, S.L. All rights reserved.

Elevated plasma factor VIII enhances venous thrombus formation in rabbits: contribution of factor XI, von Willebrand factor and tissue factor.

PubMed

Sugita, Chihiro; Yamashita, Atsushi; Matsuura, Yunosuke; Iwakiri, Takashi; Okuyama, Nozomi; Matsuda, Shuntaro; Matsumoto, Tomoko; Inoue, Osamu; Harada, Aya; Kitazawa, Takehisa; Hattori, Kunihiro; Shima, Midori; Asada, Yujiro

2013-07-01

Elevated plasma levels of factor VIII (FVIII) are associated with increased risk of deep venous thrombosis. The aim of this study is to elucidate how elevated FVIII levels affect venous thrombus formation and propagation in vivo. We examined rabbit plasma FVIII activity, plasma thrombin generation, whole blood coagulation, platelet aggregation and venous wall thrombogenicity before and one hour after an intravenous infusion of recombinant human FVIII (rFVIII). Venous thrombus induced by the endothelial denudation of rabbit jugular veins was histologically assessed. Thrombus propagation was evaluated as indocyanine green fluorescence intensity. Argatroban, a thrombin inhibitor, and neutralised antibodies for tissue factor (TF), factor XI (FXI), and von Willebrand factor (VWF) were infused before or after thrombus induction to investigate their effects on venous thrombus formation or propagation. Recombinant FVIII (100 IU/kg) increased rabbit plasma FVIII activity two-fold and significantly enhanced whole blood coagulation and total plasma thrombin generation, but did not affect initial thrombin generation time, platelet aggregation and venous wall thrombogenicity. The rFVIII infusion also increased the size of venous thrombus 1 hour after thrombus induction. Argatroban and the antibodies for TF, FXI or VWF inhibited such enhanced thrombus formation and all except TF suppressed thrombus propagation. In conclusion, elevated plasma FVIII levels enhance venous thrombus formation and propagation. Excess thrombin generation by FXI and VWF-mediated FVIII recruitment appear to contribute to the growth of FVIII-driven venous thrombus.

Staining for factor VIII related antigen and Ulex europaeus agglutinin I (UEA-I) in 230 tumours. An assessment of their specificity for angiosarcoma and Kaposi's sarcoma.

PubMed

Leader, M; Collins, M; Patel, J; Henry, K

1986-11-01

In this study we examined the staining reactivity of commercially available antisera to factor VIII related antigen (F VIII RAg) and Ulex europaeus agglutinin I (UEA-I) on sections from 230 formalin fixed paraffin embedded tumours. These included 196 sarcomas, 20 carcinomas and 14 angiomas. All angiomas showed positive staining for F VIII RAg; all carcinomas showed negative staining; the vasoformative areas of all angiosarcomas stained positively but only four of six angiosarcomas showed positive staining of their solid areas; of seven Kaposi's sarcomas, all showed positive staining of vessels and six showed positive staining of the spindle cell component. In the remaining 181 non-vascular sarcomas there was a false positive result in four tumours (2.2%), three of which had a history of irradiation. Pre-radiotherapy biopsies of these three tumours stained negatively with anti-F VIII RAg. UEA-I was demonstrated in all the angiomas studied, in all angiosarcomas (including the solid components) and in well-formed vessels of all Kaposi's sarcomas, but only in the spindle cell component of 3/6. However, there was an unacceptably high rate of false positive staining amongst the carcinomas and non-vascular sarcomas. In conclusion, F VIII RAg is a specific but not a sensitive marker of angiosarcomas; UEA-I is a sensitive but not a specific marker of angiosarcomas.

Thermodynamic analysis of the interaction of factor VIII with von Willebrand factor.

PubMed

Dimitrov, Jordan D; Christophe, Olivier D; Kang, Jonghoon; Repessé, Yohann; Delignat, Sandrine; Kaveri, Srinivas V; Lacroix-Desmazes, Sébastien

2012-05-22

Factor VIII (FVIII) is a glycoprotein that plays an important role in the intrinsic pathway of coagulation. In circulation, FVIII is protected upon binding to von Willebrand factor (VWF), a chaperone molecule that regulates its half-life, distribution, and activity. Despite the biological significance of this interaction, its molecular mechanisms are not fully characterized. We determined the equilibrium and activation thermodynamics of the interaction between FVIII and VWF. The equilibrium affinity determined by surface plasmon resonance was temperature-dependent with a value of 0.8 nM at 35 °C. The FVIII-VWF interaction was characterized by very fast association (8.56 × 10(6) M(-1) s(-1)) and fast dissociation (6.89 × 10(-3) s(-1)) rates. Both the equilibrium association and association rate constants, but not the dissociation rate constant, were dependent on temperature. Binding of FVIII to VWF was characterized by favorable changes in the equilibrium and activation entropy (TΔS° = 89.4 kJ/mol, and -TΔS(++) = -8.9 kJ/mol) and unfavorable changes in the equilibrium and activation enthalpy (ΔH° = 39.1 kJ/mol, and ΔH(++) = 44.1 kJ/mol), yielding a negative change in the equilibrium Gibbs energy. Binding of FVIII to VWF in solid-phase assays demonstrated a high sensitivity to acidic pH and a sensitivity to ionic strength. Our data indicate that the interaction between FVIII and VWF is mediated mainly by electrostatic forces, and that it is not accompanied by entropic constraints, suggesting the absence of conformational adaptation but the presence of rigid "pre-optimized" binding surfaces.

12 CFR 611.1137 - Title VIII service corporations.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 12 Banks and Banking 6 2010-01-01 2010-01-01 false Title VIII service corporations. 611.1137 Section 611.1137 Banks and Banking FARM CREDIT ADMINISTRATION FARM CREDIT SYSTEM ORGANIZATION Service Organizations § 611.1137 Title VIII service corporations. (a) What is a title VIII service corporation? A title...

Von Willebrand factor-containing factor VIII concentrates and inhibitors in haemophilia A. A critical literature review.

PubMed

Franchini, Massimo; Lippi, Giuseppe

2010-11-01

The development of inhibitors that neutralise the function of factor VIII (FVIII) is currently not only the most challenging complication associated with the treatment of haemophilia A but it also increases the disease-related morbidity as bleeding episodes do not respond to standard therapy. The main short-term goal of the treatment of inhibitor patients is to control bleeding episodes while the long-term one is to permanently eradicate the inhibitor by immune tolerance induction, particularly in the case of high-titer antibodies. Due to some in vitro studies and clinical observations, some investigators have suggested that FVIII concentrates containing von Willebrand factor (VWF) may be less immunogenic than high-purity or recombinant FVIII products. It has also been suggested that success rates for immune tolerance induction are higher when plasma-derived FVIII products are used. The currently available data from laboratory and clinical studies on the role of VWF in inhibitor development and eradication in haemophilia A is critically analysed in this review. As a result, we have not found definitive evidence supporting a role for product type on inhibitor incidence and inhibitor eradication in haemophilia A patients.

Development, Validation, and Application of a Novel Ligand-Binding Assay to Selectively Measure PEGylated Recombinant Human Coagulation Factor VIII (BAX 855).

PubMed

Weber, Alfred; Engelmaier, Andrea; Hainzelmayer, Sandra; Minibeck, Eva; Anderle, Heinz; Schwarz, Hans Peter; Turecek, Peter L

2015-10-21

BAX 855 is a PEGylated recombinant factor VIII preparation that showed prolonged circulatory half-life in nonclinical and clinical studies. This paper describes the development, validation, and application of a novel ligand-binding assay (LBA) to selectively measure BAX 855 in plasma. The LBA is based on PEG-specific capture of BAX 855, followed by immunological factor VIII (FVIII)-specific detection of the antibody-bound BAX 855. This assay principle enabled sensitive measurement of BAX 855 down to the low nanomolar range without interference from non-PEGylated FVIII as demonstrated by validation data for plasma from animals typically used for nonclinical characterization of FVIII. The selectivity of an in-house-developed anti-PEG and a commercially available preparation, shown by competition studies to primarily target the terminating methoxy group of PEG, also allowed assessment of the intactness of the attached PEG chains. Altogether, this new LBA adds to the group of methods to selectively, accurately, and precisely measure a PEGylated drug in complex biological matrices. The feasibility and convenience of using this method was demonstrated during extensive nonclinical characterization of BAX 855.

Components in Plasma-Derived Factor VIII, But Not in Recombinant Factor VIII Downregulate Anti-Inflammatory Surface Marker CD163 in Human Macrophages through Release of CXCL4 (Platelet Factor 4)

PubMed Central

Bertling, Anne; Brodde, Martin F.; Visser, Mayken; Treffon, Janina; Fennen, Michelle; Fender, Anke C.; Kelsch, Reinhard; Kehrel, Beate E.

2017-01-01

Background Hemarthrosis, or bleeding into the joints, is a hallmark of hemophilia. Heme triggers oxidative stress, inflammation, and destruction of cartilage and bone. The haptoglobin-CD163-heme oxygenase-1 (HO-1) pathway circumvents heme toxicity through enzymatic degradation of heme and transcription of antioxidant genes. Plasma-derived factor concentrates contain many proteins that might impact on cellular pathways in joints, blood, and vessels. Methods Activation of platelets from healthy volunteers was assessed by flow cytometry analysis of fibrinogen binding and CD62P expression. Platelet CXCL4 release was measured by ELISA. Human peripheral blood mononuclear cells were exposed to CXCL4 or platelet supernatants (untreated or pre-stimulated with factor VIII (FVIII) products) during their differentiation to macrophages and analyzed for CD163 expression. Some macrophage cultures were additionally incubated with autologous hemoglobin for 18 h for analysis of HO-1 expression. Results Platelet CXCL4 release was increased by all 8 tested plasma-derived FVIII products but not the 3 recombinant products. Macrophages exposed to supernatant from platelets treated with some plasma-derived FVIII products downregulated CD163 surface expression and failed to upregulate the athero- and joint protective enzyme HO-1 in response to hemoglobin. Conclusion Plasma-derived FVIII products might promote bleeding-induced joint injury via generation of macrophages that are unable to counteract redox stress. PMID:29070980

Components in Plasma-Derived Factor VIII, But Not in Recombinant Factor VIII Downregulate Anti-Inflammatory Surface Marker CD163 in Human Macrophages through Release of CXCL4 (Platelet Factor 4).

PubMed

Bertling, Anne; Brodde, Martin F; Visser, Mayken; Treffon, Janina; Fennen, Michelle; Fender, Anke C; Kelsch, Reinhard; Kehrel, Beate E

2017-09-01

Hemarthrosis, or bleeding into the joints, is a hallmark of hemophilia. Heme triggers oxidative stress, inflammation, and destruction of cartilage and bone. The haptoglobin-CD163-heme oxygenase-1 (HO-1) pathway circumvents heme toxicity through enzymatic degradation of heme and transcription of antioxidant genes. Plasma-derived factor concentrates contain many proteins that might impact on cellular pathways in joints, blood, and vessels. Activation of platelets from healthy volunteers was assessed by flow cytometry analysis of fibrinogen binding and CD62P expression. Platelet CXCL4 release was measured by ELISA. Human peripheral blood mononuclear cells were exposed to CXCL4 or platelet supernatants (untreated or pre-stimulated with factor VIII (FVIII) products) during their differentiation to macrophages and analyzed for CD163 expression. Some macrophage cultures were additionally incubated with autologous hemoglobin for 18 h for analysis of HO-1 expression. Platelet CXCL4 release was increased by all 8 tested plasma-derived FVIII products but not the 3 recombinant products. Macrophages exposed to supernatant from platelets treated with some plasma-derived FVIII products downregulated CD163 surface expression and failed to upregulate the athero- and joint protective enzyme HO-1 in response to hemoglobin. Plasma-derived FVIII products might promote bleeding-induced joint injury via generation of macrophages that are unable to counteract redox stress.

Endothelial cell markers in vascular neoplasms: an immunohistochemical study comparing factor VIII-related antigen, blood group specific antigens, 6-keto-PGF1 alpha, and Ulex europaeus 1 lectin.

PubMed

Little, D; Said, J W; Siegel, R J; Fealy, M; Fishbein, M C

1986-06-01

Markers for endothelial cells including Ulex europaeus 1 lectin, blood group A, B, and H, and the prostaglandin metabolite 6-keto-PGF1 alpha were evaluated in paraffin secretions from formalin-fixed benign and malignant vascular neoplasms using a variety of immunohistochemical techniques, and results compared with staining for factor VIII-related antigen. Staining for Ulex appeared more sensitive than factor VIII-related antigen in identifying poorly differentiated neoplasms including haemangiosarcomas and spindle cell proliferations in Kaposi's sarcoma. Staining for blood group related antigens correlated with blood group in all cases. Ulex europaeus 1 lectin was the only marker for endothelial cells in lymphangiomas.

Factor VIII brand and the incidence of factor VIII inhibitors in previously untreated UK children with severe hemophilia A, 2000-2011

PubMed Central

Palmer, Benedict P.; Chalmers, Elizabeth A.; Hart, Daniel P.; Liesner, Ri; Rangarajan, Savita; Talks, Katherine; Williams, Michael; Hay, Charles R. M.

2014-01-01

The effect of recombinant factor VIII (rFVIII) brand on inhibitor development was investigated in all 407 severe hemophilia A previously untreated patients born in the United Kingdom (UK) between 1 January 2000 and 31 December 2011. Eighty-eight (22%) had been in the RODIN study. Information was extracted from the National Haemophilia Database. Because exposure days (EDs) were not known for some patients, time from first treatment was used as a surrogate for rFVIII exposure. An inhibitor developed in 118 (29%) patients, 60 high and 58 low titer, after a median (interquartile range) of 7.8 (3.3-13.5) months from first exposure and 16 (9-30) EDs. Of 128 patients treated with Kogenate Bayer/Helixate NexGen, 45 (35.2%, 95% confidence interval [CI] 27.4-43.8) developed an inhibitor compared with 42/172 (24.4%, 95% CI 18.6% to 31.4%) with Advate (P = .04). The adjusted hazard ratio (HR) (95% CI) for Kogenate Bayer/Helixate NexGen compared with Advate was 2.14 (1.12-4.10) (P = .02) for high titer and 1.75 (1.11-2.76) (P = .02) for all inhibitors. When excluding UK-RODIN patients, the adjusted HR (95% CI) for high-titer inhibitors was 2.00 (0.93-4.34) (P = .08). ReFacto AF was associated with a higher incidence of all, but not high-titer, inhibitors than Advate. These results will help inform debate around the relative immunogenicity and use of rFVIII brands. PMID:25339360

POOLED ESTIMATES OF INCIDENCE OF ENDOPHTHALMITIS AFTER INTRAVITREAL INJECTION OF ANTI-VASCULAR ENDOTHELIAL GROWTH FACTOR AGENTS WITH AND WITHOUT TOPICAL ANTIBIOTIC PROPHYLAXIS.

PubMed

Reibaldi, Michele; Pulvirenti, Alfredo; Avitabile, Teresio; Bonfiglio, Vincenza; Russo, Andrea; Mariotti, Cesare; Bucolo, Claudio; Mastropasqua, Rodolfo; Parisi, Guglielmo; Longo, Antonio

2018-01-01

To assess the effect of topical antibiotic prophylaxis on postoperative endophthalmitis after intravitreal injection of anti-vascular endothelial growth factor agents. A systematic literature search was performed from inception to March 2016 using PubMed, Medline, Web of Science, Embase, and the Cochrane Library, to identify articles that reported cases of endophthalmitis after intravitreal injection of anti-vascular endothelial growth factor agents. We used a pooled analysis to estimate the incidence of cases of endophthalmitis who developed after injections performed with and without topical antibiotic prophylaxis. We used regression analysis to explore the effects of study characteristics on heterogeneity. From our search of electronic databases, we identified and screened 4,561 unique records. We judged 60 articles to have reported findings for cohorts of patients who met our inclusion criteria, (12 arms of randomized clinical trials, 11 prospective cohort studies, and 37 retrospective cohort studies), which included 244 cases of endophthalmitis and 639,391 intravitreal injections of anti-vascular endothelial growth factor agents. The final pooled estimate endophthalmitis proportions were 9/10,000 (95% confidence interval, 7/10,000-12/10,000) in the antibiotic-treated group and 3/10,000 (95% confidence interval, 2/10,000-5/10,000) in the untreated group. The estimated incidence of endophthalmitis with topical antibiotic prophylaxis was approximated three times the incidence without prophylaxis. Random effects regression showed that none of the study characteristics significantly affected the effect size in either group. Topical antibiotic after intravitreal injection of anti-vascular endothelial growth factor agents is associated with a higher risk of endophthalmitis.

Probiotics prophylaxis in pyelonephritis infants with normal urinary tracts.

PubMed

Lee, Seung Joo; Cha, Jihae; Lee, Jung Won

2016-11-01

Pyelonephritis in infants is considered as a major factor for the formation of renal scar. To prevent recurrent pyelonephritis and renal damage, prophylaxis is extremely important. The aim of this study was to compare the effectiveness of probiotic and antibiotic prophylaxis or no-prophylaxis in infants with pyelonephritis and normal urinary tract. Altogether 191 infants, who were diagnosed with acute pyelonephritis, proven to have normal urinary tracts and followed up for 6 months on prophylaxis, were retrospectively evaluated. According to the types of prophylaxis, the infants were divided into three groups [probiotics (Lactobacillus species), antibiotics (trimethoprim/sulfamethoxazole, TMP/SMX), and noprophylaxis]. The incidence of recurrent urinary tract infection (UTI) during 6 months after the development of pyelonephritis, main causative uropathogens, and its antimicrobial sensitivities were compared. The incidence of recurrent UTI in the probiotic group was 8.2%, which was significantly lower than 20.6% in the no-prophylaxis group (P=0.035) and was not significantly different from 10.0% of the antibiotic group (P=0.532). The significant difference between the probiotic and no-prophylaxis groups was seen only in male infants (P=0.032). The main causative organism of recurrent UTI was Escherichia coli (E.coli), which was not different among the three groups (P=0.305). The resistance rate of E. coli to TMP/SMX was 100% in the antibiotic group, which was significantly higher than 25.0% in the probiotic group and 41.7% in the no-prophylaxis group (P=0.008). Probiotic prophylaxis was more effective in infants with pyelonephritis and normal urinary tract than in those with no-prophylaxis. It could be used as a natural alternative to antibiotic prophylaxis.

NE VIII lambda 774 and time variable associated absorption in the QSO UM 675

NASA Astrophysics Data System (ADS)

Hamann, Fred; Barlow, Thomas A.; Beaver, E. A.; Burbidge, E. M.; Cohen, Ross D.; Junkkarinen, Vesa; Lyons, R.

1995-04-01

We discuss measurements of Ne VIII lambda 774 absorption and the time variability of other lines in the za approximately equal ze absorption system of the ze = 2.15 QSO UM 675 (0150-203). The C IV lambda 1549 and N V 1240 doublets at za = 2.1340 (shifted approximately 1500 km/s from ze strengthened by a factor of approximately 3 between observations by Sargent, Boksenberg and Steidel (1981 November) and our earliest measurements (1990 November and December). We have no information on changes in other za approximately equal ze absorption lines. Continued monitoring since 1990 November shows no clear changes in any of the absorptions between approximately 1100 and 1640 A rest. The short timescale of the variability (less than or approximately equal to 2.9 yr rest) strongly suggests that the clouds are dense, compact, close to the QSO, and photoionized by the QSO continuum. If the line variability is caused by changes in the ionization, the timescale requires densities greater than approximately 4000/cu cm. Photoionization calculations place the absorbing clouds within approximately 200 pc of the continuum source. The full range of line ionizations (from Ne VIII lambda 774 to C III lambda 977) in optically thin gas (no Lyman limit) implies that the absorbing regions span a factor of more than approximately 10 in distance or approximately 100 in density. Across these regions, the total hydrogen (H I + H II) column ranges from a few times 1018/sq cm in the low-ionization gas to approximately 1020/sq cm where the Ne VIII doublet forms. The metallicity is roughly solar or higher, with nitrogen possibly more enhanced by factors of a few. The clouds might contribute significant line emission if they nearly envelop the QSO. The presence of highly ionized Ne VIII lambda 774 absorption near the QSO supports recent studies that link za approximately equal to ze systems with X-ray 'wamr absorbers. We show that the Ne VIII absorbing gas would itself produce measurable warm

32 CFR 2003.8 - Records (Article VIII).

Code of Federal Regulations, 2013 CFR

2013-07-01

... 32 National Defense 6 2013-07-01 2013-07-01 false Records (Article VIII). 2003.8 Section 2003.8 National Defense Other Regulations Relating to National Defense INFORMATION SECURITY OVERSIGHT OFFICE...) BYLAWS, RULES, AND APPEAL PROCEDURES Bylaws § 2003.8 Records (Article VIII). (a) Integrity of ISCAP...

32 CFR 2003.8 - Records (Article VIII).

Code of Federal Regulations, 2014 CFR

2014-07-01

... 32 National Defense 6 2014-07-01 2014-07-01 false Records (Article VIII). 2003.8 Section 2003.8 National Defense Other Regulations Relating to National Defense INFORMATION SECURITY OVERSIGHT OFFICE...) BYLAWS, RULES, AND APPEAL PROCEDURES Bylaws § 2003.8 Records (Article VIII). (a) Integrity of ISCAP...

The structural basis for the functional comparability of Factor VIII and the long-acting variant recombinant Factor VIII Fc fusion protein

PubMed Central

Leksa, N.C.; Chiu, P.-L.; Bou-Assaf, G.M.; Quan, C.; Liu, Z.; Goodman, A.B.; Chambers, M.G.; Tsutakawa, S.E.; Hammel, M.; Peters, R.T.; Walz, T.; Kulman, J.D.

2017-01-01

SUMMARY Background Fusion of the human IgG1 Fc domain to the C-terminal C2 domain of B domain-deleted (BDD) factor VIII (FVIII) results in the rFVIIIFc fusion protein that has a 1.5-fold longer half-life in humans. Objective To assess the structural properties of rFVIIIFc by comparing its constituent FVIII and Fc elements with their respective isolated components and evaluating their structural independence within rFVIIIFc. Methods rFVIIIFc and its isolated FVIII and Fc components were compared by hydrogen-deuterium exchange mass spectrometry (HDX-MS). The structure of rFVIIIFc was also evaluated by X-ray crystallography, small-angle X-ray scattering (SAXS), and electron microscopy (EM). The degree of steric interference by the appended Fc domain was assessed by EM and surface plasmon resonance (SPR). Results HDX-MS analysis of rFVIIIFc revealed that fusion caused no structural perturbations in FVIII or Fc. The rFVIIIFc crystal structure showed that the FVIII component is indistinguishable from published BDD FVIII structures. The Fc domain was not observed, indicating high mobility. SAXS analysis was consistent with an ensemble of rigid-body models in which the Fc domain exists in a largely extended orientation relative to FVIII. Binding of Fab fragments of anti-C2 domain antibodies to BDD FVIII was visualized by EM, and the affinities of the corresponding intact antibodies for BDD FVIII and rFVIIIFc were comparable by SPR analysis. Conclusions The FVIII and Fc components of rFVIIIFc are structurally indistinguishable from their isolated constituents and exhibit a high degree of structural independence, consistent with the functional comparability of rFVIIIFc and unmodified FVIII. PMID:28397397

"Leaning" the process of venous thromboembolism prophylaxis.

PubMed

Biffl, Walter L; Beno, Matthew; Goodman, Philip; Bahia, Amit; Sabel, Allison; Snow, Karen; Steele, Andrew W; Swartwood, Claire; Thienelt, Christiane; MacKenzie, Thomas D; Mehler, Philip S

2011-03-01

Lean principles have been used at Denver Health Medical Center since 2005 to streamline nonclinical processes. Despite allocation of significant resources, particularly the expense of low molecular weight heparin (LMWH), to prophylaxis of venous thromboembolism (VTE), the incidence of postoperative VTE was significantly worse than national benchmarks. VTE risk factors were not consistently assessed, and the prescribing of prophylaxis varied widely. Lean was employed to standardize and implement risk assessment and evidence-based VTE prophylaxis for the institution. In a rapid improvement event, a multidisciplinary group formulated an evidence-based risk assessment tool and clinical practice guideline for VTE prophylaxis, with plans for hospitalwide implementation and monitoring. The effects were immediate and improved steadily with feedback to clinicians. Within six months, compliance with the standard approached 100%. One year after implementation, the use of LMWH decreased more than 60% below baseline, and the use of sequential compression devices decreased by nearly 30%. With increased use of unfractionated heparin, the cost savings on VTE prophylaxis exceeded $15,000 per month, for a total of $425,000 since implementation. Moreover, the incidence of VTE decreased markedly during the same period. By reducing VTE rates, a total cost savings of $6.2 million was estimated for the past 28 months. Applying Lean to the clinical management of VTE prophylaxis improved compliance with standards and saved the hospital a significant amount of money. This was achieved without compromising clinical outcomes. This experience could be replicated at other institutions.

Post-Exposure Prophylaxis (PEP)

MedlinePlus

... Child Transmission of HIV Post-Exposure Prophylaxis (PEP) Pre-Exposure Prophylaxis (PrEP) HIV Treatment HIV Treatment: The Basics Just ... to HIV frequently. Another HIV prevention method, called pre-exposure prophylaxis or PrEP, is when people at high risk ...

40 CFR Appendix Viii to Part 600 - Fuel Economy Label Formats

Code of Federal Regulations, 2010 CFR

2010-07-01

... 40 Protection of Environment 29 2010-07-01 2010-07-01 false Fuel Economy Label Formats VIII Appendix VIII to Part 600 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) ENERGY POLICY FUEL ECONOMY AND CARBON-RELATED EXHAUST EMISSIONS OF MOTOR VEHICLES Pt. 600, App. VIII Appendix VIII to Part 600—Fuel Economy Label Formats...

[Ehler-Danlos syndrome type VIII].

PubMed

Ciarloni, L; Perrigouard, C; Lipsker, D; Cribier, B

2010-03-01

Ehlers-Danlos syndrome (EDS) comprises a heterogeneous group of diseases involving genetic collagen fibre impairment. We describe a case of a patient presenting the rare type VIII, in which dermatitis ocre was associated with parodontal disease, and which was diagnosed late. A 29-year-old man consulted for a pretibial ulcer present for seven years, resulting from a post-traumatic haematoma that had failed to heal. In view of the longiliner morphology, it had previously been diagnosed as Marfan syndrome. Subsequently, edentation was observed as well as "alveolar bone fragility". Examination revealed a marfanoid morphotype, a pretibial ulcer set within long-standing bilateral dermatitis ocre and papyraceous scars, but no joint hyperlaxity or cutaneous hyperelasticity. The diagnosis was consequently corrected to EDS type VIII. Type VIII is a rare form of EDS, and the molecular mechanism is poorly understood. The involvement of parodontal connective tissue suggests impairment of collagen I and III proteins. It is important to identify this type of the disease since it involves parodontal disease for which early treatment is required in order to try to prevent edentation. The present case demonstrates the importance of diagnosis, which may be based upon appearance of bilateral dermatitis ocre from the age of 15 years associated with skin fragility. This sign is not part of the classical picture of Marfan syndrome, with which EDS type VIII is often confounded. Copyright 2009 Elsevier Masson SAS. All rights reserved.

Factor VIII Interacts with the Endocytic Receptor Low-density Lipoprotein Receptor-related Protein 1 via an Extended Surface Comprising "Hot-Spot" Lysine Residues.

PubMed

van den Biggelaar, Maartje; Madsen, Jesper J; Faber, Johan H; Zuurveld, Marleen G; van der Zwaan, Carmen; Olsen, Ole H; Stennicke, Henning R; Mertens, Koen; Meijer, Alexander B

2015-07-03

Lysine residues are implicated in driving the ligand binding to the LDL receptor family. However, it has remained unclear how specificity is regulated. Using coagulation factor VIII as a model ligand, we now study the contribution of individual lysine residues in the interaction with the largest member of the LDL receptor family, low-density lipoprotein receptor-related protein (LRP1). Using hydrogen-deuterium exchange mass spectrometry (HDX-MS) and SPR interaction analysis on a library of lysine replacement variants as two independent approaches, we demonstrate that the interaction between factor VIII (FVIII) and LRP1 occurs over an extended surface containing multiple lysine residues. None of the individual lysine residues account completely for LRP1 binding, suggesting an additive binding model. Together with structural docking studies, our data suggest that FVIII interacts with LRP1 via an extended surface of multiple lysine residues that starts at the bottom of the C1 domain and winds around the FVIII molecule. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

Ocular toxoplasmosis: background and evidence for an antibiotic prophylaxis.

PubMed

Reich, Michael; Mackensen, Friederike

2015-11-01

The purpose of this review was to provide an overview of current data on antibiotic prophylaxis in ocular toxoplasmosis. Studies showing the prophylactic effect of long-term antibiotics are discussed. Prophylaxis seems to be justified in patients with a high risk of recurrence because of antibiotic's potential side-effects. Therefore, predisposing factors leading to a higher risk of recurrence and the time period during which an antibiotic prophylaxis is most appropriate are reviewed. Finally, a patient-individualized treatment recommendation is summarized. In the current literature, two prospective, randomized case-control studies exist, which show the protective effect of an antibiotic prophylaxis. Hematologic, gastrointestinal and dermatologic complications are potential side-effects. Especially during the first year after suffering a recurrence, an antibiotic prophylaxis seems to be justified. The risk of a recurrence is inter alia influenced by the duration of the disease, the immune status of the host and the patient's age. Therefore, an antibiotic prophylaxis should be considered for patients who have recently been infected with ocular toxoplasmosis, for middle-aged and elderly patients and patients with a compromised immune system. This should be discussed with each patient individually, especially if the lesion is close to the macula.

Primary prophylaxis of venous thromboembolism in children.

PubMed

Cole, Catherine H

2010-06-01

Venous thromboembolism (VTE) is rare in children and young adolescents, and occurs predominantly in those with congenital heart disease in whom guidelines exist for VTE prophylaxis. For other paediatric patients, the rarity of the event makes writing an evidence-based clinical practice guideline difficult because each of the known risk factors contributes only a small increase in risk. Thrombophilia screening is controversial because few results assist with prediction of likely thrombosis and may not alter recommendations for prophylaxis. Recent publications highlight the importance of non-pharmacological prevention of VTE in children and adolescents undergoing surgery and the importance of liaison among surgeon, anaesthetist and haematologist. This annotation was written with the aim of collating current evidence for VTE prophylaxis and emphasising the need for further research in vulnerable subgroups.

[Incidence and risk factors of venous thromboembolism in major spinal surgery with no chemical or mechanical prophylaxis].

PubMed

Rojas-Tomba, F; Gormaz-Talavera, I; Menéndez-Quintanilla, I E; Moriel-Durán, J; García de Quevedo-Puerta, D; Villanueva-Pareja, F

2016-01-01

To evaluate the incidence of venous thromboembolism in spine surgery with no chemical and mechanical prophylaxis, and to determine the specific risk factors for this complication. A historical cohort was analysed. All patients subjected to major spinal surgery, between January 2010 and September 2014, were included. No chemical or mechanical prophylaxis was administered in any patient. Active mobilisation of lower limbs was indicated immediately after surgery, and early ambulation started in the first 24-48 hours after surgery. Clinically symptomatic cases were confirmed by Doppler ultrasound of the lower limbs or chest CT angiography. A sample of 1092 cases was studied. Thromboembolic events were observed in 6 cases (.54%); 3 cases (.27%) with deep venous thrombosis and 3 cases (.27%) with pulmonary thromboembolism. A lethal case was identified (.09%). There were no cases of major bleeding or epidural haematoma. The following risk factors were identified: a multilevel fusion at more than 4 levels, surgeries longer than 130 minutes, patients older than 70 years of age, hypertension, and degenerative scoliosis. There is little scientific evidence on the prevention of thromboembolic events in spinal surgery. In addition to the disparity of prophylactic methods indicated by different specialists, it is important to weigh the risk-benefit of intra- and post-operative bleeding, and even the appearance of an epidural haematoma. Prophylaxis should be assessed in elderly patients over 70 years old, who are subjected to surgeries longer than 130 minutes, when 4 or more levels are involved. Copyright © 2015 SECOT. Published by Elsevier Espana. All rights reserved.

Cost-effectiveness of granulocyte colony-stimulating factor prophylaxis in chemotherapy-induced febrile neutropenia among breast cancer and Non-Hodgkin's lymphoma patients under Taiwan's national health insurance system.

PubMed

Wen, Tsun-Jen; Wen, Yu-Wen; Chien, Chun-Ru; Chiang, Shao-Chin; Hsu, William Wei-Yuan; Shen, Li-Jiuan; Hsiao, Fei-Yuan

2017-04-01

The beneficial effects of granulocyte colony-stimulating factor (G-CSF) prophylaxis on reducing the risk of chemotherapy-induced febrile neutropenia (CIFN) were well documented throughout the literature. However, existing data regarding its cost-effectiveness were conflicting. We estimated the cost-effectiveness of G-CSF prophylaxis in CIFN under Taiwan's National Health Insurance (NHI) system. Data on clinical outcomes and direct medical costs were derived for 5179 newly diagnosed breast cancer and 629 non-Hodgkin's lymphoma (NHL) patients from the NHI claims database. Patients were further categorized into three subgroups as "primary-", "secondary-" and "no -" prophylaxis based on their patterns of G-CSF use. Generalized estimating equations were applied to estimate the impact of G-CSF use on the incidence of CIFN. The incremental cost-effectiveness ratios of primary and secondary prophylactic G-CSF use were calculated and sensitivity analyses were performed. Primary prophylaxis of G-CSF decreased the incidence of CIFN by 27% and 83%, while secondary prophylaxis by 34% and 22% in breast cancer and NHL patients, respectively. Compared with those with no prophylaxis, the incremental cost per CIFN reduced in primary prophylaxis is $931 and $52 among patients with breast cancer and NHL, respectively. In contrast, secondary prophylaxis is dominated by no prophylaxis and primary prophylaxis in both cancer patients. Primary but not secondary prophylactic use of G-CSF was cost-effective in CIFN in breast cancer and NHL patients under Taiwan's NHI system. © 2016 John Wiley & Sons, Ltd.

Native-like aggregates of Factor VIII (FVIII) are immunogenic von Willebrand Factor deficient and hemophilia A mice

PubMed Central

Pisal, Dipak S.; Kosloski, Matthew P.; Middaugh, C. Russell; Bankert, Richard B.; Balu-Iyer, Sathy V.

2013-01-01

The administration of recombinant Factor VIII (FVIII) is the first line therapy for Hemophilia A (HA), but 25–35% of patients develop an inhibitory antibody response. In general, the presence of aggregates contributes to unwanted immunogenic responses against therapeutic proteins. FVIII has been shown to form both native-like and non-native aggregates. Previously, we showed that non-native aggregates of FVIII are less immunogenic compared to the native protein. Here we investigated the effect of native-like aggregates of FVIII on immunogenicity in HA and von Willebrand Factor knockout (vWF−/−) mice. Mice immunized with native-like aggregates showed significantly higher inhibitory antibody titers compared to animals that received native FVIII. Following re-stimulation in vitro with native FVIII, the activation of CD4+ T cells isolated from mice immunized with native-like aggregates is ~4 fold higher than mice immunized with the native protein. Furthermore, this is associated with increases in the secretion of pro-inflammatory cytokines IL-6 and IL-17 in the native-like aggregate treatment group. The results indicate that the native-like aggregates of FVIII are more immunogenic than native FVIII for both the B cell and T cell responses. PMID:22388918

Colony-stimulating factors: clinical evidence for treatment and prophylaxis of chemotherapy-induced febrile neutropenia.

PubMed

Gómez Raposo, César; Pinto Marín, Alvaro; González Barón, Manuel

2006-10-01

The hematopoietic growth factors (HGFs) are a family of glycoproteins which plays a major role in the proliferation, differentiation, and survival of primitive hematopoietic stem and progenitor cells, and in the functions of some mature cells. More than 20 different molecules of HGF have been identified. Among them, granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) have been demostrated to be effective in reducing the incidence of febrile neutropenia when administered inmediately after chemotherapy and as supportive therapy in patients undergoing bone marrow transplantation. Chemotherapy used for treatment of cancer often causes neutropenia, which may be profound, requiring hospitalization, and leading to potentially fatal infection. The uses of the recombinant human hematopoietic colony-stimulating factors G-CSF and GM-CSF for treatment and prophylaxis of chemotherapy-induced febrile neutropenia will be reviewed here.

The structural basis for the functional comparability of factor VIII and the long-acting variant recombinant factor VIII Fc fusion protein

DOE PAGES

Leksa, N. C.; Chiu, P. -L.; Bou-Assaf, G. M.; ...

2017-05-03

Fusion of the human IgG 1 Fc domain to the C-terminal C2 domain of B-domain-deleted (BDD) factor VIII (FVIII) results in the recombinant FVIII Fc (rFVIIIFc) fusion protein, which has a 1.5-fold longer half-life in humans. To assess the structural properties of rFVIIIFc by comparing its constituent FVIII and Fc elements with their respective isolated components, and evaluating their structural independence within rFVIIIFc. rFVIIIFc and its isolated FVIII and Fc components were compared by the use of hydrogen–deuterium exchange mass spectrometry (HDX-MS). The structure of rFVIIIFc was also evaluated by the use of X-ray crystallography, small-angle X-ray scattering (SAXS), andmore » electron microscopy (EM). The degree of steric interference by the appended Fc domain was assessed by EM and surface plasmon resonance (SPR). HDX-MS analysis of rFVIIIFc revealed that fusion caused no structural perturbations in FVIII or Fc. The rFVIIIFc crystal structure showed that the FVIII component is indistinguishable from published BDD FVIII structures. The Fc domain was not observed, indicating high mobility. SAXS analysis was consistent with an ensemble of rigid-body models in which the Fc domain exists in a largely extended orientation relative to FVIII. Binding of Fab fragments of anti-C2 domain antibodies to BDD FVIII was visualized by EM, and the affinities of the corresponding intact antibodies for BDD FVIII and rFVIIIFc were comparable by SPR analysis. Thus, the FVIII and Fc components of rFVIIIFc are structurally indistinguishable from their isolated constituents, and show a high degree of structural independence, consistent with the functional comparability of rFVIIIFc and unmodified FVIII.« less

The structural basis for the functional comparability of factor VIII and the long-acting variant recombinant factor VIII Fc fusion protein

DOE Office of Scientific and Technical Information (OSTI.GOV)

Leksa, N. C.; Chiu, P. -L.; Bou-Assaf, G. M.

Fusion of the human IgG 1 Fc domain to the C-terminal C2 domain of B-domain-deleted (BDD) factor VIII (FVIII) results in the recombinant FVIII Fc (rFVIIIFc) fusion protein, which has a 1.5-fold longer half-life in humans. To assess the structural properties of rFVIIIFc by comparing its constituent FVIII and Fc elements with their respective isolated components, and evaluating their structural independence within rFVIIIFc. rFVIIIFc and its isolated FVIII and Fc components were compared by the use of hydrogen–deuterium exchange mass spectrometry (HDX-MS). The structure of rFVIIIFc was also evaluated by the use of X-ray crystallography, small-angle X-ray scattering (SAXS), andmore » electron microscopy (EM). The degree of steric interference by the appended Fc domain was assessed by EM and surface plasmon resonance (SPR). HDX-MS analysis of rFVIIIFc revealed that fusion caused no structural perturbations in FVIII or Fc. The rFVIIIFc crystal structure showed that the FVIII component is indistinguishable from published BDD FVIII structures. The Fc domain was not observed, indicating high mobility. SAXS analysis was consistent with an ensemble of rigid-body models in which the Fc domain exists in a largely extended orientation relative to FVIII. Binding of Fab fragments of anti-C2 domain antibodies to BDD FVIII was visualized by EM, and the affinities of the corresponding intact antibodies for BDD FVIII and rFVIIIFc were comparable by SPR analysis. Thus, the FVIII and Fc components of rFVIIIFc are structurally indistinguishable from their isolated constituents, and show a high degree of structural independence, consistent with the functional comparability of rFVIIIFc and unmodified FVIII.« less

NE VIII lambda 774 and time variable associated absorption in the QSO UM 675

NASA Technical Reports Server (NTRS)

Hamann, Fred; Barlow, Thomas A.; Beaver, E. A.; Burbidge, E. M.; Cohen, Ross D.; Junkkarinen, Vesa; Lyons, R.

1995-01-01

We discuss measurements of Ne VIII lambda 774 absorption and the time variability of other lines in the z(sub a) approximately equal z(sub e) absorption system of the z(sub e) = 2.15 QSO UM 675 (0150-203). The C IV lambda 1549 and N V 1240 doublets at z(sub a) = 2.1340 (shifted approximately 1500 km/s from z(sub e) strengthened by a factor of approximately 3 between observations by Sargent, Boksenberg and Steidel (1981 November) and our earliest measurements (1990 November and December). We have no information on changes in other z(sub a) approximately equal z(sub e) absorption lines. Continued monitoring since 1990 November shows no clear changes in any of the absorptions between approximately 1100 and 1640 A rest. The short timescale of the variability (less than or approximately equal to 2.9 yr rest) strongly suggests that the clouds are dense, compact, close to the QSO, and photoionized by the QSO continuum. If the line variability is caused by changes in the ionization, the timescale requires densities greater than approximately 4000/cu cm. Photoionization calculations place the absorbing clouds within approximately 200 pc of the continuum source. The full range of line ionizations (from Ne VIII lambda 774 to C III lambda 977) in optically thin gas (no Lyman limit) implies that the absorbing regions span a factor of more than approximately 10 in distance or approximately 100 in density. Across these regions, the total hydrogen (H I + H II) column ranges from a few times 10(exp 18)/sq cm in the low-ionization gas to approximately 10(exp 20)/sq cm where the Ne VIII doublet forms. The metallicity is roughly solar or higher, with nitrogen possibly more enhanced by factors of a few. The clouds might contribute significant line emission if they nearly envelop the QSO. The presence of highly ionized Ne VIII lambda 774 absorption near the QSO supports recent studies that link z(sub a) approximately equal to z(sub e) systems with X-ray 'wamr absorbers. We show that the

Antimicrobial Prophylaxis in Adults

PubMed Central

Enzler, Mark J.; Berbari, Elie; Osmon, Douglas R.

2011-01-01

Antimicrobial prophylaxis is commonly used by clinicians for the prevention of numerous infectious diseases, including herpes simplex infection, rheumatic fever, recurrent cellulitis, meningococcal disease, recurrent uncomplicated urinary tract infections in women, spontaneous bacterial peritonitis in patients with cirrhosis, influenza, infective endocarditis, pertussis, and acute necrotizing pancreatitis, as well as infections associated with open fractures, recent prosthetic joint placement, and bite wounds. Perioperative antimicrobial prophylaxis is recommended for various surgical procedures to prevent surgical site infections. Optimal antimicrobial agents for prophylaxis should be bactericidal, nontoxic, inexpensive, and active against the typical pathogens that can cause surgical site infection postoperatively. To maximize its effectiveness, intravenous perioperative prophylaxis should be administered within 30 to 60 minutes before the surgical incision. Antimicrobial prophylaxis should be of short duration to decrease toxicity and antimicrobial resistance and to reduce cost. PMID:21719623

Platelet-targeted gene therapy with human factor VIII establishes haemostasis in dogs with haemophilia A.

PubMed

Du, Lily M; Nurden, Paquita; Nurden, Alan T; Nichols, Timothy C; Bellinger, Dwight A; Jensen, Eric S; Haberichter, Sandra L; Merricks, Elizabeth; Raymer, Robin A; Fang, Juan; Koukouritaki, Sevasti B; Jacobi, Paula M; Hawkins, Troy B; Cornetta, Kenneth; Shi, Qizhen; Wilcox, David A

2013-01-01

It is essential to improve therapies for controlling excessive bleeding in patients with haemorrhagic disorders. As activated blood platelets mediate the primary response to vascular injury, we hypothesize that storage of coagulation Factor VIII within platelets may provide a locally inducible treatment to maintain haemostasis for haemophilia A. Here we show that haematopoietic stem cell gene therapy can prevent the occurrence of severe bleeding episodes in dogs with haemophilia A for at least 2.5 years after transplantation. We employ a clinically relevant strategy based on a lentiviral vector encoding the ITGA2B gene promoter, which drives platelet-specific expression of human FVIII permitting storage and release of FVIII from activated platelets. One animal receives a hybrid molecule of FVIII fused to the von Willebrand Factor propeptide-D2 domain that traffics FVIII more effectively into α-granules. The absence of inhibitory antibodies to platelet-derived FVIII indicates that this approach may have benefit in patients who reject FVIII replacement therapies. Thus, platelet FVIII may provide effective long-term control of bleeding in patients with haemophilia A.

Platelet-targeted gene therapy with human factor VIII establishes haemostasis in dogs with haemophilia A

PubMed Central

Du, Lily M.; Nurden, Paquita; Nurden, Alan T.; Nichols, Timothy C.; Bellinger, Dwight A.; Jensen, Eric S.; Haberichter, Sandra L.; Merricks, Elizabeth; Raymer, Robin A.; Fang, Juan; Koukouritaki, Sevasti B.; Jacobi, Paula M.; Hawkins, Troy B.; Cornetta, Kenneth; Shi, Qizhen; Wilcox, David A.

2013-01-01

It is essential to improve therapies for controlling excessive bleeding in patients with haemorrhagic disorders. As activated blood platelets mediate the primary response to vascular injury, we hypothesize that storage of coagulation Factor VIII within platelets may provide a locally inducible treatment to maintain haemostasis for haemophilia A. Here we show that haematopoietic stem cell gene therapy can prevent the occurrence of severe bleeding episodes in dogs with haemophilia A for at least 2.5 years after transplantation. We employ a clinically relevant strategy based on a lentiviral vector encoding the ITGA2B gene promoter, which drives platelet-specific expression of human FVIII permitting storage and release of FVIII from activated platelets. One animal receives a hybrid molecule of FVIII fused to the von Willebrand Factor propeptide-D2 domain that traffics FVIII more effectively into α-granules. The absence of inhibitory antibodies to platelet-derived FVIII indicates that this approach may have benefit in patients who reject FVIII replacement therapies. Thus, platelet FVIII may provide effective long-term control of bleeding in patients with haemophilia A. PMID:24253479

[Deep vein thrombosis prophylaxis.

PubMed

Sandoval-Chagoya, Gloria Alejandra; Laniado-Laborín, Rafael

2013-01-01

Background: despite the proven effectiveness of preventive therapy for deep vein thrombosis, a significant proportion of patients at risk for thromboembolism do not receive prophylaxis during hospitalization. Our objective was to determine the adherence to thrombosis prophylaxis guidelines in a general hospital as a quality control strategy. Methods: a random audit of clinical charts was conducted at the Tijuana General Hospital, Baja California, Mexico, to determine the degree of adherence to deep vein thrombosis prophylaxis guidelines. The instrument used was the Caprini's checklist for thrombosis risk assessment in adult patients. Results: the sample included 300 patient charts; 182 (60.7 %) were surgical patients and 118 were medical patients. Forty six patients (15.3 %) received deep vein thrombosis pharmacologic prophylaxis; 27.1 % of medical patients received deep vein thrombosis prophylaxis versus 8.3 % of surgical patients (p < 0.0001). Conclusions: our results show that adherence to DVT prophylaxis at our hospital is extremely low. Only 15.3 % of our patients at risk received treatment, and even patients with very high risk received treatment in less than 25 % of the cases. We have implemented strategies to increase compliance with clinical guidelines.

Possible Pasts: Historiography and Legitimation in "Henry VIII."

ERIC Educational Resources Information Center

Kamps, Ivo

1996-01-01

Aims to rehabilitate the reputation of Shakespeare's "Henry VIII" and emphasizes its potential usefulness in the classroom by reconsidering it in the context of Renaissance history writing. Shows how "Henry VIII" can be taught as a commentary on or seen as a continuation of incipient themes in "The Tempest" and…

Pegfilgrastim prophylaxis is associated with a lower risk of hospitalization of cancer patients than filgrastim prophylaxis: a retrospective United States claims analysis of granulocyte colony-stimulating factors (G-CSF)

PubMed Central

2013-01-01

Background Myelosuppressive chemotherapy can lead to dose-limiting febrile neutropenia. Prophylactic use of recombinant human G-CSF such as daily filgrastim and once-per-cycle pegfilgrastim may reduce the incidence of febrile neutropenia. This comparative study examined the effect of pegfilgrastim versus daily filgrastim on the risk of hospitalization. Methods This retrospective United States claims analysis utilized 2004–2009 data for filgrastim- and pegfilgrastim-treated patients receiving chemotherapy for non-Hodgkin’s lymphoma (NHL) or breast, lung, ovarian, or colorectal cancers. Cycles in which pegfilgrastim or filgrastim was administered within 5 days from initiation of chemotherapy (considered to represent prophylaxis) were pooled for analysis. Neutropenia-related hospitalization and other healthcare encounters were defined with a “narrow” criterion for claims with an ICD-9 code for neutropenia and with a “broad” criterion for claims with an ICD-9 code for neutropenia, fever, or infection. Odds ratios (OR) for hospitalization and 95% confidence intervals (CI) were estimated by generalized estimating equation (GEE) models and adjusted for patient, tumor, and treatment characteristics. Per-cycle healthcare utilization and costs were examined for cycles with pegfilgrastim or filgrastim prophylaxis. Results We identified 3,535 patients receiving G-CSF prophylaxis, representing 12,056 chemotherapy cycles (11,683 pegfilgrastim, 373 filgrastim). The mean duration of filgrastim prophylaxis in the sample was 4.8 days. The mean duration of pegfilgrastim prophylaxis in the sample was 1.0 day, consistent with the recommended dosage of pegfilgrastim - a single injection once per chemotherapy cycle. Cycles with prophylactic pegfilgrastim were associated with a decreased risk of neutropenia-related hospitalization (narrow definition: OR = 0.43, 95% CI: 0.16–1.13; broad definition: OR = 0.38, 95% CI: 0.24–0.59) and all-cause hospitalization (OR�

19 CFR Annex Viii-B to Part 351 - Schedule for Expedited Sunset Reviews

Code of Federal Regulations, 2010 CFR

2010-04-01

... 19 Customs Duties 3 2010-04-01 2010-04-01 false Schedule for Expedited Sunset Reviews VIII Annex VIII-B to Part 351 Customs Duties INTERNATIONAL TRADE ADMINISTRATION, DEPARTMENT OF COMMERCE ANTIDUMPING AND COUNTERVAILING DUTIES Pt. 351, Annex VIII-B Annex VIII-B to Part 351—Schedule for Expedited...

19 CFR Annex Viii-B to Part 351 - Schedule for Expedited Sunset Reviews

Code of Federal Regulations, 2011 CFR

2011-04-01

... 19 Customs Duties 3 2011-04-01 2011-04-01 false Schedule for Expedited Sunset Reviews VIII Annex VIII-B to Part 351 Customs Duties INTERNATIONAL TRADE ADMINISTRATION, DEPARTMENT OF COMMERCE ANTIDUMPING AND COUNTERVAILING DUTIES Pt. 351, Annex VIII-B Annex VIII-B to Part 351—Schedule for Expedited...

19 CFR Annex Viii-B to Part 351 - Schedule for Expedited Sunset Reviews

Code of Federal Regulations, 2013 CFR

2013-04-01

... 19 Customs Duties 3 2013-04-01 2013-04-01 false Schedule for Expedited Sunset Reviews VIII Annex VIII-B to Part 351 Customs Duties INTERNATIONAL TRADE ADMINISTRATION, DEPARTMENT OF COMMERCE ANTIDUMPING AND COUNTERVAILING DUTIES Pt. 351, Annex VIII-B Annex VIII-B to Part 351—Schedule for Expedited...

19 CFR Annex Viii-B to Part 351 - Schedule for Expedited Sunset Reviews

Code of Federal Regulations, 2014 CFR

2014-04-01

... 19 Customs Duties 3 2014-04-01 2014-04-01 false Schedule for Expedited Sunset Reviews VIII Annex VIII-B to Part 351 Customs Duties INTERNATIONAL TRADE ADMINISTRATION, DEPARTMENT OF COMMERCE ANTIDUMPING AND COUNTERVAILING DUTIES Pt. 351, Annex VIII-B Annex VIII-B to Part 351—Schedule for Expedited...

19 CFR Annex Viii-B to Part 351 - Schedule for Expedited Sunset Reviews

Code of Federal Regulations, 2012 CFR

2012-04-01

... 19 Customs Duties 3 2012-04-01 2012-04-01 false Schedule for Expedited Sunset Reviews VIII Annex VIII-B to Part 351 Customs Duties INTERNATIONAL TRADE ADMINISTRATION, DEPARTMENT OF COMMERCE ANTIDUMPING AND COUNTERVAILING DUTIES Pt. 351, Annex VIII-B Annex VIII-B to Part 351—Schedule for Expedited...

A simplified regimen of targeted antifungal prophylaxis in liver transplant recipients: A single-center experience.

PubMed

Lavezzo, B; Patrono, D; Tandoi, F; Martini, S; Fop, F; Ballerini, V; Stratta, C; Skurzak, S; Lupo, F; Strignano, P; Donadio, P P; Salizzoni, M; Romagnoli, R; De Rosa, F G

2018-04-01

Invasive fungal infection (IFI) is a severe complication of liver transplantation burdened by high mortality. Guidelines recommend targeted rather than universal antifungal prophylaxis based on tiers of risk. We aimed to evaluate IFI incidence, risk factors, and outcome after implementation of a simplified two-tiered targeted prophylaxis regimen based on a single broad-spectrum antifungal drug (amphotericin B). Patients presenting 1 or more risk factors according to literature were administered prophylaxis. Prospectively collected data on all adult patients transplanted in Turin from January 2011 to December 2015 were reviewed. Patients re-transplanted before postoperative day 7 were considered once, yielding a study cohort of 581 cases. Prophylaxis was administered to 299 (51.4%) patients; adherence to protocol was 94.1%. Sixteen patients developed 18 IFIs for an overall rate of 2.8%. All IFI cases were in targeted prophylaxis group; none of the non-prophylaxis group developed IFI. Most cases (81.3%) presented within 30 days after transplantation during prophylaxis; predominant pathogens were molds (94.4%). Only 1 case of candidemia was observed. One-year mortality in IFI patients was 33.3% vs 6.4% in patients without IFI (P = .001); IFI attributable mortality was 6.3%. At multivariate analysis, significant risk factors for IFI were renal replacement therapy (OR = 8.1) and re-operation (OR = 5.2). The implementation of a simplified targeted prophylaxis regimen appeared to be safe and applicable and was associated with low IFI incidence and mortality. Association of IFI with re-operation and renal replacement therapy calls for further studies to identify optimal prophylaxis in this subset of patients. © 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Is febrile neutropenia prophylaxis with granulocyte-colony stimulating factors economically justified for adjuvant TC chemotherapy in breast cancer?

PubMed

Skedgel, Chris; Rayson, Daniel; Younis, Tallal

2016-01-01

Febrile neutropenia (FN) during adjuvant chemotherapy is associated with morbidity, mortality risk, and substantial cost, and subsequent chemotherapy dose reductions may result in poorer outcomes. Patients at high risk of, or who develop FN, often receive prophylaxis with granulocyte colony-stimulating factors (G-CSF). We investigated whether different prophylaxis strategies with G-CSF offered favorable value-for-money. We developed a decision model to estimate the short- and long-term costs and outcomes of a hypothetical cohort of women with breast cancer receiving adjuvant taxotere + cyclophosphamide (TC) chemotherapy. The short-term phase estimated upfront costs and FN risks with adjuvant TC chemotherapy without G-CSF prophylaxis (i.e., chemotherapy dose reductions) as well as with secondary and primary G-CSF prophylaxis strategies. The long-term phase estimated the expected costs and quality-adjusted life years (QALYs) for patients who completed adjuvant TC chemotherapy with or without one or more episodes of FN. Secondary G-CSF was associated with lower costs and greater QALY gains than a no G-CSF strategy. Primary G-CSF appears likely to be cost-effective relative to secondary G-CSF at FN rates greater than 28%, assuming some loss of chemotherapy efficacy at lower dose intensities. The cost-effectiveness of primary vs. secondary G-CSF was sensitive to FN risk and mortality, and loss of chemotherapy efficacy following FN. Secondary G-CSF is more effective and less costly than a no G-CSF strategy. Primary G-CSF may be justified at higher willingness-to-pay thresholds and/or higher FN risks, but this threshold FN risk appears to be higher than the 20% rate recommended by current clinical guidelines.

Prophylaxis for Venous Thromboembolism.

PubMed

Ma, Kiet; Alhassan, Sulaiman; Sharara, Rihab; Young, Meilin; Singh, Anil C; Bihler, Eric

Venous thromboembolisms are major risk factors for many of our hospitalized patients. These events, however, can be prevented with prophylactic measurements when administered appropriately and on a timely basis. As patients are admitted, discharged, transferred, and scheduled for procedures on an hourly basis, anticoagulation and deep vein thrombosis prophylaxis are held or discontinued in anticipation for possible procedures. This results in delay of care and intervals where patients may not be covered with any prophylactic measurements. Similarly, alterations in clinical status can quickly change such as an increase in creatinine levels or the development of a new bleed, thus requiring a revision in their deep vein thrombosis prophylaxis. Nurses, therefore, play an integral role in not only administering the medicine but also routinely assessing the patients' clinical status and, therefore, their deep vein thrombosis prophylactic regimens as well. This article will review the indications, scoring systems, common prophylactic methods, and special populations at increased risks for venous thromboembolisms.

19 CFR Annex Viii-C to Part 351 - Schedule for Full Sunset Reviews

Code of Federal Regulations, 2010 CFR

2010-04-01

... 19 Customs Duties 3 2010-04-01 2010-04-01 false Schedule for Full Sunset Reviews VIII Annex VIII-C to Part 351 Customs Duties INTERNATIONAL TRADE ADMINISTRATION, DEPARTMENT OF COMMERCE ANTIDUMPING AND COUNTERVAILING DUTIES Pt. 351, Annex VIII-C Annex VIII-C to Part 351—Schedule for Full Sunset Reviews Day 1 Event...

19 CFR Annex Viii-C to Part 351 - Schedule for Full Sunset Reviews

Code of Federal Regulations, 2014 CFR

2014-04-01

... 19 Customs Duties 3 2014-04-01 2014-04-01 false Schedule for Full Sunset Reviews VIII Annex VIII-C to Part 351 Customs Duties INTERNATIONAL TRADE ADMINISTRATION, DEPARTMENT OF COMMERCE ANTIDUMPING AND COUNTERVAILING DUTIES Pt. 351, Annex VIII-C Annex VIII-C to Part 351—Schedule for Full Sunset Reviews Day 1 Event...

19 CFR Annex Viii-C to Part 351 - Schedule for Full Sunset Reviews

Code of Federal Regulations, 2011 CFR

2011-04-01

... 19 Customs Duties 3 2011-04-01 2011-04-01 false Schedule for Full Sunset Reviews VIII Annex VIII-C to Part 351 Customs Duties INTERNATIONAL TRADE ADMINISTRATION, DEPARTMENT OF COMMERCE ANTIDUMPING AND COUNTERVAILING DUTIES Pt. 351, Annex VIII-C Annex VIII-C to Part 351—Schedule for Full Sunset Reviews Day 1 Event...

19 CFR Annex Viii-C to Part 351 - Schedule for Full Sunset Reviews

Code of Federal Regulations, 2013 CFR

2013-04-01

... 19 Customs Duties 3 2013-04-01 2013-04-01 false Schedule for Full Sunset Reviews VIII Annex VIII-C to Part 351 Customs Duties INTERNATIONAL TRADE ADMINISTRATION, DEPARTMENT OF COMMERCE ANTIDUMPING AND COUNTERVAILING DUTIES Pt. 351, Annex VIII-C Annex VIII-C to Part 351—Schedule for Full Sunset Reviews Day 1 Event...

19 CFR Annex Viii-C to Part 351 - Schedule for Full Sunset Reviews

Code of Federal Regulations, 2012 CFR

2012-04-01

... 19 Customs Duties 3 2012-04-01 2012-04-01 false Schedule for Full Sunset Reviews VIII Annex VIII-C to Part 351 Customs Duties INTERNATIONAL TRADE ADMINISTRATION, DEPARTMENT OF COMMERCE ANTIDUMPING AND COUNTERVAILING DUTIES Pt. 351, Annex VIII-C Annex VIII-C to Part 351—Schedule for Full Sunset Reviews Day 1 Event...

Manufacturing process used to produce long-acting recombinant factor VIII Fc fusion protein.

PubMed

McCue, Justin; Kshirsagar, Rashmi; Selvitelli, Keith; Lu, Qi; Zhang, Mingxuan; Mei, Baisong; Peters, Robert; Pierce, Glenn F; Dumont, Jennifer; Raso, Stephen; Reichert, Heidi

2015-07-01

Recombinant factor VIII Fc fusion protein (rFVIIIFc) is a long-acting coagulation factor approved for the treatment of hemophilia A. Here, the rFVIIIFc manufacturing process and results of studies evaluating product quality and the capacity of the process to remove potential impurities and viruses are described. This manufacturing process utilized readily transferable and scalable unit operations and employed multi-step purification and viral clearance processing, including a novel affinity chromatography adsorbent and a 15 nm pore size virus removal nanofilter. A cell line derived from human embryonic kidney (HEK) 293H cells was used to produce rFVIIIFc. Validation studies evaluated identity, purity, activity, and safety. Process-related impurity clearance and viral clearance spiking studies demonstrate robust and reproducible removal of impurities and viruses, with total viral clearance >8-15 log10 for four model viruses (xenotropic murine leukemia virus, mice minute virus, reovirus type 3, and suid herpes virus 1). Terminal galactose-α-1,3-galactose and N-glycolylneuraminic acid, two non-human glycans, were undetectable in rFVIIIFc. Biochemical and in vitro biological analyses confirmed the purity, activity, and consistency of rFVIIIFc. In conclusion, this manufacturing process produces a highly pure product free of viruses, impurities, and non-human glycan structures, with scale capabilities to ensure a consistent and adequate supply of rFVIIIFc. Copyright © 2015 Biogen. Published by Elsevier Ltd.. All rights reserved.

Adherence to Antimicrobial Inhalational Anthrax Prophylaxis among Postal Workers, Washington, D.C., 2001

PubMed Central

Laserson, Kayla; Fry, Alicia M.; Roy, Sharon; Hayslett, James; Grummer-Strawn, Laurence; Kettel-Khan, Laura; Schuchat, Anne

2002-01-01

In October 2001, two envelopes containing Bacillus anthracis spores were processed at the Washington, D.C., Processing and Distribution Center of the U.S. Postal Service; inhalational anthrax developed in four workers at this facility. More than 2,000 workers were advised to complete 60 days of postexposure prophylaxis to prevent inhalational anthrax. Interventions to promote adherence were carried out to support workers, and qualitative information was collected to evaluate our interventions. A quantitative survey was administered to a convenience sample of workers to assess factors influencing adherence. No anthrax infections developed in any workers involved in the interventions or interviews. Of 245 workers, 98 (40%) reported full adherence to prophylaxis, and 45 (18%) had completely discontinued it. Experiencing adverse effects to prophylaxis, anxiety, and being <45 years old were risk factors for discontinuing prophylaxis. Interventions, especially frequent visits by public health staff, proved effective in supporting adherence. PMID:12396929

Adherence to malaria prophylaxis among Peace Corps Volunteers in the Africa region, 2013.

PubMed

Landman, Keren Z; Tan, Kathrine R; Arguin, Paul M

2015-01-01

Although malaria can be prevented with prophylaxis, it is diagnosed in over 100 Africa-region Peace Corps Volunteers annually. This suggests that prophylaxis non-adherence is a problem in these non-immune travelers. We investigated Volunteers' knowledge, attitudes, and practices regarding prophylaxis using an internet-based survey during August 19-September 30, 2013. Adherence was defined as taking doxycycline or atovaquone-proguanil daily, or taking mefloquine doses no more than 8 days apart. The survey was sent to 3248 Volunteers. Of 781 whose responses were analyzed, 514 (73%) reported adherence to prophylaxis. The most common reasons for non-adherence were forgetting (n = 530, 90%); fear of long-term adverse effects (LTAEs; n = 316, 54%); and experiencing adverse events that Volunteers attributed to prophylaxis (n = 297, 51%). Two hundred fourteen (27%) Volunteers reported not worrying about malaria. On multivariate analysis controlling for sex and experiencing adverse events Volunteers attributed to prophylaxis, the factor most strongly associated with non-adherence was being prescribed mefloquine (OR 5.4, 95% confidence interval 3.2-9.0). We found moderate adherence and a prevailing fear of LTAEs among Volunteers. Strategies to improve prophylaxis adherence may include medication reminders, increasing education about prophylaxis safety and malaria risk, and promoting prompt management of prophylaxis side effects. Published by Elsevier Ltd.

Deep vein thrombosis in elderly patients hospitalized in subacute care facilities: a multicenter cross-sectional study of risk factors, prophylaxis, and prevalence.

PubMed

Bosson, Jean-Luc; Labarere, Jose; Sevestre, Marie Antoinette; Belmin, Joel; Beyssier, Laurence; Elias, Antoine; Franco, Alain; Le Roux, Philippe

2003-11-24

The efficacy of venous thromboembolism prophylaxis has not been established, to our knowledge, in elderly patients hospitalized in subacute care facilities. To describe risk factors and physician practices in the prevention of venous thromboembolism and to estimate the prevalence of deep vein thrombosis. A multicenter cross-sectional study was conducted in the subacute care departments of 36 French hospitals. The study population included 852 inpatients older than 64 years. Systematic ultrasound examination was performed by angiologists. Of the 852 inpatients, 178 (20.9%; 95% confidence interval [CI], 18.2%-23.8%) had 3 or more risk factors other than age, while 144 patients (16.9%; 95% CI, 14.4%-19.6%) had none. The rate of prophylactic anticoagulant treatment was 56.1%, ranging from 20.0% to 86.9%, depending on the department. In multivariate analysis, prophylaxis use was associated with acute immobilization (odds ratio [OR], 4.17; 95% CI, 2.48-7.01), chronic immobilization (OR, 3.19; 95% CI, 2.22-4.60), major surgical procedure (OR, 6.81; 95% CI, 4.26-10.88), and congestive heart failure (OR, 1.65; 95% CI, 1.02-2.67). Prophylaxis use was low in patients who had cancer (OR, 0.49; 95% CI, 0.29-0.84) or myocardial infarction (OR, 0.39; 95% CI, 0.14-1.00). It was not significantly associated with paralytic stroke or history of venous thromboembolism. Deep vein thrombosis was detected in 135 patients (15.8%; 95% CI, 13.4%-18.5%): 50 (5.9%; 95% CI, 4.4%-7.7%) had proximal vein thrombosis and 85 (10.0%; 95% CI, 8.0%-12.2%) had calf vein thrombosis. The prevalence of deep venous thrombosis is high in these patients, despite wide use of prophylaxis. Further prospective studies assessing the clinical benefit of extended duration prophylaxis are needed in elderly patients hospitalized in subacute care settings.

EPICO 3.0. Antifungal prophylaxis in solid organ transplant recipients.

PubMed

Zaragoza, Rafael; Aguado, José María; Ferrer, Ricard; Rodríguez, Alejandro H; Maseda, Emilio; Llinares, Pedro; Grau, Santiago; Muñoz, Patricia; Fortún, Jesús; Bouzada, Mercedes; Pozo, Juan Carlos Del; León, Rafael

Although over the past decade the management of invasive fungal infection has improved, considerable controversy persists regarding antifungal prophylaxis in solid organ transplant recipients. To identify the key clinical knowledge and make by consensus the high level recommendations required for antifungal prophylaxis in solid organ transplant recipients. Spanish prospective questionnaire, which measures consensus through the Delphi technique, was conducted anonymously and by e-mail with 30 national multidisciplinary experts, specialists in invasive fungal infections from six national scientific societies, including intensivists, anesthetists, microbiologists, pharmacologists and specialists in infectious diseases that responded to 12 questions prepared by the coordination group, after an exhaustive review of the literature in the last few years. The level of agreement achieved among experts in each of the categories should be equal to or greater than 70% in order to make a clinical recommendation. In a second term, after extracting the recommendations of the selected topics, a face-to-face meeting was held with more than 60 specialists who were asked to validate the pre-selected recommendations and derived algorithm. Echinocandin antifungal prophylaxis should be considered in liver transplant with major risk factors (retransplantation, renal failure requiring dialysis after transplantation, pretransplant liver failure, not early reoperation, or MELD>30); heart transplant with hemodialysis, and surgical re-exploration after transplantation; environmental colonization by Aspergillus, or cytomegalovirus (CMV) infection; and pancreas and intestinal transplant in case of acute graft rejection, hemodialysis, initial graft dysfunction, post-perfusion pancreatitis with anastomotic problems or need for laparotomy after transplantation. Antifungal fluconazole prophylaxis should be considered in liver transplant without major risk factors and MELD 20-30, split or living

40 CFR Appendix Viii to Part 600 - Fuel Economy Label Formats

Code of Federal Regulations, 2011 CFR

2011-07-01

... 40 Protection of Environment 30 2011-07-01 2011-07-01 false Fuel Economy Label Formats VIII... POLICY FUEL ECONOMY AND CARBON-RELATED EXHAUST EMISSIONS OF MOTOR VEHICLES Pt. 600, App. VIII Appendix VIII to Part 600—Fuel Economy Label Formats EC01MY92.117 EC01MY92.118 EC01MY92.119 EC01MY92.120...

Guidelines for antimicrobial prophylaxis.

PubMed

Nahata, M C

1996-08-01

Antimicrobials are frequently used to prevent infections. Principles of prophylaxis, and antimicrobial prophylaxis in surgery, tuberculosis, acquired immunodeficiency syndrome, influenza A, traveller's diarrhoea, malaria, recurrent otitis media, Haemophilus influenzae type b infection, pertussis, rheumatic fever, and urinary tract infection are described. Various strategies to improve the prophylactic use of antibiotics are discussed. Collaborative efforts among health care disciplines are needed to assure optimal antimicrobial prophylaxis. This should maximize efficacy and minimize adverse effects, the development of bacterial resistance and associated costs.

Abnormal cerebellar development and ataxia in CARP VIII morphant zebrafish.

PubMed

Aspatwar, Ashok; Tolvanen, Martti E E; Jokitalo, Eija; Parikka, Mataleena; Ortutay, Csaba; Harjula, Sanna-Kaisa E; Rämet, Mika; Vihinen, Mauno; Parkkila, Seppo

2013-02-01

Congenital ataxia and mental retardation are mainly caused by variations in the genes that affect brain development. Recent reports have shown that mutations in the CA8 gene are associated with mental retardation and ataxia in humans and ataxia in mice. The gene product, carbonic anhydrase-related protein VIII (CARP VIII), is predominantly present in cerebellar Purkinje cells, where it interacts with the inositol 1,4,5-trisphosphate receptor type 1, a calcium channel. In this study, we investigated the effects of the loss of function of CARP VIII during embryonic development in zebrafish using antisense morpholino oligonucleotides against the CA8 gene. Knockdown of CA8 in zebrafish larvae resulted in a curved body axis, pericardial edema and abnormal movement patterns. Histologic examination revealed gross morphologic defects in the cerebellar region and in the muscle. Electron microscopy studies showed increased neuronal cell death in developing larvae injected with CA8 antisense morpholinos. These data suggest a pivotal role for CARP VIII during embryonic development. Furthermore, suppression of CA8 expression leads to defects in motor and coordination functions, mimicking the ataxic human phenotype. This work reveals an evolutionarily conserved function of CARP VIII in brain development and introduces a novel zebrafish model in which to investigate the mechanisms of CARP VIII-related ataxia and mental retardation in humans.

Efficacy, safety and tolerability of recombinant factor VIII (REFACTO) in patients with haemophilia A: interim data from a postmarketing surveillance study in Germany and Austria.

PubMed

Pollmann, H; Externest, D; Ganser, A; Eifrig, B; Kreuz, W; Lenk, H; Pabinger, I; Schramm, W; Schwarz, T F; Zimmermann, R; Zavazava, N; Oldenburg, J; Klamroth, R

2007-03-01

An open-label, multicentre, postmarketing surveillance study conducted in Germany and Austria with recombinant factor VIII (REFACTO) has enrolled 217 patients (mean age 26.3 years) from 38 haemophilia centres during the first 4.8 years. Most patients (188/217; 86.6%) had severe to moderately severe haemophilia A, of whom 153 completed sufficient diary information for the main efficacy analysis. These 153 patients experienced a median of 6.6 (interquartile range 1.4-18.6) bleeding episodes per year. Patients treated with prophylaxis experienced a median of 4.4 (1.1-9.3) bleeds per year, while patients treated on-demand experienced a median of 22.8 (11.3-29.0) bleeds per year. Overall, most physicians (41/43 [95.3%]) were 'very satisfied' or 'satisfied' with the efficacy of REFACTO in the treatment of bleeding episodes. A total of 137 non-serious adverse events have been reported in 52/217 patients (24.0%) to date. In addition, 129 serious adverse events in 87 patients (40%) were reported, including 41 cases of 'less than expected therapeutic effect' (LETE). Of these, 39 LETE cases were reported in one centre; however, patients in this centre experienced considerably fewer bleeding episodes per year than patients outside this centre. Overall, six patients (2.8%) have developed de novo inhibitors, three of which were considered high titre. Four of these patients were at high risk (0-50 exposure days [ED]) of inhibitor formation, one was at intermediate risk (51-100 ED) and one was at low risk (>100 ED). These results emphasize the benefit of postmarketing surveillance and, overall, this study confirms the efficacy, safety and tolerability of REFACTO in the treatment of patients with haemophilia A.

Phase I study of BAY 94-9027, a PEGylated B-domain-deleted recombinant factor VIII with an extended half-life, in subjects with hemophilia A.

PubMed

Coyle, T E; Reding, M T; Lin, J C; Michaels, L A; Shah, A; Powell, J

2014-04-01

BAY 94-9027 is a B-domain-deleted recombinant factor VIII (rFVIII) with site-specific attachment of poly(ethylene glycol) that has shown an extended half-life in animal models of hemophilia. To assess the pharmacokinetics and safety of BAY 94-9027 after single and repeated administration in subjects with severe hemophilia A. This 8-week, prospective, multicenter, open-label, phase I trial was conducted in 14 subjects aged 21–58 years with FVIII of < 1%, ≥ 150 days of exposure to FVIII, and no history of FVIII inhibitors. After a ≥ 3-day washout, subjects received a single dose of sucrose-formulated rFVIII (rFVIII-FS) (cohort 1 [n = 7], 25 IU kg−1; cohort 2 [n = 7], 50 IU kg−1) for a 48-h pharmacokinetic (PK) study. After another ≥ 3-day washout, cohort 1 received twice-weekly BAY 94-9027 at 25 IU kg−1 (16 doses), and cohort 2 received once-weekly BAY 94-9027 at 60 IU kg−1 (nine doses). A 168-h PK study was performed after the first and last BAY 94-9027 doses. BAY 94-9027 showed equivalent recovery and an improved PK profile vs. rFVIII-FS, with a half-life of ~ 19 h (vs. ~ 13.0 h for rFVIII-FS). BAY 94-9027 was well tolerated, and no immunogenicity was observed. This phase I study demonstrates that BAY 94-9027 has an extended half-life in subjects with hemophilia A and, after multiple dosing, was well tolerated with no immunogenicity during the 8-week trial. A phase III study in a larger number of subjects is underway to fully characterize how this prolonged half-life will permit less frequent prophylaxis dosing for patients with hemophilia.

Antibiotic prophylaxis for endoscopic retrograde chlangiopancreatography increases the detection rate of drug-resistant bacteria in bile.

PubMed

Minami, Tomoyuki; Sasaki, Tamito; Serikawa, Masahiro; Ishigaki, Takashi; Murakami, Yoshiaki; Chayama, Kazuaki

2014-09-01

No consensus has yet been reached regarding the utility of antibiotic prophylaxis for endoscopic retrograde cholangiopancreatography (ERCP). However, there has been little discussion of potential adverse effects of antibiotic use. This study investigated the impact of antibiotic prophylaxis on overall levels of bacterial infiltration of the biliary tract and the prevalence of drug-resistance among that population. Ninety-three patients, from whom intraoperative bile samples were collected after performing ERCP, were assigned to either an antibiotic-prophylaxis group (AP, n = 58) or a no-antibiotic-prophylaxis group (NAP, n = 35). Detection rates of biliary bacteria and antibiotic resistance were determined for each group. Multivariate analysis was also performed to identify risk factors for the development of drug-resistant biliary bacteria. The bile contamination rate was 37.1% for the NAP group and 55.2% for the AP group (P = 0.09). Drug-resistant bacteria were found in 5.7% of the NAP group and 29.3% of the AP group (P = 0.006). Biliary drainage and antibiotic prophylaxis for ERCP were identified as risk factors for the presence of drug-resistant bacteria. Administration of antibiotic prophylaxis prior to ERCP can be a risk factor for the selection of drug-resistant bacteria in the biliary tract. © 2014 Japanese Society of Hepato-Biliary-Pancreatic Surgery.

Preparing for ENDF/B-VIII

NASA Astrophysics Data System (ADS)

Brown, David

2017-09-01

Although the next major release of the ENDF/B library is not due until the 2017-2018 time frame, ENDF/B-VIII is already positioned to become the most important release of the library in some time. ENDF/B-VIII will be built around the Neutron Reaction Standards as well as the 1H, 16O, 56Fe, 235U, 238U and 239Pu evaluations developed as part of the Coordinated International Evaluation Library Organization (CIELO) pilot project. In this contribution, we summarize these improvements as well as the many other improvements to ENDF that have already been made or are scheduled to be made in the next year. Improvements already included in the ENDF/B-VIII beta releases: • Aggressive use of the flexible and physically correct LRF=7 resolved resonance format in 12 updated evaluations (35,37Cl, 40Ca, 54,56,57Fe, 63,65Cu and 182,183,184,186W) • Thermal capture gammas from the EGAF project (6,7Li, 11B, 19F, 23Na, 27Al, 28Si, 35,37Cl) • Thermal Scattering Law evaluations from NCSU (α and β phase SiO2, SiC, lucite, BeO, and polyethylene) and from the CAB-CNL collaboration (heavy and light water) • Many new evaluations in the neutron sublibrary (n, 12,13C, 40Ar, 54,57,58Fe, 58,59,60,61,62,64Ni, 63,65Cu, 73As, 120Sn, 236m1Np) Inclusion of Red Cullen's EPICS2014 library, updating the photo-atomic, electron and atomic-relaxation sublibraries. Many improvements are planned in the next year including new evaluations such as charged particle evaluations translated from LLNL's ECPL. In addition to these major changes, ENDF/B-VIII will be the first official library released simultaneously in the legacy ENDF-6 and the newly developed Generalized Nuclear Data (GND) formats.

19 CFR Annex Viii-A to Part 351 - Schedule for 90-Day Sunset Reviews

Code of Federal Regulations, 2010 CFR

2010-04-01

... 19 Customs Duties 3 2010-04-01 2010-04-01 false Schedule for 90-Day Sunset Reviews VIII Annex VIII-A to Part 351 Customs Duties INTERNATIONAL TRADE ADMINISTRATION, DEPARTMENT OF COMMERCE ANTIDUMPING AND COUNTERVAILING DUTIES Pt. 351, Annex VIII-A Annex VIII-A to Part 351—Schedule for 90-Day Sunset...

19 CFR Annex Viii-A to Part 351 - Schedule for 90-Day Sunset Reviews

Code of Federal Regulations, 2014 CFR

2014-04-01

... 19 Customs Duties 3 2014-04-01 2014-04-01 false Schedule for 90-Day Sunset Reviews VIII Annex VIII-A to Part 351 Customs Duties INTERNATIONAL TRADE ADMINISTRATION, DEPARTMENT OF COMMERCE ANTIDUMPING AND COUNTERVAILING DUTIES Pt. 351, Annex VIII-A Annex VIII-A to Part 351—Schedule for 90-Day Sunset...

19 CFR Annex Viii-A to Part 351 - Schedule for 90-Day Sunset Reviews

Code of Federal Regulations, 2012 CFR

2012-04-01

... 19 Customs Duties 3 2012-04-01 2012-04-01 false Schedule for 90-Day Sunset Reviews VIII Annex VIII-A to Part 351 Customs Duties INTERNATIONAL TRADE ADMINISTRATION, DEPARTMENT OF COMMERCE ANTIDUMPING AND COUNTERVAILING DUTIES Pt. 351, Annex VIII-A Annex VIII-A to Part 351—Schedule for 90-Day Sunset...

19 CFR Annex Viii-A to Part 351 - Schedule for 90-Day Sunset Reviews

Code of Federal Regulations, 2013 CFR

2013-04-01

... 19 Customs Duties 3 2013-04-01 2013-04-01 false Schedule for 90-Day Sunset Reviews VIII Annex VIII-A to Part 351 Customs Duties INTERNATIONAL TRADE ADMINISTRATION, DEPARTMENT OF COMMERCE ANTIDUMPING AND COUNTERVAILING DUTIES Pt. 351, Annex VIII-A Annex VIII-A to Part 351—Schedule for 90-Day Sunset...

19 CFR Annex Viii-A to Part 351 - Schedule for 90-Day Sunset Reviews

Code of Federal Regulations, 2011 CFR

2011-04-01

... 19 Customs Duties 3 2011-04-01 2011-04-01 false Schedule for 90-Day Sunset Reviews VIII Annex VIII-A to Part 351 Customs Duties INTERNATIONAL TRADE ADMINISTRATION, DEPARTMENT OF COMMERCE ANTIDUMPING AND COUNTERVAILING DUTIES Pt. 351, Annex VIII-A Annex VIII-A to Part 351—Schedule for 90-Day Sunset...

Agnostic stacking of intergalactic doublet absorption: measuring the Ne VIII population

NASA Astrophysics Data System (ADS)

Frank, Stephan; Pieri, Matthew M.; Mathur, Smita; Danforth, Charles W.; Shull, J. Michael

2018-05-01

We present a blind search for doublet intergalactic metal absorption with a method dubbed `agnostic stacking'. Using a forward-modelling framework, we combine this with direct detections in the literature to measure the overall metal population. We apply this novel approach to the search for Ne VIII absorption in a set of 26 high-quality COS spectra. We probe to an unprecedented low limit of log N>12.3 at 0.47≤z ≤1.34 over a path-length Δz = 7.36. This method selects apparent absorption without requiring knowledge of its source. Stacking this mixed population dilutes doublet features in composite spectra in a deterministic manner, allowing us to measure the proportion corresponding to Ne VIII absorption. We stack potential Ne VIII absorption in two regimes: absorption too weak to be significant in direct line studies (12.3 < log N < 13.7), and strong absorbers (log N > 13.7). We do not detect Ne VIII absorption in either regime. Combining our measurements with direct detections, we find that the Ne VIII population is reproduced with a power-law column density distribution function with slope β = -1.86 ^{+0.18 }_{ -0.26} and normalization log f_{13.7} = -13.99 ^{+0.20 }_{ -0.23}, leading to an incidence rate of strong Ne VIII absorbers dn/dz =1.38 ^{+0.97 }_{ -0.82}. We infer a cosmic mass density for Ne VIII gas with 12.3 < log N < 15.0 of Ω _{{{Ne {VIII}}}} = 2.2 ^{+1.6 }_{ _-1.2} × 10^{-8}, a value significantly lower that than predicted by recent simulations. We translate this density into an estimate of the baryon density Ωb ≈ 1.8 × 10-3, constituting 4 per cent of the total baryonic mass.

Phase 3 study of recombinant factor VIII Fc fusion protein in severe hemophilia A

PubMed Central

Mahlangu, Johnny; Powell, Jerry S.; Ragni, Margaret V.; Chowdary, Pratima; Josephson, Neil C.; Pabinger, Ingrid; Hanabusa, Hideji; Gupta, Naresh; Kulkarni, Roshni; Fogarty, Patrick; Perry, David; Shapiro, Amy; Pasi, K. John; Apte, Shashikant; Nestorov, Ivan; Jiang, Haiyan; Li, Shuanglian; Neelakantan, Srividya; Cristiano, Lynda M.; Goyal, Jaya; Sommer, Jurg M.; Dumont, Jennifer A.; Dodd, Nigel; Nugent, Karen; Vigliani, Gloria; Luk, Alvin; Brennan, Aoife

2014-01-01

This phase 3 pivotal study evaluated the safety, efficacy, and pharmacokinetics of a recombinant FVIII Fc fusion protein (rFVIIIFc) for prophylaxis, treatment of acute bleeding, and perioperative hemostatic control in 165 previously treated males aged ≥12 years with severe hemophilia A. The study had 3 treatment arms: arm 1, individualized prophylaxis (25-65 IU/kg every 3-5 days, n = 118); arm 2, weekly prophylaxis (65 IU/kg, n = 24); and arm 3, episodic treatment (10-50 IU/kg, n = 23). A subgroup compared recombinant FVIII (rFVIII) and rFVIIIFc pharmacokinetics. End points included annualized bleeding rate (ABR), inhibitor development, and adverse events. The terminal half-life of rFVIIIFc (19.0 hours) was extended 1.5-fold vs rFVIII (12.4 hours; P < .001). Median ABRs observed in arms 1, 2, and 3 were 1.6, 3.6, and 33.6, respectively. In arm 1, the median weekly dose was 77.9 IU/kg; approximately 30% of subjects achieved a 5-day dosing interval (last 3 months on study). Across arms, 87.3% of bleeding episodes resolved with 1 injection. Adverse events were consistent with those expected in this population; no subjects developed inhibitors. rFVIIIFc was well-tolerated, had a prolonged half-life compared with rFVIII, and resulted in low ABRs when dosed prophylactically 1 to 2 times per week. This trial was registered at www.clinicaltrials.gov as #NCT01181128. PMID:24227821

Intensity of factor VIII treatment and the development of inhibitors in non-severe hemophilia A patients: results of the INSIGHT case-control study.

PubMed

van Velzen, A S; Eckhardt, C L; Peters, M; Leebeek, F W G; Escuriola-Ettingshausen, C; Hermans, C; Keenan, R; Astermark, J; Male, C; Peerlinck, K; le Cessie, S; van der Bom, J G; Fijnvandraat, K

2017-07-01

Essentials Research suggests that intensive treatment episodes may increase the risk to develop inhibitors. We performed an international nested case-control study with 298 non-severe hemophilia A patients. Surgery and a high dose of factor VIII concentrate were associated with increased inhibitor risk. Physicians need to review arguments for factor VIII dose and elective surgery extra critically. Background Inhibitor development is a major complication of treatment with factor VIII concentrates in hemophilia. Findings from studies among severe hemophilia A patients suggest that intensive treatment episodes increase the risk of developing inhibitors. Objectives We set out to assess whether intensive treatment is also associated with an increased risk of inhibitor development among non-severe hemophilia A patients. Patients/Methods We performed a nested case-control study. A total of 75 inhibitor patients (cases) and 223 control patients were selected from 2709 non-severe hemophilia A patients (FVIII:C, 2-40%) of the INSIGHT cohort study. Cases and controls were matched for date of birth and cumulative number of exposure days (EDs) to FVIII concentrates. Conditional logistic regression was used to calculate both unadjusted and adjusted odds ratios (aOR); the latter were adjusted for a priori specified confounders. Results Peak treatment of 5 or 10 consecutive EDs did not increase inhibitor risk (aOR, 1.0; 95% confidence interval (CI), 0.4-2.5; and aOR, 1.8; CI, 0.6-5.5, respectively). Both surgical intervention (aOR, 4.2; CI, 1.7-10.3) and a high mean dose (> 45 IU kg -1 /ED) of FVIII concentrate (aOR, 7.5; CI, 1.6-35.6) were associated with an increased inhibitor risk. Conclusions Our findings suggest that high-dose FVIII treatment and surgery increase the risk of inhibitor development in non-severe hemophilia A. Together with the notion that non-severe hemophilia A patients are at a lifelong risk of inhibitor development, we suggest that in the future physicians

Review of thromboembolic prophylaxis in patients attending Cork University Hospital.

PubMed

Byrne, Stephen; Weaver, Daniel Timothy

2013-06-01

Although preventable, venous thromboembolism remains a common cause of hospital acquired morbidity and mortality. Guidelines, such as the one produced by the American College of Chest Physicians (ACCP), are aimed at reducing hospital associated venous thromboemboli. Unfortunately the majority of studies have revealed inadequate adherence to these guidelines. The objective of this study was to evaluate the use of venous thromboembolism prophylaxis at Cork University Hospital. Cork University Hospital, Wilton, Cork, Ireland. Data from the patient's chart, drug kardex and laboratory results were recorded during April 2010. A Caprini score, a venous thromboembolism risk factor assessment tool, was subsequently calculated for each patient based on data collected. Appropriate prophylaxis was determined after examining data collected, Caprini score and prophylactic regime according to the ACCP 8th edition guidelines. Primary outcome was to analyse adherence to VTE prophylaxis guidelines. A total of 394 patients met the inclusion criteria and were reviewed, of which, 60% (n = 236) were medical and 37% (n = 146) were surgical patients. In total 63% of patients received some form of venous thromboembolism prophylaxis. Furthermore, 54% of medical and 76% of surgical patients received prophylaxis. However only 37% of the patients studied received appropriate thromboprophylaxis according to the ACCP 8th edition guidelines (Geerts et al. in chest 133(6 Suppl):381S-453S, 2008). Additionally 51% of surgical and 27% of medical patients received appropriate prophylaxis. Data collected from Cork University Hospital revealed poor adherence to international venous thromboembolism prophylaxis guidelines. As stated in the ACCP 8th edition guidelines, every hospital should develop a formal strategy for venous thromboembolism prevention (Geerts et al. in chest 133(6 Suppl):381S-453S, 2008). In order to improve adherence to guidelines, Cork University Hospital should develop, implement and

40 CFR Appendix Viii to Part 268 - LDR Effective Dates of Injected Prohibited Hazardous Wastes

Code of Federal Regulations, 2014 CFR

2014-07-01

... Prohibited Hazardous Wastes VIII Appendix VIII to Part 268 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) SOLID WASTES (CONTINUED) LAND DISPOSAL RESTRICTIONS Pt. 268, App. VIII Appendix VIII to Part 268—LDR Effective Dates of Injected Prohibited Hazardous Wastes National Capacity LDR...

40 CFR Appendix Viii to Part 268 - LDR Effective Dates of Injected Prohibited Hazardous Wastes

Code of Federal Regulations, 2012 CFR

2012-07-01

... Prohibited Hazardous Wastes VIII Appendix VIII to Part 268 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) SOLID WASTES (CONTINUED) LAND DISPOSAL RESTRICTIONS Pt. 268, App. VIII Appendix VIII to Part 268—LDR Effective Dates of Injected Prohibited Hazardous Wastes National Capacity LDR...

40 CFR Appendix Viii to Part 268 - LDR Effective Dates of Injected Prohibited Hazardous Wastes

Code of Federal Regulations, 2011 CFR

2011-07-01

... Prohibited Hazardous Wastes VIII Appendix VIII to Part 268 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) SOLID WASTES (CONTINUED) LAND DISPOSAL RESTRICTIONS Pt. 268, App. VIII Appendix VIII to Part 268—LDR Effective Dates of Injected Prohibited Hazardous Wastes National Capacity LDR...

40 CFR Appendix Viii to Part 268 - LDR Effective Dates of Injected Prohibited Hazardous Wastes

Code of Federal Regulations, 2013 CFR

2013-07-01

... Prohibited Hazardous Wastes VIII Appendix VIII to Part 268 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) SOLID WASTES (CONTINUED) LAND DISPOSAL RESTRICTIONS Pt. 268, App. VIII Appendix VIII to Part 268—LDR Effective Dates of Injected Prohibited Hazardous Wastes National Capacity LDR...

What do women know about breast cancer prophylaxis and a healthy style of life?

PubMed

Sielska, Jolanta; Matecka, Monika; Dąbrowska, Eliza; Jakubek, Ewa; Urbaniak, Monika

2015-01-01

The aim of the study was to determine the factors influencing women's knowledge concerning breast cancer prophylaxis and find out the sources of the knowledge. In the Greater Poland region, breast cancer has been the most frequently detected tumour for years. The percentage of breast cancer cases has increased by 31% in the last decade. The study encompassed 337 women aged 40-59 who participated in the mammographic examinations. An original research tool was used which assessed the level of knowledge concerning breast cancer prophylaxis, the knowledge of health-oriented behaviour in this regard and the influence of the medical personnel on women's education. Age is a factor diversifying the knowledge of the breast self-examination method. Doctors and nurses were rarely indicated as a source of knowledge concerning breast cancer prophylaxis. The subjects presented a high level of knowledge of the factors increasing the risk of developing cancer. A correlation between the level of education and the knowledge of one's own breast to a degree which enables a woman to detect even a slight change was observed. Vital findings also concern the sources of knowledge concerning breast cancer prophylaxis. The results of the studies indicated little informative support on the part of the medical personnel; therefore, one should call for supplementing training courses for doctors and nurses focusing on the issues of prophylaxis, including the method of breast self-examination.

Lonoctocog Alfa: A Review in Haemophilia A.

PubMed

Al-Salama, Zaina T; Scott, Lesley J

2017-10-01

Lonoctocog alfa (rVIII-SingleChain; Afstyla ® ) is a novel single-chain recombinant factor VIII (FVIII) molecule, with a truncated B-domain and the heavy and light chains covalently linked to form a stable and homogenous drug that binds with high affinity to von Willebrand factor (VWF). Intravenous lonoctocog alfa is approved for the prophylaxis and treatment of bleeding in patients with haemophilia A in several countries worldwide. In two pivotal, multicentre trials, lonoctocog alfa was effective in the treatment of bleeding episodes and as prophylaxis, including for perioperative management in adults, adolescents and children. In terms of haemostatic efficacy in controlling bleeding episodes, overall treatment and investigator-assessed success rates were high across all age groups, with the majority of these bleeds controlled with a single injection of lonoctocog alfa. Low median spontaneous, overall and traumatic annualized bleeding rates were evident with prophylactic lonoctocog alfa regimens in both trials. Lonoctocog alfa was generally well-tolerated, with very low rates of injection-site reactions. No previously treated patient experienced an anaphylactic reaction or developed an inhibitor. In conclusion, lonoctocog alfa is an effective and generally well-tolerated alternative to conventional FVIII products for the treatment and prophylaxis of bleeding, including in the surgical setting, in adults, adolescents and children with haemophilia A.

Predictors of chemoradiation related febrile neutropenia prophylaxis in older adults - Experience from a limited resource setting.

PubMed

Gangopadhyay, Aparna

2018-01-01

To identify risk factors that lower efficacy of antibiotic prophylaxis of febrile neutropenia among older patients on chemoradiation. Audit of institutional data showed that older adults are at higher risk of febrile neutropenia during chemoradiation. In limited resource settings widespread use of Granulocyte-Colony Stimulating Factor (G-CSF) is not economically feasible and antibiotics are used commonly. Despite compliance with antibiotics, prophylaxis is inadequate in many patients owing to patient and tumor related factors. Data from records of 219 older patients receiving antibiotic prophylaxis during chemoradiation were studied. Baseline assessment data and predisposing factors for febrile neutropenia were recorded. All patients received prophylactic fluoroquinolones. Incidence of febrile neutropenia and association with predisposing factors at baseline was analyzed by multiple logistic regression. 38.4% developed febrile neutropenia despite compliance. Multiple logistic regression revealed geriatric assessment (G8) score and tumor stage to be significant predictors of febrile neutropenia while on antibiotics ( p  < 0.0001). Odds ratios for two significant predictors G8 score and tumor stage, respectively, were 2.9 (95% CI 1.8036-4.6815) and 2.7 (95% CI 1.7501-4.1318). Correlation between these two significant predictors was found to be low in our cohort (Spearman's coefficient of rank correlation (rho) - 0.431, p  < 0.0001). G8 score and tumor burden are significant predictors of efficacy of antibiotic prophylaxis among older adults receiving chemoradiation. In older patients having poor G8 scores and advanced tumors, antibiotic prophylaxis is unsuitable. Interestingly, co-morbidities and poor performance status did not impact efficacy of antibiotic prophylaxis among our elderly patients.

21 CFR 872.6290 - Prophylaxis cup.

Code of Federal Regulations, 2014 CFR

2014-04-01

... DEVICES DENTAL DEVICES Miscellaneous Devices § 872.6290 Prophylaxis cup. (a) Identification. A prophylaxis cup is a device made of rubber intended to be held by a dental handpiece and used to apply polishing agents during prophylaxis (cleaning). The dental handpiece spins the rubber cup holding the polishing...

21 CFR 872.6290 - Prophylaxis cup.

Code of Federal Regulations, 2013 CFR

2013-04-01

... DEVICES DENTAL DEVICES Miscellaneous Devices § 872.6290 Prophylaxis cup. (a) Identification. A prophylaxis cup is a device made of rubber intended to be held by a dental handpiece and used to apply polishing agents during prophylaxis (cleaning). The dental handpiece spins the rubber cup holding the polishing...

21 CFR 872.6290 - Prophylaxis cup.

Code of Federal Regulations, 2012 CFR

2012-04-01

... DEVICES DENTAL DEVICES Miscellaneous Devices § 872.6290 Prophylaxis cup. (a) Identification. A prophylaxis cup is a device made of rubber intended to be held by a dental handpiece and used to apply polishing agents during prophylaxis (cleaning). The dental handpiece spins the rubber cup holding the polishing...

Cyclophosphamide Treatment for Acquired Factor VIII Inhibitor in a Patient with AIDS-Associated Progressive Multifocal Leukoencephalopathy.

PubMed

Malhotra, Uma; Aboulafia, David M

2016-01-01

Acquired hemophilia A (AHA) is a severe bleeding disorder with high mortality rates resulting from the development of autoantibodies to factor VIII (FVIII). Patients typically present with hemorrhages in the skin, subcutaneous tissues, and muscles, which are frequently severe. They can also develop life-threatening retroperitoneal hematomas and compartment syndromes. We describe the case of a man with a long history of AIDS complicated by progressive multifocal leukoencephalopathy (PML), who developed AHA while on stable antiretroviral therapy and then presented with new onset bleeding and hypotension. We treated our patient with incrementally increasing doses of cyclophosphamide resulting in resolution of coagulopathy. We review the medical literature for additional cases of HIV-associated AHA and discuss the challenges in the care of our patient, since the immunosuppression needed to eradicate the FVIII inhibitor had the potential to cause recrudescence of his PML. © The Author(s) 2015.

Efficacy of palivizumab prophylaxis on the frequency of RSV-associated lower respiratory tract infections in preterm infants: determination of the ideal target population for prophylaxis.

PubMed

Cetinkaya, M; Oral, T K; Karatekin, S; Cebeci, B; Babayigit, A; Yesil, Y

2017-09-01

Respiratory syncytial virus (RSV) prophylaxis in high-risk infants is an effective intervention for the prevention of severe disease. The aim of this study was to determine the ideal target preterm population that might benefit from palivizumab prophylaxis by establishing the main risk factors for acute RSV-related infections. Former premature infants born with a gestational age ≤37 weeks and ≤1 year of age at the beginning of the RSV season and admitted with respiratory infection were included. RSV status was evaluated by RSV strip test in all infants. RSV-positive and -negative infants were compared in terms of demographic features, risk factors, requirement of hospitalisation and palivizumab administration. A total of 202 preterm infants under 1 year of age were enrolled. The RSV test was positive in 34 (16.8%) infants. Maternal age was significantly lower in RSV-positive infants compared with RSV-negative infants (p = 0.03). RSV-positive infants were found to be significantly discharged during the RSV season (p = 0.03). RSV-positive infants required significantly higher rates of hospitalisation and need for mechanical ventilation. Of the RSV-positive infants, 28 (82%) had a gestational age ≥29 weeks. Seventeen (77%) RSV-positive infants that required hospitalisation were ≥29 weeks of gestation. All infants with a gestational age ≥29 weeks and without palivizumab prophylaxis developed RSV infection. Palivizumab prophylaxis should be implemented into guidelines to cover preterm infants with a gestational age >29 weeks. Palivizumab prophylaxis should also be considered in high-risk infants ≤6 months of age during the RSV season.

A retrospective study of antibiotic prophylaxis value in surgical treatment of lower limb fracture.

PubMed

Bandalović, Ante; Zindović, Antonija; Boschi, Vladimir; Bakota, Bore; Marinović, Marin; Čoklo, Miran; Rošin, Matko; Parać, Zlatko; Čukelj, Fabijan

2015-11-01

Surgical site infections (SSI) are nosocomial infections that cause considerable problems in orthopaedic surgery. Antibiotic prophylaxis can be used to reduce the risk for SSI. There is no universal antibiotic that can be recommended for prophylaxis in terms of coverage of all possible pathogens because of antibiotic resistance, and there are no universal recommendations for different types of patients in terms of injury type, selected operation and risk factors for development of SSI. The aim of this study was to analyse the effectiveness of antibiotic prophylaxis in surgical treatment (ORIF) of closed lower limb fractures in young, healthy patients. Patient details were collected from the patient histories. Inclusion criteria for participants were age 20-30 years, not suffering from any type of chronic disease or state that may affect postoperative infection and ISS≤9. Antibiotic prophylaxis use and outcome (SSI) were compared between two groups of patients. Data were analysed using descriptive statistics, Fisher's exact test and t-test for proportions. A total of 347 patients with closed lower limb fractures treated with ORIF met the inclusion criteria. There were 290 male and 57 female patients, with an average age of 24.47 years. Prophylactic antibiotics were given to 242 patients (69.74%); 2g ceftriaxone was administered to 88.02% of the patients who received antibiotic prophylaxis. Ten patients developed postoperative infection (eight out of 242 with antibiotic prophylaxis and two out of 105 without antibiotic prophylaxis). The difference between the two groups was not statistically significant (Fisher's exact test, P=0.749). Antibiotic prophylaxis was ineffective in preventing SSI in patients with no risk factors for SSI who were undergoing ORIF for closed lower limb fractures. Copyright © 2015 Elsevier Ltd. All rights reserved.

Chromosome VIII disomy influences the nonsense suppression efficiency and transition metal tolerance of the yeast Saccharomyces cerevisiae.

PubMed

Zadorsky, S P; Sopova, Y V; Andreichuk, D Y; Startsev, V A; Medvedeva, V P; Inge-Vechtomov, S G

2015-06-01

The SUP35 gene of the yeast Saccharomyces cerevisiae encodes the translation termination factor eRF3. Mutations in this gene lead to the suppression of nonsense mutations and a number of other pleiotropic phenotypes, one of which is impaired chromosome segregation during cell division. Similar effects result from replacing the S. cerevisiae SUP35 gene with its orthologues. A number of genetic and epigenetic changes that occur in the sup35 background result in partial compensation for this suppressor effect. In this study we showed that in S. cerevisiae strains in which the SUP35 orthologue from the yeast Pichia methanolica replaces the S. cerevisiae SUP35 gene, chromosome VIII disomy results in decreased efficiency of nonsense suppression. This antisuppressor effect is not associated with decreased stop codon read-through. We identified SBP1, a gene that localizes to chromosome VIII, as a dosage-dependent antisuppressor that strongly contributes to the overall antisuppressor effect of chromosome VIII disomy. Disomy of chromosome VIII also leads to a change in the yeast strains' tolerance of a number of transition metal salts. Copyright © 2015 John Wiley & Sons, Ltd.

21 CFR 872.6290 - Prophylaxis cup.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 8 2011-04-01 2011-04-01 false Prophylaxis cup. 872.6290 Section 872.6290 Food... DEVICES DENTAL DEVICES Miscellaneous Devices § 872.6290 Prophylaxis cup. (a) Identification. A prophylaxis cup is a device made of rubber intended to be held by a dental handpiece and used to apply polishing...

21 CFR 872.6290 - Prophylaxis cup.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Prophylaxis cup. 872.6290 Section 872.6290 Food... DEVICES DENTAL DEVICES Miscellaneous Devices § 872.6290 Prophylaxis cup. (a) Identification. A prophylaxis cup is a device made of rubber intended to be held by a dental handpiece and used to apply polishing...

Prospective surveillance study of haemophilia A patients switching from moroctocog alfa or other factor VIII products to moroctocog alfa albumin-free cell culture (AF-CC) in usual care settings.

PubMed

Parra Lopez, Rafael; Nemes, Laszlo; Jimenez-Yuste, Victor; Rusen, Luminita; Cid, Ana R; Charnigo, Robert J; Baumann, James A; Smith, Lynne; Korth-Bradley, Joan M; Rendo, Pablo

2015-10-01

This prospective, open-label, postauthorisation safety surveillance study assessed clinically significant inhibitor development in patients with severe haemophilia A transitioning from moroctocog alfa or other factor VIII (FVIII) replacement products to reformulated moroctocog alfa (AF-CC). Males aged ≥ 12 years with severe haemophilia A (FVIII:C) < 1 IU/dl), > 150 exposure days (EDs) to recombinant or plasma-derived FVIII products, and no detectable inhibitor at screening were enrolled. Primary end point was the incidence of clinically significant FVIII inhibitor development. Secondary end points included annualised bleeding rate (ABR), less-than-expected therapeutic effect (LETE), and FVIII recovery. Patients were assigned to one of two cohorts based on whether they were transitioning to moroctocog alfa (AF-CC) from moroctocog alfa (cohort 1; n=146) or from another recombinant or plasma-derived FVIII product (cohort 2; n=62). Mean number of EDs on study was 94 (range, 1-139). Six positive FVIII inhibitor results, as determined by local laboratories, were reported in four patients; none were confirmed by a central laboratory, no inhibitor-related clinical manifestations were reported, and all anti-FVIII antibody assays were negative. Median ABRs were 23.4 and 3.4 in patients categorised at baseline as following on-demand and prophylactic regimens, respectively; 86.5% of bleeding episodes resolved after one infusion. LETE incidence was 0.06% and 0.19% in the on-demand and prophylaxis settings, respectively. FVIII recovery remained constant throughout the study. No new safety concerns were identified. This study found no increased risk of clinically significant FVIII inhibitor development in patients transitioning from moroctocog alfa or other FVIII replacement products to moroctocog alfa (AF-CC).

In vivo recovery of factor VIII and factor IX: intra- and interindividual variance in a clinical setting.

PubMed

Björkman, S; Folkesson, A; Berntorp, E

2007-01-01

In vivo recovery (IVR) is traditionally used as a parameter to characterize the pharmacokinetic properties of coagulation factors. It has also been suggested that dosing of factor VIII (FVIII) and factor IX (FIX) can be adjusted according to the need of the individual patient, based on an individually determined IVR value. This approach, however, requires that the individual IVR value is more reliably representative for the patient than the mean value in the population, i.e. that there is less variance within than between the individuals. The aim of this investigation was to compare intra- and interindividual variance in IVR (as U dL1 per U kg1) for FVIII and plasma-derived FIX in a cohort of non-bleeding patients with haemophilia. The data were collected retrospectively from six clinical studies, yielding 297 IVR determinations in 50 patients with haemophilia A and 93 determinations in 13 patients with haemophilia B. For FVIII, the mean variance within patients exceeded the between-patient variance. Thus, an individually determined IVR value is apparently no more informative than an average, or population, value for the dosing of FVIII. There was no apparent relationship between IVR and age of the patient (1.5-67 years). For FIX, the mean variance within patients was lower than the between-patient variance, and there was a significant positive relationship between IVR and age (13-69 years). From these data, it seems probable that using an individual IVR confers little advantage in comparison to using an age-specific population mean value. Dose tailoring of coagulation factor treatment has been applied successfully after determination of the entire single-dose curve of FVIII:C or FIX:C in the patient and calculation of the relevant pharmacokinetic parameters. However, the findings presented here do not support the assumption that dosing of FVIII or FIX can be individualized on the basis of a clinically determined IVR value.

What do women know about breast cancer prophylaxis and a healthy style of life?

PubMed Central

Sielska, Jolanta; Matecka, Monika; Dąbrowska, Eliza; Jakubek, Ewa; Urbaniak, Monika

2015-01-01

Aim The aim of the study was to determine the factors influencing women's knowledge concerning breast cancer prophylaxis and find out the sources of the knowledge. Background In the Greater Poland region, breast cancer has been the most frequently detected tumour for years. The percentage of breast cancer cases has increased by 31% in the last decade. Materials and methods The study encompassed 337 women aged 40–59 who participated in the mammographic examinations. An original research tool was used which assessed the level of knowledge concerning breast cancer prophylaxis, the knowledge of health-oriented behaviour in this regard and the influence of the medical personnel on women's education. Results Age is a factor diversifying the knowledge of the breast self-examination method. Doctors and nurses were rarely indicated as a source of knowledge concerning breast cancer prophylaxis. The subjects presented a high level of knowledge of the factors increasing the risk of developing cancer. Conclusions A correlation between the level of education and the knowledge of one's own breast to a degree which enables a woman to detect even a slight change was observed. Vital findings also concern the sources of knowledge concerning breast cancer prophylaxis. The results of the studies indicated little informative support on the part of the medical personnel; therefore, one should call for supplementing training courses for doctors and nurses focusing on the issues of prophylaxis, including the method of breast self-examination. PMID:26549989

Cost analysis of prophylaxis with activated prothrombin complex concentrate vs. on-demand therapy with activated factor VII in severe haemophilia A patients with inhibitors, in Spain.

PubMed

Villarrubia, R; Oyagüez, I; Álvarez-Román, M T; Mingot-Castellano, M E; Parra, R; Casado, M A

2015-05-01

A cost analysis model was developed to compare annual cost of prophylaxis with activated prothrombin complex concentrate (aPCC) vs. on-demand therapy with activated recombinant factor VII (rFVIIa) in severe haemophilia A patients with inhibitors for the Spanish National Health System (NHS). Model inputs were drug cost for prophylaxis (aPCC) and for on-demand treatment (rFVIIa or aPCC); bleeding episodes management (excluding bypassing agent cost); surgical costs and disease management (excluding bleeding episodes). Annual bleeding episodes treated on-demand was assumed to be 25, whereas breakthrough bleeds on prophylaxis was 8. Dose for prophylaxis was 75.72 U kg(-1) , three times per week. The total on-demand dose/bleeding episode was 679.66 μg kg(-1) (rFVIIa) and 235.28 U kg(-1) (aPCC). The average bleeding cost (€2998) considered different bleeding sites (62.5% joints, 28.6% muscles and soft tissues, 3.6% mucocutaneous tissues and 5.4% other areas). A 7.5% deduction was applied to ex-factory drug prices. Unitary costs (€2013) derived from local databases. Sensitivity analyses (SA) were performed. Annual cost of aPCC prophylaxis (€524,358) was 16% lower than on-demand treatment with rFVIIa (€627,876). Yearly drug costs were €497,017 for aPCC (€73,166 for on-demand treatment and €423,850 for prophylaxis), and €548,870 for rFVIIa. Disease management cost (€2645 per year) and surgical procedures (€708 per year) were common for both strategies. In the SA prophylactic treatment led to savings between €26,225 and €-1,008,960. Prophylaxis with aPCC reduces number of bleeding episodes in severe haemophilia A patients with inhibitors. aPCC prophylaxis resulted in savings in excess of €100,000 per-patient per year, being 16% less costly than on-demand treatment with rFVIIa, for the Spanish NHS. © 2015 John Wiley & Sons Ltd.

Genotyping the factor VIII intron 22 inversion locus using fluorescent in situ hybridization.

PubMed

Sheen, Campbell R; McDonald, Margaret A; George, Peter M; Smith, Mark P; Morris, Christine M

2011-02-15

The factor VIII intron 22 inversion is the most common cause of hemophilia A, accounting for approximately 40% of all severe cases of the disease. Southern hybridization and multiplex long distance PCR are the most commonly used techniques to detect the inversion in a diagnostic setting, although both have significant limitations. Here we describe our experience establishing a multicolor fluorescent in situ hybridization (FISH) based assay as an alternative to existing methods for genetic diagnosis of the inversion. Our assay was designed to apply three differentially labelled BAC DNA probes that when hybridized to interphase nuclei would exhibit signal patterns that are consistent with the normal or the inversion locus. When the FISH assay was applied to five normal and five inversion male samples, the correct genotype was assignable with p<0.001 for all samples. When applied to carrier female samples the assay could not assign a genotype to all female samples, probably due to a lower proportion of informative nuclei in female samples caused by the added complexity of a second X chromosome. Despite this complication, these pilot findings show that the assay performs favourably compared to the commonly used methods. Copyright © 2010 Elsevier Inc. All rights reserved.

Association of ABO blood groups with von Willebrand factor, factor VIII and ADAMTS-13 in patients with lung cancer.

PubMed

Liu, Xia; Chen, Xiaogang; Yang, Jiezuan; Guo, Renyong

2017-09-01

Coagulative and fibrinolytic disorders appear to be associated with the development of lung cancer. The aim of the present study was to determine plasma levels of von Willebrand factor (VWF) and a disintegrin and metalloproteinase with a thrombospondin type 1 motif 13 (ADAMTS-13), and factor VIII (FVIII) activity, in association with O and non-O blood groups in patients with lung cancer. Plasma levels of VWF and ADAMTS-13, and FVIII activity were measured in 115 patients with lung cancer and 98 healthy subjects. Phenotyping of the ABO blood groups was also performed for the two groups. Significantly increased VWF levels and FVIII activity, as well as significantly decreased ADAMTS-13 levels, were observed in patients with distant metastasis as compared with those without distant metastasis and the healthy controls. Plasma VWF levels and FVIII activity were significantly increased in subjects with non-O type blood compared with those with type O blood in the two groups. However, a significant decrease in ADAMTS-13 levels was observed only in the control group among those with non-O type blood, compared with those with type O blood. The results of the present study indicate that increased VWF and decreased ADAMTS-13 levels facilitate the invasiveness and metastasis of lung cancer. Non-O blood groups constitute a risk factor for increased VWF and FVIII in plasma. Continued monitoring of VWF and ADAMTS-13 levels, and of FVIII activity in patients with lung cancer with distinct blood groups may help to minimize the incidence of thrombotic events and improve assessment of disease progression.

Manufacturing challenges in the commercial production of recombinant coagulation factor VIII.

PubMed

Jiang, R; Monroe, T; McRogers, R; Larson, P J

2002-03-01

Advances in gene technology have led to the development of a method to manufacture recombinant coagulation Factor VIII (rFVIII) for haemophilia A. Because rFVIII is a large and complex protein, its commercialization has required that many challenges in manufacturing, purification and processing be overcome. In order to license the first generation of rFVIII (Kogenate) in 1993, Bayer Corporation invested over 10 years in research and manufacturing development. Seven additional years were subsequently devoted to research and manufacturing improvements in order to accomplish the recent licensing of a second rFVIII product (KOGENATE Bayer or Kogenate FS). This product differs from its predecessor, in that human albumin is removed from the purification and the formulation steps. In addition, fewer chromatography steps are involved resulting in greater yields per mL of conditioned medium, and a solvent-detergent viral inactivation step replaces the heat-processing step used for the previous product. Despite these changes in the manufacturing, the protein backbone and carbohydrate structure of the final rFVIII molecule are identical. The complexity of the production processes is reflected by over 100 000 manufacturing data entries and by 600 quality control tests for each batch of rFVIII. Manufacturers are continuing to develop the next generation of rFVIII, which will be produced without the addition of any human or animal proteins or byproducts. Investments in research, development and manufacturing technology are expected to result in the development of new products with enhanced safety profiles, and in an increase in the production capacity for products that are chronically in short supply.

Antibiotic prophylaxis adequacy in knee arthroplasty and surgical wound infection: Prospective cohort study.

PubMed

Del-Moral-Luque, J A; Checa-García, A; López-Hualda, Á; Villar-Del-Campo, M C; Martínez-Martín, J; Moreno-Coronas, F J; Montejo-Sancho, J; Rodríguez-Caravaca, G

Antibiotic prophylaxis is the most suitable tool for preventing surgical wound infection. This study evaluated adequacy of antibiotic prophylaxis in surgery for knee arthroplasty and its effect on surgical site infection. Prospective cohort study. We assessed the degree of adequacy of antibiotic prophylaxis, the causes of non-adequacy, and the effect of non-adequacy on surgical site infection. Incidence of surgical site infection was studied after a maximum incubation period of a year. To assess the effect of prophylaxis non-adequacy on surgical site infection we used the relative risk adjusted with the aid of a logistic regression model. The study covered a total of 1749 patients. Antibiotic prophylaxis was indicated in all patients and administered in 99.8% of cases, with an overall protocol adequacy of 77.6%. The principal cause of non-compliance was the duration of prescription of the antibiotics (46.5%). Cumulative incidence of surgical site infection was 1.43%. No relationship was found between prophylaxis adequacy and surgical infection (RR=1.15; 95% CI: .31-2.99) (P>.05). Surveillance and infection control programs enable risk factors of infection and improvement measures to be assessed. Monitoring infection rates enables us to reduce their incidence. Adequacy of antibiotic prophylaxis was high but could be improved. We did not find a relationship between prophylaxis adequacy and surgical site infection rate. Copyright © 2017 SECOT. Publicado por Elsevier España, S.L.U. All rights reserved.

Pre-exposure rabies prophylaxis: a systematic review.

PubMed

Kessels, Jocelyn A; Recuenco, Sergio; Navarro-Vela, Ana Maria; Deray, Raffy; Vigilato, Marco; Ertl, Hildegund; Durrheim, David; Rees, Helen; Nel, Louis H; Abela-Ridder, Bernadette; Briggs, Deborah

2017-03-01

To review the safety and immunogenicity of pre-exposure rabies prophylaxis (including accelerated schedules, co-administration with other vaccines and booster doses), its cost-effectiveness and recommendations for use, particularly in high-risk settings. We searched the PubMed, Centre for Agriculture and Biosciences International, Cochrane Library and Web of Science databases for papers on pre-exposure rabies prophylaxis published between 2007 and 29 January 2016. We reviewed field data from pre-exposure prophylaxis campaigns in Peru and the Philippines. Pre-exposure rabies prophylaxis was safe and immunogenic in children and adults, also when co-administered with routine childhood vaccinations and the Japanese encephalitis vaccine. The evidence available indicates that shorter regimens and regimens involving fewer doses are safe and immunogenic and that booster intervals could be extended up to 10 years. The few studies on cost suggest that, at current vaccine and delivery costs, pre-exposure prophylaxis campaigns would not be cost-effective in most situations. Although pre-exposure prophylaxis has been advocated for high-risk populations, only Peru and the Philippines have implemented appropriate national programmes. In the future, accelerated regimens and novel vaccines could simplify delivery and increase affordability. Pre-exposure rabies prophylaxis is safe and immunogenic and should be considered: (i) where access to postexposure prophylaxis is limited or delayed; (ii) where the risk of exposure is high and may go unrecognized; and (iii) where controlling rabies in the animal reservoir is difficult. Pre-exposure prophylaxis should not distract from canine vaccination efforts, provision of postexposure prophylaxis or education to increase rabies awareness in local communities.

Pre-exposure rabies prophylaxis: a systematic review

PubMed Central

Recuenco, Sergio; Navarro-Vela, Ana Maria; Deray, Raffy; Vigilato, Marco; Ertl, Hildegund; Durrheim, David; Rees, Helen; Nel, Louis H; Abela-Ridder, Bernadette; Briggs, Deborah

2017-01-01

Abstract Objective To review the safety and immunogenicity of pre-exposure rabies prophylaxis (including accelerated schedules, co-administration with other vaccines and booster doses), its cost–effectiveness and recommendations for use, particularly in high-risk settings. Methods We searched the PubMed, Centre for Agriculture and Biosciences International, Cochrane Library and Web of Science databases for papers on pre-exposure rabies prophylaxis published between 2007 and 29 January 2016. We reviewed field data from pre-exposure prophylaxis campaigns in Peru and the Philippines. Findings Pre-exposure rabies prophylaxis was safe and immunogenic in children and adults, also when co-administered with routine childhood vaccinations and the Japanese encephalitis vaccine. The evidence available indicates that shorter regimens and regimens involving fewer doses are safe and immunogenic and that booster intervals could be extended up to 10 years. The few studies on cost suggest that, at current vaccine and delivery costs, pre-exposure prophylaxis campaigns would not be cost-effective in most situations. Although pre-exposure prophylaxis has been advocated for high-risk populations, only Peru and the Philippines have implemented appropriate national programmes. In the future, accelerated regimens and novel vaccines could simplify delivery and increase affordability. Conclusion Pre-exposure rabies prophylaxis is safe and immunogenic and should be considered: (i) where access to postexposure prophylaxis is limited or delayed; (ii) where the risk of exposure is high and may go unrecognized; and (iii) where controlling rabies in the animal reservoir is difficult. Pre-exposure prophylaxis should not distract from canine vaccination efforts, provision of postexposure prophylaxis or education to increase rabies awareness in local communities. PMID:28250534

[Detection of intron 22 inversion of factor VIII gene in severe hemophilia A patients].

PubMed

Guo, Zhi-ping; Chen, Jian-fang; Qin, Xiu-yu; Zhang, Yao-fang; Yang, Lin-hua

2013-11-01

To investigate the incidence of intron 22 inversion (INV22) of factor VIII (FVIII) gene in severe hemophilia A (HA) patients, clarify its pathological mechanism, and identify INV22 carrier in the female family members. One-stage method was used to assay the FVIII activity (FVIII:C)in 126 severe HA patients with a median age of 14 years old (range: 4 months-63 years). INV22 was analyzed by long-distance polymerase chain reaction (LD-PCR) and pulsed field gel electrophoresis (PFGE), and pedigree were conducted in 3 involved HA families. Of all the 126 severe HA, 52 (41.3%) cases had the INV22. Four females including 3 mothers and 1 sister of probands were diagnosed as INV22 carriers among 11 suspected carrier mosaicisms from 3 INV22 positive HA families. In 8 females from one family without HA history, the patient's mother was a INV22 carrier, but her maternal grandmother, 2 maternal aunts, 2 female siblings and 1 elder female cousin were negative. LD-PCR and PFGE could be used to diagnose severe HA patients with INV22 and identify the carriers.

Relationship between ABO blood groups and von Willebrand factor, ADAMTS13 and factor VIII in patients undergoing hemodialysis.

PubMed

Rios, Danyelle R A; Fernandes, Ana Paula; Figueiredo, Roberta C; Guimarães, Daniela A M; Ferreira, Cláudia N; Simões E Silva, Ana C; Carvalho, Maria G; Gomes, Karina B; Dusse, Luci Maria Sant' Ana

2012-05-01

Several studies have demonstrated that non-O blood groups subjects present an increased VTE risk as compared to those carrying O blood group. The aim of this study was to investigate the ABO blood groups influence on factor VIII (FVIII) activity, von Willebrand factor (VWF), and ADAMTS13 plasma levels in patients undergoing hemodialysis (HD). Patients undergoing HD (N=195) and 80 healthy subjects (control group) were eligible for this cross-sectional study. The ABO blood group phenotyping was performed by the reverse technique. FVIII activity was measured through coagulometric method, and VWF and ADAMTS13 antigens were assessed by ELISA. FVIII activity and VWF levels were significantly higher and ADAMTS13 levels was decreased in HD patients, as compared to healthy subjects (P < 0.001, in three cases). HD patients carrying non-O blood groups showed a significant increase in FVIII activity (P = 0.001) and VWF levels (P < 0.001) when compared to carriers of O blood group. However, no significant difference was observed in ADAMTS13 levels (P = 0.767). In the control group, increased in FVIII activity (P = 0.001) and VWF levels (P = 0.002) and decreased in ADAMTS13 levels (P = 0.005) were observed in subjects carrying non-O blood groups as compared to carriers of O blood group.Our data confirmed that ABO blood group is an important risk factor for increased procoagulant factors in plasma, as FVIII and VWF. Admitting the possible role of kidneys in ADAMTS13 synthesis or on its metabolism, HD patients were not able to increase ADAMTS13 levels in order to compensate the increase of VWF levels mediated by ABO blood groups. Considering that non-O blood groups constitute a risk factor for thrombosis, it is reasonable to admit that A, B and AB HD patients need a careful and continuous follow-up in order to minimize thrombotic events.

Discrete choice experiment to evaluate factors that influence preferences for antibiotic prophylaxis in pediatric oncology.

PubMed

Regier, Dean A; Diorio, Caroline; Ethier, Marie-Chantal; Alli, Amanda; Alexander, Sarah; Boydell, Katherine M; Gassas, Adam; Taylor, Jonathan; Kellow, Charis; Mills, Denise; Sung, Lillian

2012-01-01

Bacterial and fungal infections in pediatric oncology patients cause morbidity and mortality. The clinical utility of antimicrobial prophylaxis in children is uncertain and the personal utility of these agents is disputed. Objectives were to use a discrete choice experiment to: (1) describe the importance of attributes to parents and healthcare providers when deciding between use and non-use of antibacterial and antifungal prophylaxis; and (2) estimate willingness-to-pay for prophylactic strategies. Attributes were chances of infection, death and side effects, route of administration and cost of pharmacotherapy. Respondents were randomized to a discrete choice experiment outlining hypothetical treatment options to prevent antibacterial or antifungal infections. Each respondent was presented 16 choice tasks and was asked to choose between two unlabeled treatment options and an opt-out alternative (no prophylaxis). 102 parents and 60 healthcare providers participated. For the antibacterial discrete choice experiment, frequency of administration was significantly associated with utility for parents but not for healthcare providers. Increasing chances of infection, death, side effects and cost were all significantly associated with decreased utility for parents and healthcare providers in both the antibacterial and antifungal discrete choice experiment. Parental willingness-to-pay was higher than healthcare providers for both strategies. Chances of infection, death, side effects and costs were all significantly associated with utility. Parents have higher willingness-to-pay for these strategies compared with healthcare providers. This knowledge can help to develop prophylaxis programs.

Factor VIII in Acute Cerebral Ischemia Pilot Study: Biomarker in Patients With Large Vessel Occlusion?

PubMed

Navalkele, Digvijaya; Boehme, Amelia; Albright, Karen; Leissinger, Cindy; Schluter, Laurie; Freeman, Melissa; Drury, Stacy; Khoury, Ramy El; Beasley, T Mark; Martin-Schild, Sheryl

2018-01-01

We conducted a prospective serial laboratory cohort study to assess the correlation of factor VIII (FVIII) levels in response to thrombolysis in patients with large vessel occlusion (LVO) and acute ischemic stroke (AIS). Patients with AIS with anterior circulation LVO were eligible for enrollment if treated within 4.5 hours from last seen normal with intravenous tissue plasminogen activator (tPA). Patients (n = 29) had a mean age of 71 years and median National Institute of Health Stroke Scale of 14. Baseline pre-tPA FVIII was not significantly correlated with clot burden score (-0.147, P = .447) or vessel recanalization (-0.133, P = .499). Median FVIII decreased significantly from baseline to 6 hours post-tPA (282% to 161%, P = .002), but delta in FVIII level did not correlate with vessel recanalization (0.013, P = .948). There was no difference between median FVIII level at baseline and 90 days post-AIS. FVIII level decreased significantly after tPA, but baseline FVIII level and early change in FVIII level were not significant predictors of clot burden, vessel recanalization after thrombolysis, or symptomatic hemorrhage.

Storage and regulated secretion of factor VIII in blood outgrowth endothelial cells

PubMed Central

van den Biggelaar, Maartje; Bouwens, Eveline A.M.; Kootstra, Neeltje A.; Hebbel, Robert P.; Voorberg, Jan; Mertens, Koen

2009-01-01

Background Gene therapy provides an attractive alternative for protein replacement therapy in hemophilia A patients. Recent studies have shown the potential benefit of directing factor (F)VIII gene delivery to cells that also express its natural carrier protein von Willebrand factor (VWF). In this study, we explored the feasibility of blood outgrowth endothelial cells as a cellular FVIII delivery device with particular reference to long-term production levels, intracellular storage in Weibel-Palade bodies and agonist-induced regulated secretion. Design and Methods Human blood outgrowth endothelial cells were isolated from peripheral blood collected from healthy donors, transduced at passage 5 using a lentiviral vector encoding human B-domain deleted FVIII-GFP and characterized by flow cytometry and confocal microscopy. Results Blood outgrowth endothelial cells displayed typical endothelial morphology and expressed the endothelial-specific marker VWF. Following transduction with a lentivirus encoding FVIII-GFP, 80% of transduced blood outgrowth endothelial cells expressed FVIII-GFP. Levels of FVIII-GFP positive cells declined slowly upon prolonged culturing. Transduced blood outgrowth endothelial cells expressed 1.6±1.0 pmol/1×106 cells/24h FVIII. Morphological analysis demonstrated that FVIII-GFP was stored in Weibel-Palade bodies together with VWF and P-selectin. FVIII levels were only slightly increased following agonist-induced stimulation, whereas a 6- to 8-fold increase of VWF levels was observed. Subcellular fractionation revealed that 15–22% of FVIII antigen was present within the dense fraction containing Weibel-Palade bodies. Conclusions We conclude that blood outgrowth endothelial cells, by virtue of their ability to store a significant portion of synthesized FVIII-GFP in Weibel-Palade bodies, provide an attractive cellular on-demand delivery device for gene therapy of hemophilia A. PMID:19336741

Antibiotic prophylaxis in cirrhosis: Good and bad.

PubMed

Fernández, Javier; Tandon, Puneeta; Mensa, Jose; Garcia-Tsao, Guadalupe

2016-06-01

Patients with cirrhosis, particularly those with decompensated cirrhosis, are at increased risk of bacterial infections that may further precipitate other liver decompensations including acute-on-chronic liver failure. Infections constitute the main cause of death in patients with advanced cirrhosis, and strategies to prevent them are essential. The main current strategy is the use of prophylactic antibiotics targeted at specific subpopulations at high risk of infection: prior episode of spontaneous bacterial peritonitis, upper gastrointestinal bleeding, and low-protein ascites with associated poor liver function. Antibiotic prophylaxis effectively prevents not only the development of bacterial infections in all these indications but also further decompensation (variceal bleeding, hepatorenal syndrome) and improves survival. However, antibiotic prophylaxis is also associated with a clinically relevant and increasing drawback, the development of infections due to multidrug-resistant organisms. Several strategies have been suggested to balance the risks and benefits of antibiotic prophylaxis. Antibiotic stewardship principles such as the restriction of antibiotic prophylaxis to subpopulations at a very high risk for infection, the avoidance of antibiotic overuse, and early deescalation policies are key to achieve this balance; nonantibiotic prophylactic measures such as probiotics, prokinetics, bile acids, statins, and hematopoietic growth factors could also contribute to ameliorate the development and spread of multidrug-resistant bacteria in cirrhosis. (Hepatology 2016;63:2019-2031). © 2015 by the American Association for the Study of Liver Diseases. This article has been contributed to by U.S. government employees, and their contribution is in the public domain in the U.S.A.

Targeting factor VIII expression to platelets for hemophilia A gene therapy does not induce an apparent thrombotic risk in mice.

PubMed

Baumgartner, C K; Mattson, J G; Weiler, H; Shi, Q; Montgomery, R R

2017-01-01

Essentials Platelet-Factor (F) VIII gene therapy is a promising treatment in hemophilia A. This study aims to evaluate if platelet-FVIII expression would increase the risk for thrombosis. Targeting FVIII expression to platelets does not induce or elevate thrombosis risk. Platelets expressing FVIII are neither hyper-activated nor hyper-responsive. Background Targeting factor (F) VIII expression to platelets is a promising gene therapy approach for hemophilia A, and is successful even in the presence of inhibitors. It is well known that platelets play important roles not only in hemostasis, but also in thrombosis and inflammation. Objective To evaluate whether platelet-FVIII expression might increase thrombotic risk and thereby compromise the safety of this approach. Methods In this study, platelet-FVIII-expressing transgenic mice were examined either in steady-state conditions or under prothrombotic conditions induced by inflammation or the FV Leiden mutation. Native whole blood thrombin generation assay, rotational thromboelastometry analysis and ferric chloride-induced vessel injury were used to evaluate the hemostatic properties. Various parameters associated with thrombosis risk, including D-dimer, thrombin-antithrombin complexes, fibrinogen, tissue fibrin deposition, platelet activation status and activatability, and platelet-leukocyte aggregates, were assessed. Results We generated a new line of transgenic mice that expressed 30-fold higher levels of platelet-expressed FVIII than are therapeutically required to restore hemostasis in hemophilic mice. Under both steady-state conditions and prothrombotic conditions induced by lipopolysaccharide-mediated inflammation or the FV Leiden mutation, supratherapeutic levels of platelet-expressed FVIII did not appear to be thrombogenic. Furthermore, FVIII-expressing platelets were neither hyperactivated nor hyperactivatable upon agonist activation. Conclusion We conclude that, in mice, more than 30-fold higher levels of

Recommendations for reporting economic evaluations of haemophilia prophylaxis: a nominal groups consensus statement on behalf of the Economics Expert Working Group of The International Prophylaxis Study Group.

PubMed

Nicholson, A; Berger, K; Bohn, R; Carcao, M; Fischer, K; Gringeri, A; Hoots, K; Mantovani, L; Schramm, W; van Hout, B A; Willan, A R; Feldman, B M

2008-01-01

The need for clearly reported studies evaluating the cost of prophylaxis and its overall outcomes has been recommended from previous literature. To establish minimal ''core standards'' that can be followed when conducting and reporting economic evaluations of hemophilia prophylaxis. Ten members of the IPSG Economic Analysis Working Group participated in a consensus process using the Nominal Groups Technique (NGT). The following topics relating to the economic analysis of prophylaxis studies were addressed; Whose perspective should be taken? Which is the best methodological approach? Is micro- or macro-costing the best costing strategy? What information must be presented about costs and outcomes in order to facilitate local and international interpretation? The group suggests studies on the economic impact of prophylaxis should be viewed from a societal perspective and be reported using a Cost Utility Analysis (CUA) (with consideration of also reporting Cost Benefit Analysis [CBA]). All costs that exceed $500 should be used to measure the costs of prophylaxis (macro strategy) including items such as clotting factor costs, hospitalizations, surgical procedures, productivity loss and number of days lost from school or work. Generic and disease specific quality of lífe and utility measures should be used to report the outcomes of the study. The IPSG has suggested minimal core standards to be applied to the reporting of economic evaluations of hemophilia prophylaxis. Standardized reporting will facilitate the comparison of studies and will allow for more rational policy decisions and treatment choices.

Thrombomodulin as a marker for vascular tumors. Comparative study with factor VIII and Ulex europaeus I lectin.

PubMed

Yonezawa, S; Maruyama, I; Sakae, K; Igata, A; Majerus, P W; Sato, E

1987-10-01

Thrombomodulin (TM) is a newly described endothelial cell-associated protein that functions as a potent natural anticoagulant by converting thrombin from a procoagulant protease to an anticoagulant. Various vascular tumors were characterized with immunoperoxidase staining with the use of a polyclonal anti-TM serum. The staining patterns of TM were compared with those of Factor VIII-related antigen (FVIII-RAG) and Ulex europaeus agglutinin-I (UEA-I), which have been used as markers for endothelial cells. The results showed that TM is a specific and a highly sensitive marker for angiosarcomas in comparison with FVIII-RAG or UEA-I. In contrast, UEA-I is more sensitive for benign vascular tumors than TM or FVIII-RAG. The other mesenchymal tumors of nonvascular origin showed negative staining for three endothelial markers. These results indicate that TM is a new specific and sensitive tool for the diagnosis of angiosarcomas.

Venous thromboembolism prophylaxis in mental health in-patient services: a qualitative study.

PubMed

Purcell, Audrey; Clarke, Mary; Maidment, Ian

2018-06-01

Background Venous thromboembolism (VTE) is an important and potentially preventable cause of morbidity and mortality in hospitalised patients. It is a significant, international patient safety issue affecting medical, surgical and mental health in-patients. There is a paucity of published evidence on the incidence of VTE, and the role of VTE risk-assessment and prophylaxis, in mental healthcare settings. Epidemiological evidence indicates that antipsychotic medications are an independent risk factor for VTE. Objective To explore healthcare practitioners' experiences and perspectives regarding VTE prophylaxis for in-patients in mental health services in Ireland. Setting This study was conducted in two national teaching hospitals in Dublin, Ireland. Method This experiential, qualitative study was conducted using face-to-face, semi-structured interviews. Purposive sampling was used to allow strategic selection of participants from the pharmacy, medical and nursing disciplines. Data was analysed using inductive thematic analysis. Consolidated criteria for reporting qualitative studies guidelines were used as a reporting framework. Main outcome measure Participants' views on VTE prophylaxis for mental health in-patients. Results Five key themes were derived: risk factors in mental health, attitudes to risk-assessment, challenges with VTE prophylaxis, lack of awareness, and lack of evidence in mental health. Conclusion The results indicate considerable diversities in perceived risk of VTE, and in experiences with VTE risk-assessment and prophylaxis. VTE risk was considered in practice specifically for immobile, older adults and eating disorder patients on bed rest. Specific research is required to address this area of clinical uncertainty in mental health.

The Effect of rFVIIa on Pro- and Anti-Inflamatory Cytokines in Serum and Cerebrospinal Fluid in a Swine Model of Traumatic Brain Injury

DTIC Science & Technology

2011-01-01

6) While the rate of ventilator associated pneumonia ( VAP ) has been estimated at between 8% and 28% in non-trauma patients , intubated patients ...Recombinant Factor VIla (rFVIIa) is approved for use in the treatment and prophylaxis of bleeding in patients with Factor VIII and IX deficiencies...injured patients [3). In all of these trials, rFVIIa was administered only in the hospi- tal setting, after identification of either clinically relevant

Novel factor VIII variants with a modified furin cleavage site improve the efficacy of gene therapy for hemophilia A.

PubMed

Nguyen, G N; George, L A; Siner, J I; Davidson, R J; Zander, C B; Zheng, X L; Arruda, V R; Camire, R M; Sabatino, D E

2017-01-01

Essentials Factor (F) VIII is an inefficiently expressed protein. Furin deletion FVIII variants were purified and characterized using in vitro and in vivo assays. These minimally modified novel FVIII variants have enhanced function. These variants provide a strategy for increasing FVIII expression in hemophilia A gene therapy. Background The major challenge for developing gene-based therapies for hemophilia A is that human factor VIII (hFVIII) has intrinsic properties that result in inefficient biosynthesis. During intracellular processing, hFVIII is predominantly cleaved at a paired basic amino acid cleaving enzyme (PACE) or furin cleavage site to yield a heterodimer that is the major form of secreted protein. Previous studies with B-domain-deleted (BDD) canine FVIII and hFVIII-R1645H, both differing from hFVIII by a single amino acid at this site, suggested that these proteins are secreted mainly in a single polypeptide chain (SC) form and exhibit enhanced function. Objective We hypothesized that deletion(s) of the furin site modulates FVIII biology and may enhance its function. Methods A series of recombinant hFVIII-furin deletion variants were introduced into hFVIII-BDD [Δ1645, 1645-46(Δ2), 1645-47(Δ3), 1645-48(Δ4), or Δ1648] and characterized. Results In vitro, recombinant purified Δ3 and Δ4 were primarily SC and, interestingly, had 2-fold higher procoagulant activity compared with FVIII-BDD. In vivo, the variants also have improved hemostatic function. After adeno-associated viral (AAV) vector delivery, the expression of these variants is 2-4-fold higher than hFVIII-BDD. Protein challenges of each variant in mice tolerant to hFVIII-BDD showed no anti-FVIII immune response. Conclusions These data suggest that the furin deletion hFVIII variants are superior to hFVIII-BDD without increased immunogenicity. In the setting of gene-based therapeutics, these novel variants provide a unique strategy to increase FVIII expression, thus lowering the vector dose, a

Efficacy of granulocyte colony stimulating factor as a secondary prophylaxis along with full-dose chemotherapy following a prior cycle of febrile neutropenia.

PubMed

Gupta, Seema; Singh, Pankaj K; Bhatt, Madan L B; Pant, Mohan C; Gupta, Rajeev; Negi, Mahendra P S

2010-10-01

Secondary prophylaxis with recombinant human granulocyte colony stimulating factor (G-CSF) is recommended where patients have experienced febrile neutropenia in an earlier chemotherapy cycle and for whom the maintenance of chemotherapy dose intensity is important; or where febrile neutropenia has not occurred but prolonged neutropenia is causing excessive dose delay or reduction, where maintenance of dose intensity is important. The objective of this study was to determine the efficacy and feasibility of G-CSF as secondary prophylaxis when used along with full dose moderately myelotoxic chemotherapy following a prior cycle with febrile-neutropenia. Fifty-two patients aged 22-75 years with febrile neutropenia that required intravenous antibiotics following moderately myelotoxic chemotherapy were included. These patients received the next cycle of the same chemotherapy regime without dose modification but with support of filgrastim 24 h after completion of chemotherapy (300 μg/day/subcutaneously (s.c.) for weight < 60 kg, 480 μg/day/s.c. for weight > 60 kg, for at least 10 consecutive days), patients in whom neutropenia was associated with a life-threatening infection and those who developed prolonged myelosuppression were excluded. The use of the hematopoietic growth factor G-CSF was shown to shorten the neutrophil recovery time, resulting in significant reduction of incidence of febrile neutropenia, hospitalization and use of broad spectrum antibiotics. There was no drug related death or adverse events associated with either cycle. In conclusion, recombinant human G-CSF is effective and relatively safe as a secondary prophylaxis with full dose chemotherapy in patients who develop febrile neutropenia following prior cycles of moderately myelotoxic chemotherapy.

Antibiotic prophylaxis in open inguinal hernia repair: a literature review and summary of current knowledge

PubMed Central

Makarewicz, Wojciech; Ropel, Jerzy; Bobowicz, Maciej; Kąkol, Michał; Śmietański, Maciej

2016-01-01

More than 1 million inguinal hernia repairs are performed in Europe and the US annually. Although antibiotic prophylaxis is not required in clean, elective procedures, the routine use of implants (90% of inguinal hernia repairs are performed with mesh) makes the topic controversial. The European Hernia Society does not recommend routine antibiotic prophylaxis for elective inguinal hernia repairs. However, the latest randomized controlled trial, published by Mazaki et al., indicates that the use of prophylaxis is effective for the prevention of surgical site infection. Unnecessary prophylaxis contributes to the development of bacterial resistance and significantly increases healthcare costs. This review documents clinical trials on inguinal hernia repairs with mesh and summarizes the current knowledge. It also tries to solve certain problems, namely: what constitutes a real risk factor, late-onset infection, and how the “surgical environment” impacts on the need to use antibiotic prophylaxis. PMID:27829934

Potency determination of factor VIII and factor IX for new product labelling and postinfusion testing: challenges for caregivers and regulators.

PubMed

Dodt, J; Hubbard, A R; Wicks, S J; Gray, E; Neugebauer, B; Charton, E; Silvester, G

2015-07-01

A workshop organized by the European Medicines Agency and the European Directorate for the Quality of Medicines and HealthCare was held in London, UK on November 28-29, 2013, to provide an overview of the current knowledge of the characterization of new factor VIII (FVIII) and factor IX (FIX) concentrates with respect to potency assays and testing of postinfusion material. The objective was to set the basis for regulatory authorities' discussion on the most appropriate potency assay for the individual products, and European Pharmacopoeia (Ph. Eur.) discussion on whether to propose revision of the Ph. Eur. monographs with respect to potency assays in the light of information on new FVIII and FIX concentrates. The workshop showed that for all products valid assays vs. the international concentrate standards were obtained and potency could be expressed in International Units. The Ph. Eur. chromogenic potency assay gave valid assay results which correlate with in vivo functionality of rFVIII products. For some modified rFVIII products and all modified rFIX products, one-stage clotting assay methods result in different potencies depending on the activated partial thromboplastin time reagent. As a consequence, monitoring of patients' postinfusion levels is challenging but it was pointed out that manufacturers are responsible for providing the users with appropriate information for use and laboratory testing of their product. Strategies to avoid misleading determination of patents' plasma levels, e.g. information on suitable assays, laboratory standards or correction factors were discussed. © 2015 John Wiley & Sons Ltd.

Extracorporeal adsorption of anti-factor VIII allo-antibodies on randomly functionalized polystyrene resins.

PubMed

Huguet, Hélène-Céline; Lasne, Dominique; Rothschild, Chantal; Siali, Rosa; Jozefonvicz, Jacqueline

2004-02-01

The occurrence of anti-factor VIII (FVIII) allo-antibodies is a severe complication of the treatment of haemophilia A patients, leading to the inhibition of transfused FVIII activity. The effective elimination of these inhibitory antibodies plays a decisive role in the management of affected patients. To achieve this, immunoadsorption devices employing synthetic adsorbers, which selectively eliminate inhibitors, are of interest in the treatment strategy of haemophilia A patients with inhibitors. Adsorbers consisting of polystyrene-based beads substituted with sulphonate and L-tyrosyl methylester groups, which mimic part of epitope of FVIII molecule recognized by inhibitors, exhibit selective binding capacities towards anti-FVIII antibodies. The adsorption of FVIII inhibitors was investigated by simulating an extracorporeal circulation of haemophilic plasma over these functionalized resins. These innovative adsorbers are able to remove around 25% of anti-FVIII antibodies in 15 minutes depending on the plasma tested. Furthermore, they do not modify the amount of essential plasmatic proteins or residual immunoglobulins G. Experiments which were carried out using different plasmas with various inhibitor titres demonstrate a good reproducibility regarding the adsorption capacity of the synthetic resin. The characteristics of adsorption are similar on either native or regenerated resins. Both the purely synthetic nature of the resin and its easy processability demonstrate the real advantages over currently available protocols. This synthetic adsorber is a major technological advance in selective removal of FVIII inhibitory antibodies.

[Scar prophylaxis and treatment].

PubMed

Hammer-Hansen, Niels; Damsgaard, Tine Engberg; Rødgaard, Jes Christian

2015-10-12

Scarring is an expected result of trauma to the skin. Scars are a heterogenic group varying from small white non elevated scars to hypertrophic scars and keloids. Many different algorithms for scar prophylaxis and treatment have been presented in the literature. We discuss different types of scar formation and recently published evidence-based guidelines in regards to prophylaxis and treatment of scars written by 24 experts on scar management.

Timeliness and use of antibiotic prophylaxis in selected inpatient surgical procedures. The Antibiotic Prophylaxis Study Group.

PubMed

Silver, A; Eichorn, A; Kral, J; Pickett, G; Barie, P; Pryor, V; Dearie, M B

1996-06-01

Twenty-five percent of all nosocomial infections are wound infections. Professional guidelines support the timely use of preoperative prophylaxis for prevention of postoperative wound infections. Barriers exist in implementing this practice. IPRO, the New York State peer review organization, as part of the Health Care Financing Administration's Health Care Quality Improvement Program, sought to determine the proportion of patients receiving timely antibiotic prophylaxis for aortic grafts, hip replacements and colon resections in 44 hospitals in New York State. IPRO conducted a retrospective medical record review of 44 hospitals through out New York State stratified for teaching, nonteaching status. A sample was drawn of 2651 patients, 2256 from Medicare and 395 from Medicaid, undergoing either abdominal aortic aneurysm repair, partial or total hip replacement or large bowel resection. The study determined the proportion of patients who had documentation of receiving antibiotics and those who received antibiotics timely, that is less than or equal to 2 hours preoperatively. Eighty-six percent of patients had documentation of receiving an antibiotic. Forty-six percent of aneurysm repairs and 60% of hip replacements had evidence of receiving timely antibiotic prophylaxis, that is within 2 hours prior to surgery. For colon resections, 73% of cases had either oral prophylaxis or timely parenteral therapy. An increased proportion of patients had received parenteral antibiotics prematurely as the surgical start time occurred later in the day. A total of 44 different antibiotics were recorded for prophylaxis. Antibiotic prophylaxis was performed in 81% to 94% of cases, however, anywhere from 27% to 54% of all cases did not receive antibiotics in a timely fashion. By delegating implementation of ordered antibiotic prophylaxis to the anesthesia team, timing may be improved and the incidence of postoperative wound infections may decrease.

Detection of Ne VIII in an Intervening Multiphase Absorption System Toward 3C 263

NASA Astrophysics Data System (ADS)

Narayanan, Anand; Wakker, Bart P.; Savage, Blair D.

2009-09-01

We report the detection of Ne VIII in an intervening multiphase absorption line system at z = 0.32566 in the Far Ultraviolet Spectroscopic Explorer spectrum of the quasar 3C 263 (zem = 0.646). The Ne VIII λ770 Å detection has a 3.9σ significance. At the same velocity, we also find absorption lines from C IV, O III, O IV, and N IV. The line parameter measurements yield log [N(Ne VIII) cm-2] = 13.98+0.10 -0.13 and b = 49.8 ± 5.5 km s-1. We find that the ionization mechanism in the gas phase giving rise to the Ne VIII absorption is inconsistent with photoionization. The absorber has a multiphase structure, with the intermediate ions produced in cool photoionized gas and the Ne VIII most likely in a warm collisionally ionized medium in the temperature range (0.5-1.0) × 106 K. This is the second ever detection of an intervening Ne VIII absorption system. Its properties resemble the previous Ne VIII absorber reported by Savage and colleagues. Direct observations of H I and O VI are needed to better constrain the physical conditions in the collisionally ionized gas phase of this absorber. Based on observations with the NASA-CNES-CSA Far Ultraviolet Spectroscopic Explorer operated by Johns Hopkins University, supported by NASA contract NAS5-32985.

Changing perspectives of stress gastritis prophylaxis.

PubMed

Smythe, M A; Zarowitz, B J

1994-09-01

To present recent advances in stress gastritis prophylaxis in the critically ill and review considerations in selection of a prophylactic agent. Information was obtained from MEDLINE search, reference lists from articles identified in search, and from review articles. Emphasis was placed on controlled trials conducted within the last 5 years. All literature was assessed for methodology, results, and conclusions. Results of prospective, randomized trials, and meta-analyses are summarized. Histamine2-receptor antagonists, antacids, and sucralfate appear equally effective in preventing stress gastritis in the critically ill. A definitive cause-effect relationship between histamine2-receptor antagonists and increased incidence of nosocomial pneumonia has not yet been established. The indications for using a prophylactic agent and consideration in selecting an agent should include an evaluation of the following: risk factors for gastritis including the type of intensive care patient, comparative efficacy, adverse effects, drug interactions, cost, and ease of administration. The least expensive, safest agent requiring minimal monitoring is sucralfate. Prevention of stress gastritis has never been shown to reduce morbidity or mortality significantly. Controversies still exist regarding the need to provide prophylaxis, the choice of an agent, and the relative importance of previously identified risk factors. Further well-designed studies are needed before consensus can be reached.

Impact of an electronic tool in prescribing primary prophylaxis with ciprofloxacin or granulocyte colony-stimulating factor for breast cancer patients receiving TC chemotherapy.

PubMed

Sulpher, Jeffrey; Giguere, Pierre; Hopkins, Sean; Dent, Susan

2016-07-01

The US Oncology Trial 9735 (doxorubicin and cyclophosphamide (AC) versus docetaxel and cyclophosphamide (TC)) reported febrile neutropenia (FN) in 5 % of patients receiving TC chemotherapy, in the absence of routine primary prophylaxis with granulocyte colony-stimulating factor (G-CSF) or antibiotics. In contrast, higher rates of FN have been reported in the 'real world' setting. This retrospective study compares the incidence and severity of FN and other TC-related toxicities before and after implementation of a primary prophylaxis computerized prescribing tool. Medical records of 207 patients receiving adjuvant TC between May 1, 2006, and November 1, 2011, were reviewed for toxicity. The incidence for each TC adverse event was measured by an incident rate ratio (IRR), and chi-square analysis was used to compare the differences in severity of TC toxicities before and after use of a primary prophylaxis computerized prescribing tool, and to compare G-CSF and ciprofloxacin groups. The implementation of a computerized prescribing tool significantly increased the proportion of patients prescribed primary prophylaxis (18.2 vs. 97.4 %; p < 0.001). Prior to the change in practice, the incidence of FN (incidence rate ratio 3.87; 95 % CI [1.3, 11.5]) and neutropenia (OR 4.8; 95 % CI [2.0, 11.7]) was significantly higher. Primary prophylaxis significantly reduced the rate of febrile neutropenia (20 vs. 5.3 %, p = 0.003). No significant differences were found in incidence and severity of other TC-related toxicities. Patients who did not receive G-CSF were at a greater risk for neutropenia (OR 5.1, 95 % CI [1.06, 24.3]). There were insufficient patients treated with antibiotics alone to compare to those treated with G-CSF. Implementation of a computerized prescribing tool significantly increased the use of primary prophylaxis by treating physicians in patients receiving TC chemotherapy, which was associated with reduced incidence of febrile neutropenia

Effectiveness of Mind Mapping in English Teaching among VIII Standard Students

ERIC Educational Resources Information Center

Hallen, D.; Sangeetha, N.

2015-01-01

The aim of the study is to find out the effectiveness of mind mapping technique over conventional method in teaching English at high school level (VIII), in terms of Control and Experimental group. The sample of the study comprised, 60 VIII Standard students in Tiruchendur Taluk. Mind Maps and Achievement Test (Pretest & Posttest) were…

Use of routine histopathology and factor VIII-related antigen/von Willebrand factor immunohistochemistry to differentiate primary hemangiosarcoma of bone from telangiectatic osteosarcoma in 54 dogs.

PubMed

Giuffrida, M A; Bacon, N J; Kamstock, D A

2017-12-01

Hemangiosarcoma (HSA) of bone and telangiectatic osteosarcoma (tOSA) can appear similar histologically, but differ in histogenesis (malignant endothelial cells versus osteoblasts), and may warrant different treatments. Immunohistochemistry (IHC) for endothelial cell marker factor VIII-related antigen/von Willebrand factor (FVIII-RAg/vWF) is a well-documented ancillary test to confirm HSA diagnoses in soft tissues, but its use in osseous HSA is rarely described. Archived samples of 54 primary appendicular bone tumours previously diagnosed as HSA or tOSA were evaluated using combination routine histopathology (RHP) and IHC. Approximately 20% of tumours were reclassified on the basis of FVIII-RAg/vWF immunoreactivity, typically from an original diagnosis of tOSA to a reclassified diagnosis of HSA. No sample with tumour osteoid clearly identified on RHP was immunopositive for FVIII-RAg/vWF. RHP alone was specific but not sensitive for diagnosis of HSA, compared with combination RHP and IHC. Routine histopathological evaluation in combination with FVIII-RAg/vWF IHC can help differentiate canine primary appendicular HSA from tOSA. © 2016 John Wiley & Sons Ltd.

PrEP (Pre-Exposure Prophylaxis) 101

MedlinePlus

... Español (Spanish) Recommend on Facebook Tweet Share Compartir Pre-exposure prophylaxis (or PrEP) is when people at ... A Brief Intro Protect yourself. Learn about PrEP (Pre-Exposure Prophylaxis) and how it works in this ...

Appropriate VTE prophylaxis is associated with lower direct medical costs.

PubMed

Amin, Alpesh; Hussein, Mohamed; Battleman, David; Lin, Jay; Stemkowski, Stephen; Merli, Geno J

2010-11-01

To calculate and compare the direct medical costs of guideline-recommended prophylaxis with prophylaxis that does not fully adhere with guideline recommendations in a large, real-world population. Discharge records were retrieved from the US Premier Perspective™ database (January 2003-December 2003) for patients aged≥40 years with a primary diagnosis of cancer, chronic heart failure, lung disease, or severe infectious disease who received some form of thromboprophylaxis. Univariate analysis and multivariate regression modeling were performed to compare direct medical costs between discharges who received appropriate prophylaxis (correct type, dose, and duration based on sixth edition American College of Chest Physicians [ACCP] recommendations) and partial prophylaxis (not in full accordance with ACCP recommendations). Market segmentation analysis was used to compare costs stratified by hospital and patient characteristics. Of the 683 005 discharges included, 148,171 (21.7%) received appropriate prophylaxis and 534,834 (78.3%) received partial prophylaxis. The total direct unadjusted costs were $15,439 in the appropriate prophylaxis group and $17,763 in the partial prophylaxis group. After adjustment, mean adjusted total costs per discharge were lower for those receiving appropriate prophylaxis ($11,713; 95% confidence interval [CI], $11,675-$11,753) compared with partial prophylaxis ($13,369; 95% CI, $13,332-$13 406; P<0.01). Appropriate prophylaxis appeared to be associated with numerically lower unadjusted costs than partial prophylaxis, regardless of hospital size, rural/urban location, teaching status, and patient age and gender. This large, real-world analysis suggests that appropriate prophylaxis, in adherence with ACCP guidelines, is potentially cost-saving compared with partial prophylaxis in at-risk medical patients.

Factors Associated with the Time of Admission among Notified Dengue Fever Cases in Region VIII Philippines from 2008 to 2014

PubMed Central

Gil Cuesta, Julita; Cerro, Boyd Roderick; Guha-Sapir, Debarati

2016-01-01

In cases of Dengue fever, late hospital admission can lead to treatment delay and even death. In order to improve early disease notification and management, it is essential to investigate the factors affecting the time of admission of Dengue cases. This study determined the factors associated with the time of admission among notified Dengue cases. The study covered the period between 2008 and 2014 in Region VIII, Philippines. The factors assessed were age, sex, hospital sector, hospital level, disease severity based on the 1997 WHO Dengue classification, and period of admission (distinguishing between the 2010 Dengue epidemic and non-epidemic time). We analysed secondary data from the surveillance of notified Dengue cases. We calculated the association through chi-square test, ordinal logistic regression and linear regression at p value < 0.05. The study included 16,357 admitted Dengue cases. The reported cases included a majority of children (70.09%), mild cases of the disease (64.00%), patients from the public sector (69.82%), and non-tertiary hospitals (62.76%). Only 1.40% of cases had a laboratory confirmation. The epidemic period in 2010 comprised 48.68% of all the admitted cases during this period. Late admission was more likely among adults than children (p<0.05). The severe type of the disease was more likely to be admitted late than the mild type (p<0.05). Late admission was also more likely in public hospitals than in private hospitals (p<0.05); and within tertiary level hospitals than non-tertiary hospitals (p<0.05). Late admission was more likely during the non-epidemic period than the 2010 epidemic period (p<0.05). A case fatality rate of 1 or greater was significantly associated with children, severe diseases, tertiary hospitals and public hospitals when admitted late (p<0.05). Data suggests that early admission among child cases was common in Region VIII. This behavior is encouraging, and should be continued. However, further study is needed on the

[Determinants of the elevated factor VIII activity in patients following venous thromboembolism].

PubMed

Lech, Monika; Kościelniak, Barbara; Bryk, Agata; Undas, Anetta

2016-01-01

Activity of factor VIII (FVIII) increased above 150% of reference range predisposes to venous thromboembolism (VTE). The aim of this study was to identify predictors of increased FVIII activity in patients following VTE. 241 (38% men) patients presented due to objectively documented VTE episode at least 3 months ago were included in this study. FVIII activity was measured using a clotting assay on the analyzer BCS XP. Among 241 patients with VTE, activity of FVIII above 150% (FVIII ≥ 150%) was observed in 96 (40%). These patients were older (p = 0.035) and their concentrations of fibrinogen and C-reactive protein (CRP) were higher by 12% and 88% (p < 0.001), respectively, compared with other patients. There was a positive correlation between FVIII and fibrinogen (r = 0.34; p < 0.001), FVIII and CRP (r = 0.30; p < 0.001). Type of treatment, time from the VTE episode and type of VTE were not associated with FVIII. Twenty patients (8%) had activity of FVIII increased above 200% (FVIII > 200%) and this group was also older (p = 0.015), more patients in that group had obesity (p = 0.015), idiopathic VTE (p = 0.043), less of them had positive family history (p = 0.010) and they were characterized by fibrinogen and CRP increased by 28% (p < 0.001) and 102% (p = 0.004), respectively, compared with patients with FVIII between 150-200%. Independent predictors of FVIII ≥ 150% were: fibrinogen (p < 0.001), bilirubin (p = 0.002), hemoglobin (p = 0.016), glucose (p = 0.040), CRP (p = 0.023), total homocysteine (p = 0.032). Fibrinogen was the only independent predictor of FVIII > 200% (p = 0.016). The activity of FVIII in patients after VTE episode is influenced by age, concentration of fibrinogen, bilirubin, hemoglobin, glucose, CRP and homocysteine. Our results suggest the role of environmental factors, mainly inflammatory response in maintaining elevated FVIII activity following VTE.

Reviewing current and emerging antiemetics for chemotherapy-induced nausea and vomiting prophylaxis.

PubMed

Natale, James J

2015-01-01

This review provides background information on chemotherapy-induced nausea and vomiting (CINV) classification and pathophysiology and reviews various antiemetic agents for CINV prophylaxis, including corticosteroids, serotonin receptor antagonists (5-HT3 RAs), tachykinin NK1 receptor antagonists (NK1 RAs), and olanzapine. Other less commonly used agents are briefly discussed. Practical considerations are reviewed as well, including emetogenicity of chemotherapeutic regimens, patient-specific risk factors for CINV, principles of CINV management, health economics outcome research, and quality of life. Available data on the newly FDA-approved antiemetic combination netupitant/palonosetron (NEPA) is also reviewed. Prevention of CINV is an important goal in managing patients with cancer and is especially difficult with respect to nausea and delayed CINV. Corticosteroids are a mainstay of CINV prophylaxis and are usually given in combination with other therapies. The 5-HT3 RA palonosetron has shown increased efficacy over other agents in the same class for prevention of delayed emesis with moderately emetogenic chemotherapy and NK1 RAs improve emesis prevention in combination with 5-HT3 RAs and dexamethasone. Olanzapine has shown efficacy for CINV prophylaxis and the treatment of breakthrough CINV. The new combination therapy, NEPA, has been shown to be efficacious for the prevention of acute, delayed, and overall CINV. Risk factors that have been identified for CINV include gender, age, and alcohol intake. It is important to assess the emetogenicity of chemotherapy regimens as well as the potential impact of patient risk factors in order to provide adequate prophylaxis. Acute and delayed CINV are severe, burdensome side effects of chemotherapy; however, new data on prevention and the discovery of new agents can further improve CINV control.

Functional assembly of intrinsic coagulation proteases on monocytes and platelets. Comparison between cofactor activities induced by thrombin and factor Xa

PubMed Central

1992-01-01

Generation of coagulation factor Xa by the intrinsic pathway protease complex is essential for normal activation of the coagulation cascade in vivo. Monocytes and platelets provide membrane sites for assembly of components of this protease complex, factors IXa and VIII. Under biologically relevant conditions, expression of functional activity by this complex is associated with activation of factor VIII to VIIIa. In the present studies, autocatalytic regulatory pathways operating on monocyte and platelet membranes were investigated by comparing the cofactor function of thrombin-activated factor VIII to that of factor Xa-activated factor VIII. Reciprocal functional titrations with purified human factor VIII and factor IXa were performed at fixed concentrations of human monocytes, CaCl2, factor X, and either factor IXa or factor VIII. Factor VIII was preactivated with either thrombin or factor Xa, and reactions were initiated by addition of factor X. Rates of factor X activation were measured using chromogenic substrate specific for factor Xa. The K1/2 values, i.e., concentration of factor VIIIa at which rates were half maximal, were 0.96 nM with thrombin- activated factor VIII and 1.1 nM with factor Xa-activated factor VIII. These values are close to factor VIII concentration in plasma. The Vsat, i.e., rates at saturating concentrations of factor VIII, were 33.3 and 13.6 nM factor Xa/min, respectively. The K1/2 and Vsat values obtained in titrations with factor IXa were not significantly different from those obtained with factor VIII. In titrations with factor X, the values of Michaelis-Menten coefficients (Km) were 31.7 nM with thrombin- activated factor VIII, and 14.2 nM with factor Xa-activated factor VIII. Maximal rates were 23.4 and 4.9 nM factor Xa/min, respectively. The apparent catalytic efficiency was similar with either form of factor VIIIa. Kinetic profiles obtained with platelets as a source of membrane were comparable to those obtained with monocytes

Population pharmacokinetic characterization of BAY 81-8973, a full-length recombinant factor VIII: lessons learned - importance of including samples with factor VIII levels below the quantitation limit.

PubMed

Garmann, D; McLeay, S; Shah, A; Vis, P; Maas Enriquez, M; Ploeger, B A

2017-07-01

The pharmacokinetics (PK), safety and efficacy of BAY 81-8973, a full-length, unmodified, recombinant human factor VIII (FVIII), were evaluated in the LEOPOLD trials. The aim of this study was to develop a population PK model based on pooled data from the LEOPOLD trials and to investigate the importance of including samples with FVIII levels below the limit of quantitation (BLQ) to estimate half-life. The analysis included 1535 PK observations (measured by the chromogenic assay) from 183 male patients with haemophilia A aged 1-61 years from the 3 LEOPOLD trials. The limit of quantitation was 1.5 IU dL -1 for the majority of samples. Population PK models that included or excluded BLQ samples were used for FVIII half-life estimations, and simulations were performed using both estimates to explore the influence on the time below a determined FVIII threshold. In the data set used, approximately 16.5% of samples were BLQ, which is not uncommon for FVIII PK data sets. The structural model to describe the PK of BAY 81-8973 was a two-compartment model similar to that seen for other FVIII products. If BLQ samples were excluded from the model, FVIII half-life estimations were longer compared with a model that included BLQ samples. It is essential to assess the importance of BLQ samples when performing population PK estimates of half-life for any FVIII product. Exclusion of BLQ data from half-life estimations based on population PK models may result in an overestimation of half-life and underestimation of time under a predetermined FVIII threshold, resulting in potential underdosing of patients. © 2017 Bayer AG. Haemophilia Published by John Wiley & Sons Ltd.

Intermittent diazepam prophylaxis in febrile convulsions. Pros and cons.

PubMed

Knudsen, F U

1991-01-01

Major cohort studies document that the long-term prognosis for most children with febrile convulsions (FC) is excellent. The 2 main treatment alternatives so far have been long-term prophylaxis with phenobarbital or valproate or no prophylaxis at all. Phenobarbital at times of fever is ineffective and obsolete. Consensus has emerged that long-term prophylaxis with antiepileptic drugs is rarely justified in FC considering the side effects and the favourable prognosis. No treatment at all does not appear quite satisfactory either, as FC have a high recurrence rate, disrupt family life and may have emotional consequences for the family. Moreover, all FC children face a risk, although admittedly low, of subsequent long-lasting potentially central nervous system (CNS)-damaging seizures. However, 2 further options exist: treatment with rapid-acting benzodiazepines solely at times of greatest risk, i.e., at high fever or at renewed seizures. Several clinical trials have confirmed that intermittent diazepam prophylaxis by way of a few doses of the drug per year provides effective seizure control and reduces the recurrence rate by one half or two thirds. The treatment is feasible and cheap, well tolerated by the child and well accepted by the parents. Compliance problems are common and only partly abatable. Trivial side effects are frequent. Transient respiratory apnoea does occur, but 15 years' experience substantiates that serious side effects are remarkably rare. Acute anticonvulsant treatment with rectal diazepam in solution given by the parents to stop ongoing seizures and to prevent immediate recurrences is an attractive alternative. It is feasible, is probably effective and minimizes the use of drugs, but compliance problems are common and protracted seizures are not always controlled. The subsequent management should include a risk profile approach considering a combination of risk factors for new FC rather than a single factor. By means of a risk index, based on

New isochromophilones VII and VIII produced by Penicillium sp. FO-4164.

PubMed

Yang, D J; Tomoda, H; Tabata, N; Masuma, R; Omura, S

1996-03-01

New isochromophilones VII and VIII were isolated from the culture broth of Penicillium sp. FO-4164. The structures were elucidated as 6H-2-benzopyran-6,8(7H)-dione, 5-chloro-3-(3',5'-dimethyl-1',3'-heptadienyl)-1,7,8a-trihydro-7, 8a-dihydroxy-7-methyl-7-acetate for isochromophilone VII and 6H-2-benzopyran-6-one,5-chloro-3-(3',5'-dimethyl-1', 3'-heptadienyl)-1,7,8,8a-tetrahydro-7,8-dihydroxy-7-methyl-8-acetate for isochromophilone VIII. Isochromophilones VII and VIII inhibited diacylglycerol acyltransferase activity with IC50 values of 20.0 and 127 microM and acyl-CoA: cholesterol acyltransferase activity with IC50 values of 24.5 and 47.0 microM, respectively.

40 CFR Appendix Viii to Part 86 - Aging Bench Equipment and Procedures

Code of Federal Regulations, 2014 CFR

2014-07-01

... 40 Protection of Environment 19 2014-07-01 2014-07-01 false Aging Bench Equipment and Procedures.... VIII Appendix VIII to Part 86—Aging Bench Equipment and Procedures This appendix provides specifications for standard aging bench equipment and aging procedures which may be used to conduct bench aging...

Pharmacokinetic-based prediction of real-life dosing of extended half-life clotting factor concentrates on hemophilia

PubMed Central

Gherardini, Stefano

2018-01-01

The improvement of clotting factor concentrates (CFCs) has undergone an impressive boost during the last six years. Since 2010, several new recombinant factor (rF)VIII/IX concentrates entered phase I/II/III clinical trials. The improvements are related to the culture of human embryonic kidney (HEK) cells, post-translational glycosylation, PEGylation, and co-expression of the fragment crystallizable (Fc) region of immunoglobulin (Ig)G1 or albumin genes in the manufacturing procedures. The extended half-life (EHL) CFCs allow an increase of the interval between bolus administrations during prophylaxis, a very important advantage for patients with difficulties in venous access. Although the inhibitor risk has not been fully established, phase III studies have provided standard prophylaxis protocols, which, compared with on-demand treatment, have achieved very low annualized bleeding rates (ABRs). The key pharmacokinetics (PK) parameter to tailor patient therapy is clearance, which is more reliable than the half-life of CFCs; the clearance considers the decay rate of the drug concentration–time profile, while the half-life considers only the half concentration of the drug at a given time. To tailor the prophylaxis of hemophilia patients in real-life, we propose two formulae (expressed in terms of the clearance, trough and dose interval between prophylaxis), respectively based on the one- and two-compartmental models (CMs), for the prediction of the optimal single dose of EHL CFCs. Once the data from the time decay of the CFCs are fitted by the one- or two-CMs after an individual PK analysis, such formulae provide to the treater the optimal trade-off among trough and time-intervals between boluses. In this way, a sufficiently long time-interval between bolus administration could be guaranteed for a wider class of patients, with a preassigned level of the trough. Finally, a PK approach using repeated dosing is discussed, and some examples with new EHL CFCs are shown

40 CFR Appendix Viii to Part 86 - Aging Bench Equipment and Procedures

Code of Federal Regulations, 2013 CFR

2013-07-01

... 40 Protection of Environment 20 2013-07-01 2013-07-01 false Aging Bench Equipment and Procedures.... 86, App. VIII Appendix VIII to Part 86—Aging Bench Equipment and Procedures This appendix provides specifications for standard aging bench equipment and aging procedures which may be used to conduct bench aging...

40 CFR Appendix Viii to Part 86 - Aging Bench Equipment and Procedures

Code of Federal Regulations, 2012 CFR

2012-07-01

... 40 Protection of Environment 20 2012-07-01 2012-07-01 false Aging Bench Equipment and Procedures.... 86, App. VIII Appendix VIII to Part 86—Aging Bench Equipment and Procedures This appendix provides specifications for standard aging bench equipment and aging procedures which may be used to conduct bench aging...

Current Practice Trends for Use of Early Venous Thromboembolism Prophylaxis After Intracerebral Hemorrhage.

PubMed

Cherian, Laurel J; Smith, Eric E; Schwamm, Lee H; Fonarow, Gregg C; Schulte, Phillip J; Xian, Ying; Wu, Jingjing; Prabhakaran, Shyam K

2018-01-01

Venous thromboembolism (VTE) is common after intracerebral hemorrhage (ICH). Guidelines recommend early VTE prophylaxis. To determine characteristics associated with early chemoprophylaxis (CP) after ICH in the Get With The Guidelines-Stroke registry. In this observational cohort study, we identified patients with ICH between January 1, 2009 and September 30, 2013, who (1) were non-ambulatory and/or not comfort care measures by hospital day 2; (2) were not transferred to another acute care facility; and (3) had known VTE prophylaxis status at end of hospital day 2. Categories for VTE prophylaxis were as follows: (1) mechanical non-CP or (2) CP with or without mechanical prophylaxis. Early prophylaxis was defined as occurring by hospital day 2. Using multivariable logistic regression, we assessed patient, hospital, and geographic factors independently associated with early CP use. Among 74 283 patients with ICH from 1358 hospitals, 5929 (7.9%) received early CP, 66 444 (89.4%) received early mechanical/non-CP, and 1910 (2.6%) had no prophylaxis, mechanical or CP, within the first 2 days. There was no increase in early CP use over the study period; 60% of hospitals provided early CP to <9% of patients. In multivariable analysis, female sex, atrial fibrillation, diabetes, coronary, carotid, and peripheral artery disease, prior ischemic stroke or transient ischemic attack, hospital size >500 beds, and geographic region were independently associated with early vs no early CP use. Nationwide, the large majority of ICH patients receive early mechanical VTE prophylaxis only, without CP. Patient comorbidities and hospital characteristics such as geographic location are determinants of higher use of early CP. Copyright © 2017 by the Congress of Neurological Surgeons

The Effect of Prophylaxis on Pediatric HIV Costs

PubMed Central

Wilson, Leslie S.; Hensic, Lori; Paoli, Carly J.; Basu, Rituparna; Christenson, Maria; Moskowitz, Judith K.; Wara, Diane

2011-01-01

The objective of this study was to determine and compare the cost to treat HIV(+) and HIV(−) pediatric patients both before and after HIV prophylaxis became the standard of care. Retrospective chart review of a pediatric HIV/AIDS specialty clinic’s medical charts was conducted for clinical and healthcare utilization data on 125 children diagnosed from 1986–2007. Mean HIV-related costs were compared using bootstrapped t-tests for children born in the pre-prophylaxis (1979–1993) and prophylaxis eras (1994–2007). Patients were also stratified into two categories based on death during the follow-up period. Lastly, national cost-savings were estimated using mean costs, national number of at-risk births and national perinatal HIV transmission rates in each era. For HIV(+) children, mean annual per patient treatment cost was $15,067 (95% CI: $10,169–$19,965) in the pre-prophylaxis era (n=40) and $14,959 (95% CI: $9,140–$20,779) in the prophylaxis era (n=14), difference not statistically significant (p>0.05). For HIV(−) children, mean annual per patient treatment cost was $204 (95% CI: −$219–$627) for the pre-prophylaxis era (n=2) and $427 (95% CI: $277–$579) for the prophylaxis era (n=69), different statistically significant (p<0.05). A projected cost-savings of $16–23 million annually in the US was observed due to the adoption of prophylaxis treatment guidelines in pediatric HIV care. The prophylaxis era of pediatric HIV treatment has been successful in decreasing perinatal HIV transmission and mortality, as reflected by clinical trials and national cost-savings data, and emphasizes the value of the rapid adoption of evidence-based practice guidelines. PMID:21780991

[Views of students of extension nursing studies about cancer prophylaxis].

PubMed

Majewski, Włodzimierz D; Majewska, Aleksandra

2007-01-01

Cancer prophylaxis seems nowadays to be the more and more powerful tool in fight with these serious diseases. The aim of this work is to find out opinions of students of nursing extension studies on contemporary cancer prophylaxis. The question about possibilities of practical efforts for prophylaxis and early detection of cancer was directed to 160 students of four consecutive years (2002-2006), at the end of the fourth year of lasting five and a half years extension nursing studies, during ending exam on subject: oncological nursing. There were 154 women and 6 men, predominantly at their third decade of life, with nursing experience approximately more than 5 years. Out of 160 asked students, 131 of them firstly indicated necessity of breast cancer prophylaxis, 117 mentioned lung cancer, 113 cervix cancer, 95 colorectal cancer, 33 prostate cancer. In families with cancer problems, more frequent control investigations (23 answers), and genetic tests (16) were called for. Patients should be qualified to appropriate risk groups (13) and controlled more frequently there (24). Apart from necessary wide education in media (126) personal contact with patient to discuss his or her personal problems relating to cancer is needed (91). If atypical symptoms are self-detected by patients it should alert them to not neglect and contact family physician (33). Healthy diet (62) containing fresh vegetables and fruits (73), high fibre diet (42) with less animal fat (38) and less red meat (30), containing no preservative agents (45) is recommended. Increased physical activity (84) to cease or reduce smoking (102), and alcohol intake (55), limited exposition to ultraviolet rays (49), and systematic controls of breast (105), uterus cervix (88), lungs (77), colon (55) and prostate (28) are proposed. The pollution of environment by combustion gases and smokes (34) not excluding risk factors of medical workplace (29) are mentioned as cancerogenic factors. In the time of increasing

Pregnancy and delivery in women with von Willebrand's disease and different von Willebrand factor mutations.

PubMed

Castaman, Giancarlo; Tosetto, Alberto; Rodeghiero, Francesco

2010-06-01

Pregnancy in von Willebrand's disease may carry a significant risk of bleeding. Information on changes in factor VIII and von Willebrand factor and pregnancy outcome in relation to von Willebrand factor gene mutations are very scanty. We examined biological response to desmopressin, changes in factor VIII and von Willebrand factor and pregnancy outcome in a cohort of 23 women with von Willebrand's disease characterized at molecular level and prospectively followed during 2000-2007. Thirty-one pregnancies occurred during the study period. Remarkably, similar changes of factor VIII and von Willebrand factor were observed after desmopressin and during pregnancy in nine women with R854Q, R1374H, V1665E, V1822G and C2362F mutations. Women with von Willebrand's disease and R1205H and C1130F mutations (17 pregnancies in 12 women) had only a slight increase of factor VIII and von Willebrand factor during pregnancy while their response to desmopressin was marked but short-lived. For these women, two to three desmopressin administrations within the first 48 hours were sufficient to successfully manage vaginal delivery. Two women with recessive von Willebrand's disease due to compound heterozygosity for different gene mutations had a spontaneous, major increase in factor VIII while von Willebrand factor remained severely reduced. Desmopressin increased factor VIII and was clinically useful in the first case, while a factor VIII/von Willebrand factor concentrate was required in the second patient not responsive to the compound. Factor VIII/von Willebrand factor concentrate was also required for two women with type 2 A von Willebrand's disease with V1665E mutations who had no von Willebrand factor activity change during pregnancy. In one of them, delayed bleeding occurred 15 days later requiring treatment with Factor VIII/von Willebrand factor concentrate. No miscarriages or stillbirths occurred. Close follow-up and detailed guidelines for the management of parturition have

Stabilization of a human recombinant factor VIII by poloxamer 188 in relation to polysorbate 80.

PubMed

Clark, Jakson; Montgomery, Jade; Squires, Ryan; McGuire, Joseph

2016-03-01

Detection of enhanced surface tension depression by surfactant in the presence of protein was recently suggested as a basis for determining whether protein stabilization by that surfactant is owing to surfactant forming a steric barrier at interfaces or surfactant association with the protein. In particular, protein interaction with surfactant aggregates may lead to an increased concentration of monomers thus enhancing surfactant adsorption, or to formation of surfactant-protein complexes having little or no effect on adsorption. We compared the initial rates of surface tension depression by poloxamer 188 and polysorbate 80 (PS 80) in the presence and absence of a human recombinant factor VIII (rFVIII). Indirect evidence had suggested poloxamer 188 enters into stable associations with rFVIII in solution but does not form a steric barrier at the interface, while PS 80 behaves in contrary fashion. In this study, we show the presence of rFVIII caused an increase in the rate (reduction in the activation energy) of PS 80 adsorption, while no such change was recorded in the case of poloxamer 188. Thus, we provide substantiation for detection of protein-mediated acceleration of surfactant adsorption as a means to compare different surfactants in relation to their favored mechanism for protein stabilization.

The role of nerve growth factor in the prophylaxis and treatment of diabetic foot ulcers

PubMed Central

Tiaka, Elisavet K; Papanas, Nikolaos; Manolakis, Anastassios C; Maltezos, Efstratios

2011-01-01

Diabetic foot ulcers are still particularly difficult to heal. Therefore, preventing and therapeutic adjuncts are increasingly being explored. Nerve growth factor (NGF) is a promising agent exhibiting beneficial actions on both diabetic peripheral neuropathy, one of the main causes of foot ulcers, and on ulcer healing. Indeed, preclinical research in animal models of diabetes has revealed the trophic effect of NGF on small C-fibres, while phase 2 human trials have provided evidence for a favourable effect on sensory neuropathy. However, the results of a phase 3 trial were moderate and, therefore, not enough to encourage widespread use of NGF in the treatment of diabetic neuropathy. Available literature on the role of NGF on diabetic wound healing is sparse but encouraging. Exogenous supplementation of NGF or the use of alternative techniques to increase its endogenous expression could emerge as a protective and therapeutic modality for diabetic foot ulcers in addition to standard treatment and other growth factors. The present review provides an outlook on the role of NGF in the prophylaxis and treatment of diabetic foot ulcers. PMID:22928161

VIII Olimpíada Brasileira de Astronomia e Astronáutica

NASA Astrophysics Data System (ADS)

Garcia Canalle, João Batista; Villas da Rocha, Jaime Fernando; Wuensche de Souza, Carlos Alexandre; Pereira Ortiz, Roberto; Aguilera, Nuricel Villalonga; Padilha, Maria De Fátima Catta Preta; Pessoa Filho, José Bezerra; Soares Rodrigues, Ivette Maria

2007-07-01

Neste trabalho apresentamos as motivações pelas quais organizamos, em conjunto, pela primeira vez, a Olimpíada Brasileira de Astronomia incluindo a Astronáutica, em colaboração com a Agência Espacial Brasileira. Esta ampliação contribuiu para atrair ainda mais alunos, professores, escolas e patrocinadores para participarem desta Olimpíada. Em 2005 participaram da VIII Olimpíada Brasileira de Astronomia e Astronáutica (VIII OBA) 187.726 alunos distribuídos por 3.229 escolas, pertencentes a todos os estados brasileiros, incluindo o Distrito Federal. O crescimento em número de alunos participantes foi 52,4% maior do que em 2004. Em abril de 2005 organizamos, em Itapecerica da Serra, SP, um curso para os 50 alunos previamente selecionados e participantes da VII OBA e ao final selecionamos, dentre eles, uma equipe de 5 alunos, os quais representaram o Brasil na X Olimpíada Internacional de Astronomia, na China, em outubro de 2005. Ganhamos, pela primeira vez, uma medalha de ouro naquele evento. Em Agosto de 2005, organizamos a VIII Escola de Agosto para 50 alunos e respectivos professores, em Águas de Lindóia, SP, juntamente com a XXXI reunião anual da Sociedade Astronômica Brasileira (SAB). Em novembro de 2005 realizamos a I Jornada Espacial, em São José dos Campos, com 22 alunos e 22 professores selecionados dentre os participantes que melhores resultados obtiveram nas questões de Astronáutica da VIII OBA. Neste trabalho detalhamos os resultados da VIII OBA bem como as ações subseqüentes.

40 CFR Appendix Viii to Part 85 - Vehicle and Engine Parameters and Specifications

Code of Federal Regulations, 2014 CFR

2014-07-01

...) AIR PROGRAMS (CONTINUED) CONTROL OF AIR POLLUTION FROM MOBILE SOURCES Pt. 85, App. VIII Appendix VIII.... Air Inlet System. 1. Temperature control system calibration. IV. Fuel System. 1. General. a. Engine idle speed. b. Engine idle mixture. 2. Carburetion. a. Air-fuel flow calibration. b. Transient...

40 CFR Appendix Viii to Part 85 - Vehicle and Engine Parameters and Specifications

Code of Federal Regulations, 2013 CFR

2013-07-01

...) AIR PROGRAMS (CONTINUED) CONTROL OF AIR POLLUTION FROM MOBILE SOURCES Pt. 85, App. VIII Appendix VIII.... Air Inlet System. 1. Temperature control system calibration. IV. Fuel System. 1. General. a. Engine idle speed. b. Engine idle mixture. 2. Carburetion. a. Air-fuel flow calibration. b. Transient...

40 CFR Appendix Viii to Part 85 - Vehicle and Engine Parameters and Specifications

Code of Federal Regulations, 2012 CFR

2012-07-01

...) AIR PROGRAMS (CONTINUED) CONTROL OF AIR POLLUTION FROM MOBILE SOURCES Pt. 85, App. VIII Appendix VIII.... Air Inlet System. 1. Temperature control system calibration. IV. Fuel System. 1. General. a. Engine idle speed. b. Engine idle mixture. 2. Carburetion. a. Air-fuel flow calibration. b. Transient...

Nonadherence to Primary Prophylaxis against Pneumocystis jirovecii Pneumonia

PubMed Central

Heffelfinger, James D.; Voetsch, Andrew C.; Nakamura, Glenn V.; Sullivan, Patrick S.; McNaghten, A. D.; Huang, Laurence

2009-01-01

Background Despite the effectiveness of prophylaxis, Pneumocystis jirovecii pneumonia (PCP) continues to be the most common serious opportunistic infection among HIV-infected persons. We describe factors associated with nonadherence to primary PCP prophylaxis. Methodology/Principal Findings We used 2000–2004 data from the Supplement to HIV/AIDS Surveillance (SHAS) project, a cross-sectional interview project of HIV-infected persons ≥18 years conducted in 18 states. We limited the analysis to persons who denied having prior PCP, reported having a current prescription to prevent PCP, and answered the question “In the past 30 days, how often were you able to take the PCP medication(s) exactly the way your doctor told you to take them?” We used multivariable logistic regression to describe factors associated with nonadherence. Of 1,666 subjects prescribed PCP prophylaxis, 305 (18.3%) were nonadherent. Persons were more likely to be nonadherent if they reported using marijuana (adjusted odds ratio [aOR] = 1.6, 95% confidence interval [CI] = 1.1–2.4), non-injection drugs other than marijuana (aOR = 1.5, 95% CI = 1.0–2.1), or injection drugs (aOR = 2.3, 95% CI = 1.3–4.1) in the past year; their mental health was “not good” for ≥1 day during the past month (aOR = 1.6, 95% CI = 1.2–2.2); their most recent CD4 count was <200 cells/μL (aOR = 1.6, 95% CI = 1.1–2.2); or taking ART usually (aOR = 9.6, 95% CI = 6.7–13.7) or sometimes/rarely/never (aOR = 18.4, 95% CI = 11.1–30.4), compared with always, as prescribed. Conclusion/Significance Providers should inquire about and promote strategies to improve adherence to PCP prophylaxis, particularly among persons who use illicit drugs, have mental health issues, and who are not compliant with ART to reduce the occurrence of PCP. PMID:19319199

Cost-effectiveness analysis of alternative factor VIII products in treatment of haemophilia A.

PubMed

Hay, J W; Ernst, R L; Kessler, C M

1999-05-01

Manufactured factor VIII (FVIII) concentrates of varying purity are available for managing patients with haemophilia A. This study is a cost-effectiveness analysis of ultra-high purity and recombinant (UHP/R) FVIII products relative to intermediate and very-high purity (IP/VHP) preparations. Because the societal (including research and development) costs of FVIII products are unknown and product prices vary with market conditions, we conducted the analysis with treatment cost as a variable quantity. We estimated the largest price premium that could be paid for a UHP/R concentrate relative to an IP/VHP concentrate such that the UHP/R product is the more cost-effective preparation. In the analysis haemophilic patients were assumed to be seropositive for human immunodeficiency virus, seropositive for hepatitis C (HCV), or at risk for seroconversion of hepatitis A (HAV) or hepatitis B (HBV). The results showed that the maximum cost-effective UHP/R price premium is essentially zero if the patient is only at risk of HAV or HBV infection, positive but small for the base-case HCV+ patient, and positive and large for the base-case HIV+ patient having a short life expectancy. Thus UHP/R preparations are not uniformly more cost-effective than IP/VHP products across the spectrum of haemophilic patients' health problems, and the relative cost-effectiveness of the two classes of prepared FVIII products is sensitive to product prices. The methodology employed here can be used in other circumstances where multiple treatments exist for illnesses for which there are significant multiple comorbidities or health risks.

Clot stability as a determinant of effective factor VIII replacement in hemophilia A.

PubMed

Leong, L; Chernysh, I N; Xu, Y; Sim, D; Nagaswami, C; de Lange, Z; Kosolapova, S; Cuker, A; Kauser, K; Weisel, J W

2017-10-01

Factor VIII (FVIII) replacement is standard of care for patients with hemophilia A (HemA); however, patient response does not always correlate with FVIII levels. We hypothesize this may be in part due to the physical properties of clots and contributions of fibrin, platelets, and erythrocytes, which may be important for hemostasis. To understand how FVIII contributes to effective hemostasis in terms of clot structure and mechanical properties. In vitro HemA clots in human plasma or whole blood were analyzed using turbidity waveform analysis, confocal microscopy, and rheometry with or without added FVIII. In vivo clots from saphenous vein puncture in wild-type and HemA mice with varying FVIII levels were examined using scanning electron microscopy. FVIII profoundly affected HemA clot structure and physical properties; added FVIII converted the open and porous fibrin meshwork and low stiffness of HemA clots to a highly branched and dense meshwork with higher stiffness. Platelets and erythrocytes incorporated into clots modulated clot properties. The clots formed in the mouse saphenous vein model contained variable amounts of compressed erythrocytes (polyhedrocytes), fibrin, and platelets depending on the levels of FVIII, correlating with bleeding times. FVIII effects on clot characteristics were dose-dependent and reached a maximum at ~25% FVIII, such that HemA clots formed with this level of FVIII resembled clots from unaffected controls. Effective clot formation can be achieved in HemA by replacement therapy, which alters the architecture of the fibrin network and associated cells, thus increasing clot stiffness and decreasing clot permeability.

[Respiratory syncytial virus prophylaxis among preterm infants--four seasons' experience].

PubMed

Klimek, Małgorzata; Kwinta, Przemko; Kruczek, Piotr; Pietrzyk, Jacek J

2009-01-01

Respiratory syncitial virus (RSV) is the main reason of hospitalizations due to respiratory tract infection in children within the first year of life. The course of infection is more severe in children from a risk group, which includes children who were born preterm, these with bronchopulmonary dysplasia (BPD), children with heart defects significantly influencing their hemodynamics, and immunocompromised children. Palivizumab is a humanized monoclonal antibody class IgG-1 used to prevent RSV infection. To assess the results of treatment and to evaluate factors influencing the efficacy of RSV infection prophylaxis in preterm newborns. The study included 55 preterm newborns (mean birth weight-970g, mean gestational age-27 weeks), who were given a dose of palmivizumab of 15mg per kg body weight every four weeks in autumn and winter from season 2004/ 2005 to season 2007/2008. Ten children (18%) required hospitalization between the doses and within 28 days after the last dose of palmivizumab. Among these, 2 children (3.6%) were hospitalized because of very severe RSV infection. Eight children (16%) were hospitalized due to respiratory tract infection within 12 months after completing the prophylaxis; none of them was infected with RSV. The episodes of respiratory tract infection between the doses and within 28 days after the last dose occurred in 19 children (31%), and in 26 patients included in the follow-up (51%) within 12 months after completing the prophylaxis. The effect of treatment was most beneficial in preterm neonates with extremely low birth weight and in children who did not require respiratory medications at the moment of discharge from the neonatal unit. RSV infection prophylaxis is of most benefit in children born with extremely low birth weight. In this group of children the prophylaxis should be considered both for children suffering from BPD and in children free of this disease.

Early discontinuation of antibiotic prophylaxis in patients with persistent primary vesicoureteral reflux initially detected during infancy: outcome analysis and risk factors for febrile urinary tract infection.

PubMed

Moriya, Kimihiko; Mitsui, Takahiko; Kitta, Takeya; Nakamura, Michiko; Kanno, Yukiko; Kon, Masafumi; Nishimura, Yoko; Shinohara, Nobuo; Nonomura, Katsuya

2015-02-01

We retrospectively assessed the incidence of and risk factors for febrile urinary tract infection in children during active surveillance after early discontinuation of antibiotic prophylaxis. We retrospectively evaluated 9 females and 61 uncircumcised males diagnosed with primary vesicoureteral reflux before age 1 year who had persistent reflux on followup voiding cystourethrogram and were subsequently followed under active surveillance without continuous antibiotic prophylaxis. Patients with secondary vesicoureteral reflux or associated urological abnormality were excluded. Clinical outcomes, including incidence of febrile urinary tract infection and new scar formation, were evaluated. Risk factors for febrile urinary tract infection were also analyzed. Mean age at stopping continuous antibiotic prophylaxis was 21 months, and mean followup was 61 months. During active surveillance 21 patients had febrile urinary tract infection, and the 5-year infection-free rate under active surveillance was 67.5%. One or 2 foci of minimal new scarring developed in 4 of 16 patients who underwent followup dimercapto-succinic acid scan after febrile urinary tract infection. On multivariate analysis dilated vesicoureteral reflux on followup voiding cystourethrogram was the only significant risk factor for febrile urinary tract infection. This study revealed that about two-thirds of patients with persistent vesicoureteral reflux were free of febrile urinary tract infection during 5 years of active surveillance. Those with dilated vesicoureteral reflux on followup voiding cystourethrogram are at significantly greater risk for febrile urinary tract infection. Accordingly active surveillance, especially in patients with nondilated vesicoureteral reflux on followup voiding cystourethrogram, seems to be a safe option even in children who have not yet been toilet trained. Copyright © 2015 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights

Discontinuing Pneumocystis jirovecii Pneumonia Prophylaxis in HIV-Infected Patients With a CD4 Cell Count <200 cells/mm3.

PubMed

Sidhu, Vaninder K; Foisy, Michelle M; Hughes, Christine A

2015-12-01

To review the evidence for discontinuing primary and secondary Pneumocystis jirovecii pneumonia (PJP) prophylaxis in HIV-infected patients with a CD4 count <200 cells/mm(3). We conducted a literature search in MEDLINE, EMBASE, Cochrane Library, Google Scholar, and the International Aids Society Library (up to August 2015) using the following key search terms: Pneumocystis jirovecii, pneumonia, human immunodeficiency virus, primary prophylaxis, secondary prophylaxis, and discontinuation. All English-language studies that evaluated discontinuation of primary and/or secondary PJP prophylaxis in HIV-infected patients with CD4 count <200 cells/mm(3) were included. Five studies were identified, which varied in design, sample size, outcomes, and duration of follow-up. Three studies examined discontinuation of primary and secondary PJP prophylaxis; 1 study evaluated discontinuing primary PJP prophylaxis; and 1 study evaluated stopping secondary PJP prophylaxis. Two out of the 5 studies pooled data for all opportunistic infections. Overall, there was a low incidence of PJP among HIV-infected patients who discontinued primary PJP prophylaxis and were well controlled on antiretroviral therapy (ART). Discontinuation of primary PJP prophylaxis appears to be safe in patients on combination ART with a suppressed HIV viral load and a CD4 count >100 cells/mm(3). Additional data are needed to support the safety of discontinuing secondary PJP prophylaxis. Decisions to discontinue PJP prophylaxis in patients with a CD4 count <200 cells/mm(3) should be done on an individual patient basis, taking into consideration clinical factors, including ongoing adherence to ART. © The Author(s) 2015.

The vestibulocochlear nerve (VIII).

PubMed

Benoudiba, F; Toulgoat, F; Sarrazin, J-L

2013-10-01

The vestibulocochlear nerve (8th cranial nerve) is a sensory nerve. It is made up of two nerves, the cochlear, which transmits sound and the vestibular which controls balance. It is an intracranial nerve which runs from the sensory receptors in the internal ear to the brain stem nuclei and finally to the auditory areas: the post-central gyrus and superior temporal auditory cortex. The most common lesions responsible for damage to VIII are vestibular Schwannomas. This report reviews the anatomy and various investigations of the nerve. Copyright © 2013. Published by Elsevier Masson SAS.

Biochemical and functional characterization of a recombinant monomeric factor VIII-Fc fusion protein.

PubMed

Peters, R T; Toby, G; Lu, Q; Liu, T; Kulman, J D; Low, S C; Bitonti, A J; Pierce, G F

2013-01-01

Hemophilia A results from a deficiency in factor VIII activity. Current treatment regimens require frequent dosing, owing to the short half-life of FVIII. A recombinant FVIII-Fc fusion protein (rFVIIIFc) was molecularly engineered to increase the half-life of FVIII, by 1.5-2-fold, in several preclinical animal models and humans. To perform a biochemical and functional in vitro characterization of rFVIIIFc, with existing FVIII products as comparators.  rFVIIIFc was examined by utilizing a series of structural and analytic assays, including mass spectrometry following lysyl endopeptidase or thrombin digestion. rFVIIIFc activity was determined in both one-stage clotting (activated partial thromboplastin time) and chromogenic activity assays, in the context of the FXase complex with purified components, and in both in vitro and ex vivo rotational thromboelastometry (ROTEM) assays performed in whole blood.  rFVIIIFc contained the predicted primary structure and post-translational modifications, with an FVIII moiety that was similar to other recombinant FVIII products. The von Willebrand factor-binding and specific activity of rFVIIIFc were also found to be similar to those of other recombinant FVIII molecules. Both chromogenic and one-stage assays of rFVIIIFc gave similar results. Ex vivo ROTEM studies demonstrated that circulating rFVIIIFc activity was prolonged in mice with hemophilia A in comparison with B-domain-deleted or full-length FVIII. Clot parameters at early time points were similar to those for FVIII, whereas rFVIIIFc showed prolonged improvement of clot formation.  rFVIIIFc maintains normal FVIII interactions with other proteins necessary for its activity, with prolonged in vivo activity, owing to fusion with the Fc region of IgG(1) . © 2012 International Society on Thrombosis and Haemostasis.

Venous thromboembolism prophylaxis in gynecologic surgery: a systematic review.

PubMed

Rahn, David D; Mamik, Mamta M; Sanses, Tatiana V D; Matteson, Kristen A; Aschkenazi, Sarit O; Washington, Blair B; Steinberg, Adam C; Harvie, Heidi S; Lukban, James C; Uhlig, Katrin; Balk, Ethan M; Sung, Vivian W

2011-11-01

unfractionated heparin and intermittent pneumatic compression are both superior to placebo or no intervention but insufficient to determine whether heparins are superior to intermittent pneumatic compression for venous thromboembolism prevention. Combining two of three risks (aged 60 years or older, cancer, or personal venous thromboembolism history) substantially elevated the risk of venous thromboembolism. Intermittent pneumatic compression provides sufficient prophylaxis for the majority of gynecology patients undergoing benign surgery. Additional risk factors warrant the use of combined mechanical and pharmacologic prophylaxis.

[Visual development and amblyopia prophylaxis in pediatric glaucoma].

PubMed

Steffen, H

2011-07-01

In children with congenital glaucoma the functional long-term result is often disappointing even if the intraocular pressure is well controlled. The reason for this discrepancy is attributed to amblyogenic factors responsible for interfering with normal visual development. These amblyogenic factors are corneal edema, irregular astigmatism and non-corrected ametropia as monocular causes. Binocular causes are anisometropia-induced suppression and strabismus. Full ametropic correction and a very early prophylaxis and treatment of amblyopia with a close follow-up are mandatory to reduce amblyogenic visual impairment in children with congenital glaucoma.

Venous Thromboembolism Risk and Adequacy of Prophylaxis in High Risk Pregnancy in the Arabian Gulf

PubMed Central

Alsayegh, Faisal; Al-Jassar, Waleed; Wani, Salima; Tahlak, Muna; Al-Bahar, Awatef; Al-Kharusi, Lamya; Al-Tamimi, Halima; El-Taher, Faten; Mahmood, Naeema; Al-Zakwani, Ibrahim

2016-01-01

Objectives: To estimate the prevalence of venous thromboembolism (VTE) risk factors in pregnancy and the proportion of pregnancies at risk of VTE that received the recommended prophylaxis according to the American College of Chest Physicians (ACCP) 2012 published guidelines in antenatal clinics in the Arabian Gulf. Methods: The evaluation of venous thromboembolism (EVE)-Risk project was a non-interventional, cross-sectional, multi-centre, multi-national study of all eligible pregnant women (≥17 years) screened during antenatal clinics from 7 centres in the Arabian Gulf countries (United Arab Emirates, Kuwait, Bahrain, Qatar and Oman). Pregnant women were recruited during a 3-month period between September and December 2012. Results: Of 4,131 screened pregnant women, 32% (n=1,337) had ≥1 risk factors for VTE. Common VTE risk factors included obesity (76%), multiparity (33%), recurrent miscarriages (9.1%), varicose veins (6.9%), thrombophilia (2.6%), immobilization (2.0%), sickle cell disease (2.8%) and previous VTE (1.6%). Only 8.3% (n=111) of the high risk patients were on the recommended VTE prophylaxis. Enoxaparin was used in 80% (n=89) of the cases followed by tinzaparin (4%; n=4). Antiplatelet agents were prescribed in 11% (n=149) of pregnant women. Of those on anticoagulants (n=111), 59% (n=66) were also co-prescribed antiplatelet agents. Side effects (mainly local bruising at the injection site) were reported in 12% (n=13) of the cases. Conclusion: A large proportion of pregnant women in the Arabian Gulf countries have ≥1 VTE risk factor with even a smaller fraction on prophylaxis. VTE risk assessment must be adopted to identify those at risk who would need VTE prophylaxis. PMID:26517701

Local antimicrobial administration for prophylaxis of surgical site infections.

PubMed

Huiras, Paul; Logan, Jill K; Papadopoulos, Stella; Whitney, Dana

2012-11-01

Despite a lack of consensus guidelines, local antibiotic administration for prophylaxis of surgical site infections is used during many surgical procedures. The rationale behind this practice is to provide high antibiotic concentrations at the site of surgery while minimizing systemic exposure and adverse effects. Local antibiotic administration for surgical site prophylaxis has inherent limitations in that antibiotics are applied after the incision is made, rather than the current standard for surgical site prophylaxis that recommends providing adequate antibiotic concentrations at the site before the incision. The efficacy and safety of local application of antibiotics for surgical site prophylaxis have been assessed in different types of surgery with a variety of antibiotic agents and methods of application. We identified 22 prospective, randomized, controlled trials that evaluated local application of antibiotics for surgical site prophylaxis. These trials were subsequently divided and analyzed based on the type of surgical procedure: dermatologic, orthopedic, abdominal, colorectal, and cardiothoracic. Methods of local application analyzed included irrigations, powders, ointments, pastes, beads, sponges, and fleeces. Overall, there is a significant lack of level I evidence supporting this practice for any of the surgical genres evaluated. In addition, the literature spans several decades, and changes in surgical procedures, systemic antibiotic prophylaxis, and microbial flora make conclusions difficult to determine. Based on available data, the efficacy of local antibiotic administration for the prophylaxis of surgical site infections remains uncertain, and recommendations supporting this practice for surgical site prophylaxis cannot be made. © 2012 Pharmacotherapy Publications, Inc.

Pharmacokinetic properties of BAY 81-8973, a full-length recombinant factor VIII.

PubMed

Shah, A; Delesen, H; Garger, S; Lalezari, S

2015-11-01

BAY 81-8973 is a full-length recombinant factor VIII (FVIII) with the same primary amino acid sequence as sucrose-formulated recombinant FVIII (rFVIII-FS) but is produced with advanced manufacturing technologies. To analyse the pharmacokinetics (PK) of BAY 81-8973 after single and multiple dosing across different age and ethnic groups in the LEOPOLD clinical trial programme. The LEOPOLD trials enrolled patients with severe haemophilia A aged 12-65 years (LEOPOLD I and II) or ≤12 years (LEOPOLD Kids) with ≥150 (LEOPOLD I and II) or ≥50 (LEOPOLD Kids) exposure days to any FVIII product and no history of FVIII inhibitors. PK were assessed using chromogenic and one-stage assays (only chromogenic assay for LEOPOLD Kids) after a single 50-IU kg(-1) dose of BAY 81-8973 and, in a subset of patients in LEOPOLD I, after repeated dosing. Pharmacokinetic analyses were also performed based on age (18 to 65, 12 to <18, 6 to <12 and <6 years) and ethnicity (Asian and non-Asian). Pharmacokinetic assessments in the LEOPOLD I trial showed non-inferiority of BAY 81-8973 vs. rFVIII-FS. The PK of BAY 81-8973 were comparable after single and multiple dosing. Age-based analysis in the three trials showed that plasma concentrations were slightly lower for children, but similar for adolescents compared with adults. Pharmacokinetic results were similar in the different ethnic groups. Results of the LEOPOLD trials show that the BAY 81-8973 pharmacokinetic profile is non-inferior to rFVIII-FS. Similar BAY 81-8973 pharmacokinetic values were observed following single and repeated dosing and across ethnic groups. © 2015 John Wiley & Sons Ltd.

Use of anticonvulsants as prophylaxis for seizures in patients on clozapine.

PubMed

Caetano, Dorgival

2014-02-01

The aim of this study is to conduct a critical review of the literature regarding the use of anticonvulsants in the prophylaxis of clozapine-induced seizures, to examine the relationship of the latter with clozapine daily dose, serum concentration and other factors than dosage that effect clozapine blood concentration, and to make recommendations for the management of clozapine-induced seizures. A systematic review of English-language MEDLINE articles was undertaken. Clozapine-induced seizures may occur at any dose; the risk increases with dose and goes up to 4% at ≥ 600 mg/day. Some authors have advocated that patients on that dose regimen have anticonvulsant added as a primary prophylactic measure. The author discusses the pitfalls of this recommendation and highlights that seizures are better predicted from serum concentration (1300 ng/ml) rather than dose alone, and that serum concentration is strongly influenced by sex, age, smoking habit, drug-drug interactions and variations in the 1A2, 2D6 and 3A4 genotypes. Anticonvulsants are not recommended as a primary prophylaxis for clozapine-induced seizures. When deemed necessary as secondary prophylaxis, the clinician's choice should consider drug-drug interactions that may increase/decrease clozapine serum concentration and lead to more side effects, including neutropenia/agranulocytosis and seizures, or compromise therapeutic response. Recommendations for primary and secondary prophylaxis of clozapine related-seizures are provided.

Variation in seizure prophylaxis in severe pediatric traumatic brain injury.

PubMed

Ostahowski, Paige J; Kannan, Nithya; Wainwright, Mark S; Qiu, Qian; Mink, Richard B; Groner, Jonathan I; Bell, Michael J; Giza, Christopher C; Zatzick, Douglas F; Ellenbogen, Richard G; Boyle, Linda Ng; Mitchell, Pamela H; Vavilala, Monica S

2016-10-01

OBJECTIVE Posttraumatic seizure is a major complication following traumatic brain injury (TBI). The aim of this study was to determine the variation in seizure prophylaxis in select pediatric trauma centers. The authors hypothesized that there would be wide variation in seizure prophylaxis selection and use, within and between pediatric trauma centers. METHODS In this retrospective multicenter cohort study including 5 regional pediatric trauma centers affiliated with academic medical centers, the authors examined data from 236 children (age < 18 years) with severe TBI (admission Glasgow Coma Scale score ≤ 8, ICD-9 diagnosis codes of 800.0-801.9, 803.0-804.9, 850.0-854.1, 959.01, 950.1-950.3, 995.55, maximum head Abbreviated Injury Scale score ≥ 3) who received tracheal intubation for ≥ 48 hours in the ICU between 2007 and 2011. RESULTS Of 236 patients, 187 (79%) received seizure prophylaxis. In 2 of the 5 centers, 100% of the patients received seizure prophylaxis medication. Use of seizure prophylaxis was associated with younger patient age (p < 0.001), inflicted TBI (p < 0.001), subdural hematoma (p = 0.02), cerebral infarction (p < 0.001), and use of electroencephalography (p = 0.023), but not higher Injury Severity Score. In 63% cases in which seizure prophylaxis was used, the patients were given the first medication within 24 hours of injury, and 50% of the patients received the first dose in the prehospital or emergency department setting. Initial seizure prophylaxis was most commonly with fosphenytoin (47%), followed by phenytoin (40%). CONCLUSIONS While fosphenytoin was the most commonly used medication for seizure prophylaxis, there was large variation within and between trauma centers with respect to timing and choice of seizure prophylaxis in severe pediatric TBI. The heterogeneity in seizure prophylaxis use may explain the previously observed lack of relationship between seizure prophylaxis and outcomes.

Identification of Risk Factors for the Development of Pressure Ulcers Despite Standard Screening Methodology and Prophylaxis in Trauma Patients.

PubMed

Raff, Lauren A; Waller, Holly; Griffin, Russell L; Kerby, Jeffrey D; Bosarge, Patrick L

2016-07-01

To present information about a study of risk factors for development of pressure ulcers (PrUs) in trauma patients. This continuing education activity is intended for physicians and nurses with an interest in skin and wound care. After participating in this educational activity, the participant should be better able to:1. Describe the previous PrU research, scope of the problem, and methodology of the study.2. Explain the results of the study identifying PrU risk factors for trauma patients. Pressure ulceration prevention has been emphasized  over the past several years in inpatient hospital settings with  subsequent decreases in the development of pressure ulcers (PrUs).  However, there remains a subset of trauma and burn patients  that develop PrUs despite standard screening methodology and  prophylaxis. This study determines the conditions that predict  development of pressure ulcers (PrUs) despite conventional  prophylaxis and screening.  Demographic and PrU data were collected over a  5-year period from June 2008 to May 2013. Patients diagnosed  with PrUs upon arrival in the trauma bay were excluded from  analysis. An ordinal logistic regression of PrU stage was used to  estimate odds ratios (ORs) and associated 95% confidence intervals  (CIs) for the association between characteristics of interest and  odds of a PrU. A backward selection process was used to select the  most parsimonious model.  During the study period, 14,616 trauma patients were  admitted and had available data. A total of 124 patients (0.85%) that met inclusion criteria went on to develop PrUs during their hospital course. Factors associated with the development of PrUs included spine Abbreviated Injury Scale (AIS) >3 (OR, 5.72; CI, 3.63-9.01), mechanical ventilation (OR, 1.95; CI, 1.23-3.10) and age 40 to 64 (OR, 2.09; CI, 1.24-3.52) and age ≥ 65 (OR, 4.48; CI, 2.52-7.95). Interestingly, head injury AIS >3 was protective from the development of PrUs (OR

Circumventing furin enhances factor VIII biological activity and ameliorates bleeding phenotypes in hemophilia models

PubMed Central

Siner, Joshua I.; Samelson-Jones, Benjamin J.; Crudele, Julie M.; French, Robert A.; Lee, Benjamin J.; Zhou, Shanzhen; Merricks, Elizabeth; Raymer, Robin; Camire, Rodney M.; Arruda, Valder R.

2016-01-01

Processing by the proprotein convertase furin is believed to be critical for the biological activity of multiple proteins involved in hemostasis, including coagulation factor VIII (FVIII). This belief prompted the retention of the furin recognition motif (amino acids 1645–1648) in the design of B-domain–deleted FVIII (FVIII-BDD) products in current clinical use and in the drug development pipeline, as well as in experimental FVIII gene therapy strategies. Here, we report that processing by furin is in fact deleterious to FVIII-BDD secretion and procoagulant activity. Inhibition of furin increases the secretion and decreases the intracellular retention of FVIII-BDD protein in mammalian cells. Our new variant (FVIII-ΔF), in which this recognition motif is removed, efficiently circumvents furin. FVIII-ΔF demonstrates increased recombinant protein yields, enhanced clotting activity, and higher circulating FVIII levels after adeno-associated viral vector–based liver gene therapy in a murine model of severe hemophilia A (HA) compared with FVIII-BDD. Moreover, we observed an amelioration of the bleeding phenotype in severe HA dogs with sustained therapeutic FVIII levels after FVIII-ΔF gene therapy at a lower vector dose than previously employed in this model. The immunogenicity of FVIII-ΔF did not differ from that of FVIII-BDD as a protein or a gene therapeutic. Thus, contrary to previous suppositions, FVIII variants that can avoid furin processing are likely to have enhanced translational potential for HA therapy. PMID:27734034

Common and rare von Willebrand factor (VWF) coding variants, VWF levels, and factor VIII levels in African Americans: the NHLBI Exome Sequencing Project.

PubMed

Johnsen, Jill M; Auer, Paul L; Morrison, Alanna C; Jiao, Shuo; Wei, Peng; Haessler, Jeffrey; Fox, Keolu; McGee, Sean R; Smith, Joshua D; Carlson, Christopher S; Smith, Nicholas; Boerwinkle, Eric; Kooperberg, Charles; Nickerson, Deborah A; Rich, Stephen S; Green, David; Peters, Ulrike; Cushman, Mary; Reiner, Alex P

2013-07-25

Several rare European von Willebrand disease missense variants of VWF (including p.Arg2185Gln and p.His817Gln) were recently reported to be common in apparently healthy African Americans (AAs). Using data from the NHLBI Exome Sequencing Project, we assessed the association of these and other VWF coding variants with von Willebrand factor (VWF) and factor VIII (FVIII) levels in 4468 AAs. Of 30 nonsynonymous VWF variants, 6 were significantly and independently associated (P < .001) with levels of VWF and/or FVIII. Each additional copy of the common VWF variants encoding p.Thr789Ala or p.Asp1472His was associated with 6 to 8 IU/dL higher VWF levels. The VWF variant encoding p.Arg2185Gln was associated with 7 to 13 IU/dL lower VWF and FVIII levels. The type 2N-related VWF variant encoding p.His817Gln was associated with 17 IU/dL lower FVIII level but normal VWF level. A novel, rare missense VWF variant that predicts disruption of an O-glycosylation site (p.Ser1486Leu) and a rare variant encoding p.Arg2287Trp were each associated with 30 to 40 IU/dL lower VWF level (P < .001). In summary, several common and rare VWF missense variants contribute to phenotypic differences in VWF and FVIII among AAs.

Effect of intrapartum antibiotic prophylaxis against group B streptococcal infection on comparisons of rates of endometritis and urinary tract infection in multicenter surveillance.

PubMed

Dumas, Anne-Marie; Girard, Raphaëlle; Ayzac, Louis; Beaumont, Geneviève; Caillat-Vallet, Emmanuelle; Depaix, Florence; Gignoux, Chantal; Haond, Catherine; Pral, Noelle; Robert, Jacqueline; Tissot-Guerraz, Françoise; Vincent-Bouletreau, Agnès; Berland, Michel; Fabry, Jacques

2008-04-01

To establish whether antibiotic prophylaxis against group B streptococcal infection may be a confounding factor in comparisons of rates of endometritis and urinary tract infection after vaginal delivery. Prospective study. Maternity units at 48 hospitals in a regional surveillance network in France during 2001-2004. The maternity units used a common protocol to establish whether antibiotic prophylaxis was indicated. Risk factors for endometritis and urinary tract infections were evaluated using multiple logistic regression. We analyzed 49,786 vaginal deliveries. The percentage of women receiving antibiotic prophylaxis varied widely and significantly among the maternity units (range, 4.4%-26.0%; median, 15.8%; 25th percentile, 12.1%; 75th percentile, 19.0%) (P < .001, by Mantel-Haenszel chi(2) test). The incidence rate of endometritis was significantly reduced from 0.25% to 0.11% by antibiotic prophylaxis (P = .001). There was a decrease in the incidence of urinary tract infection from 0.37% to 0.32%, but it was not statistically significant (P = .251). A reduction in the incidence of endometritis was observed when intrapartum antibiotic prophylaxis against group B streptococcal infection was used. However, the proportion of women considered to be at risk of infection varied widely among institutions. Comparisons of rates of endometritis among maternity units, but not urinary tract infection rates, should take into account antibiotic prophylaxis as a significant confounding factor.

Use of combination neonatal prophylaxis for the prevention of mother-to-child transmission of HIV infection in European high-risk infants.

PubMed

Chiappini, Elena; Galli, Luisa; Giaquinto, Carlo; Ene, Luminita; Goetghebuer, Tessa; Judd, Ali; Lisi, Catiuscia; Malyuta, Ruslan; Noguera-Julian, Antoni; Ramos, Jose Tomas; Rojo-Conejo, Pablo; Rudin, Christoph; Tookey, Pat; de Martino, Maurizio; Thorne, Claire

2013-03-27

To evaluate use of combination neonatal prophylaxis (CNP) in infants at high risk for mother-to-child transmission (MTCT) of HIV in Europe and investigate whether CNP is more effective in preventing MTCT than single drug neonatal prophylaxis (SNP). Individual patient-data meta-analysis across eight observational studies. Factors associated with CNP receipt and with MTCT were explored by logistic regression using data from nonbreastfed infants, born between 1996 and 2010 and at high risk for MTCT. In 5285 mother-infant pairs, 1463 (27.7%) had no antenatal or intrapartum antiretroviral prophylaxis, 915 (17.3%) had only intrapartum prophylaxis and 2907 (55.0%) mothers had detectable delivery viral load despite receiving antenatal antiretroviral therapy. Any neonatal prophylaxis was administered to 4623 (87.5%) infants altogether; 1105 (23.9%) received CNP. Factors significantly associated with the receipt of CNP were later calendar birth year, no elective caesarean section, maternal CD4 cell count less than 200 cells/μl, maternal delivery viral load more than 1000 copies/ml, no antenatal antiretroviral therapy, receipt of intrapartum single-dose nevirapine and cohort. After adjustment, absence of neonatal prophylaxis was associated with higher risk of MTCT compared to neonatal prophylaxis [adjusted odds ratio (aOR) 2.29; 95% confidence interval (95% CI) 1.46-2.59; P < 0.0001]. Further, there was no association between CNP and MTCT compared to SNP (aOR 1.41; 95% CI 0.97-2.5; P = 0.07). In this European population, CNP use is increasing and associated with presence of MTCT risk factors. The finding of no observed difference in MTCT risk between one drug and CNP may reflect residual confounding or the fact that CNP may be effective only in a subgroup of infants rather than the whole population of high-risk infants.

Fluconazole prophylaxis in preterm infants: a systematic review.

PubMed

Rios, Juliana Ferreira da Silva; Camargos, Paulo Augusto Moreira; Corrêa, Luísa Petri; Romanelli, Roberta Maia de Castro

This article aims to review the use of antifungal prophylaxis with intravenous fluconazole in premature newborns and the occurrence of Invasive Candidiasis. This is a systematic review with search at databases: PubMed, Capes Portal, Virtual Health Library (BVS - Biblioteca Virtual em Saúde)/Lilacs, Scopus and Cochrane. The keywords used were: "Antifungal", "Candida" "Fluconazole prophylaxis" and "Preterm infants". Invasive Candidiasis was evaluated in all the twelve items. In eleven of them, there was a statistically significant difference between the groups receiving prophylactic fluconazole, with lower frequency of Invasive Candidiasis, compared to placebo or no prophylaxis group. Colonization by Candida species was also evaluated in five studies; four of them presented statistically lower proportion of colonization in patients with Fluconazole prophylaxis, compared to placebo or no drugs. In one study, there was a significant difference, favoring the use of fluconazole, and reduction of death. Studies indicate the effectiveness of prophylaxis with fluconazole, with reduction in the incidence of colonization and invasive fungal disease. The benefits of prophylaxis should be evaluated considering the incidence of candidiasis in the unit, the mortality associated with candidiasis, the safety and toxicity of short and long-term medication, and the potential for development of resistant pathogens. Copyright © 2017 Sociedade Brasileira de Infectologia. Published by Elsevier Editora Ltda. All rights reserved.

Prevalence of IgG antibodies to human parvovirus B19 in haemophilia children treated with recombinant factor (F)VIII only or with at least one plasma-derived FVIII or FIX concentrate: results from the French haemophilia cohort.

PubMed

Gaboulaud, Valérie; Parquet, Armelle; Tahiri, Cedric; Claeyssens, Ségolène; Potard, Valérie; Faradji, Albert; Peynet, Jocelyne; Costagliola, Dominique

2002-02-01

Human parvovirus B19 (B19) has been transmitted by some brands of virally attenuated plasma-derived factor VIII (FVIII) or IX (FIX) concentrates. To quantify the differences of human parvovirus B19 risk transmission between albumin-stabilized recombinant factor and plasma-derived factor, we studied the prevalence of IgG antibodies to B19 (anti-B19) in 193 haemophiliac children between 1 and 6-years of age who had previously been treated with albumin-stabilized recombinant FVIII only (n = 104), and in children previously treated with solvent/detergent high-purity non-immunopurified and non-nanofiltered FVIII or IX concentrates (n = 89). Association between the prevalence of anti-B19 and the treatment group was analysed using multivariate logistic regression. Age, severity and type of haemophilia, number of cumulative days of exposure to factor VIII or IX, previous history of red blood cells or plasma transfusion were considered as potential confounding variables. A higher prevalence of anti-B19 was found in children previously treated with solvent/detergent high-purity non-immunopurified and non-nanofiltered FVIII or IX concentrates than in children treated with albumin- stabilized recombinant FVIII only (OR: 22.3; CI: 7.9-62.8), independently of the other factors studied.

Cost-effectiveness of culture-guided antimicrobial prophylaxis for the prevention of infections after prostate biopsy.

PubMed

Li, Chi-Kong; Tong, Brian C Y; You, Joyce H S

2016-02-01

Clinical findings suggest that the use of rectal culture-guided antibiotic prophylaxis reduces the infection rate following transrectal ultrasound-guided prostate biopsy (TRUSBx). A decision-analytic model was designed to compare the outcomes of TRUSBx performed with (rectal culture-guided group) and without (standard ciprofloxacin prophylaxis) rectal swab culture-guided antimicrobial prophylaxis in Hong Kong. The post-biopsy infection rate, infection-related costs, quality-adjusted life years (QALYs) lost for infection, and incremental cost per QALY saved (ICER) were assessed. Model inputs were retrieved from local epidemiology data and the medical literature. A sensitivity analysis was performed to test the robustness of the model results. Base-case analysis showed that the infection rate in the culture-guided group was reduced from 2.42% to 0.23% and saved 0.0002 QALYs, with a lower cost (USD 31.4 versus USD 55.6) (USD 1=HKD 7.8). The number needed to screen to prevent an infection episode was 45.7. The hospital days avoided per 100 patients using culture-guided prophylaxis was 7.08 days. The relative effectiveness of culture-guided antimicrobial prophylaxis versus standard prophylaxis in carriers and non-carriers of FQ-resistant rectal flora were identified as potential influencing factors. In 10000 Monte Carlo simulations, ICERs of the culture-guided group were below the willingness-to-pay threshold 99.12% of the time. Using rectal culture-guided antimicrobial prophylaxis for men undergoing TRUSBx appears to be a cost-saving strategy to avert post-biopsy infection and QALY loss in Hong Kong. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

Impact of being overweight on factor VIII dosing in children with haemophilia A.

PubMed

Henrard, S; Hermans, C

2016-05-01

Treatment of haemophilia A (HA) requires infusions of factor VIII (FVIII) concentrates. The number of FVIII units infused to obtain a specific circulating FVIII level is calculated with the formula: [body weight (BW) (kg) × desired FVIII increase (%)]/2, with the assumption that each unit of FVIII infused per kg of BW increases the circulating FVIII level by 2%. The aim of this study was to evaluate the impact of several morphometric parameters (BW, body mass index (BMI)-for-age, height), age and type of FVIII concentrate on FVIII recovery in children with HA. A total of 66 children aged between 10 and 18 with severe HA selected from six pharmacokinetic (PK) clinical trials using two recombinant FVIII concentrates were included in the analysis. Regression tree (RT) was used to identify predictors of FVIII recovery. The median age was 14.5 years with a median FVIII recovery of 2.09 for all children. The median FVIII recovery was not significantly different between age groups. Two groups were created by RT: children with a BMI-for-age percentile

Frequencies of VNTR and RFLP polymorphisms associated with factor VIII gene in Singapore

DOE Office of Scientific and Technical Information (OSTI.GOV)

Fong, I.; Lai, P.S.; Ouah, T.C.

1994-09-01

The allelic frequency of any polymorphism within a population determines its usefulness for genetic counselling. This is important in populations of non-Caucasian origin as RFLPs may significantly differ among ethnic groups. We report a study of five intragenic polymorphisms in factor VIII gene carried out in Singapore. The three PCR-based RFLP markers studied were Intron 18/Bcl I, Intron 19/Hind III and Intron 22/Xba I. In an analysis of 148 unrelated normal X chromosomes, the allele frequencies were found to be A1 = 0.18, A2 = 0.82 (Bcl I RFLP), A1 = 0.80, A2 = 0.20 (Hind III RFLP) and A1more » = 0.58, and A2 = 0.42 (Xba I RFLP). The heterozygosity rates of 74 females analyzed separately were 31%, 32% and 84.2%, respectively. Linkage disequilibrium was also observed to some degree between Bcl I and Hind III polymorphism in our population. We have also analyzed a sequence polymorphism in Intron 7 using hybridization with radioactive-labelled {sup 32}P allele-specific oligonucleotide probes. This polymorphism was not very polymorphic in our population with only 2% of 117 individuals analyzed being informative. However, the use of a hypervariable dinucleotide repeat sequence (VNTR) in Intron 13 showed that 25 of our of 27 (93%) females were heterozygous. Allele frequencies ranged from 1 to 55 %. We conclude that a viable strategy for molecular analysis of Hemophilia A families in our population should include the use of Intron 18/Bcl I and Intron 22/Xba I RFLP markers and the Intron 13 VNTR marker.« less

Factor Activity Assays for Monitoring Extended Half-Life FVIII and Factor IX Replacement Therapies.

PubMed

Kitchen, Steve; Tiefenbacher, Stefan; Gosselin, Robert

2017-04-01

The advent of modified factor VIII (FVIII) and factor IX (FIX) molecules with extended half-lives (EHLs) compared with native FVIII and FIX represents a major advance in the field of hemophilia care, with the potential to reduce the frequency of prophylactic injections and/or to increase the trough level prior to subsequent injections. Monitoring treatment through laboratory assays will be an important part of ensuring patient safety, including any tailoring of prophylaxis. Several approaches have been used to extend half-lives, including PEGylation, and fusion to albumin or immunoglobulin. Some of these modifications affect factor assays as routinely performed in hemophilia centers; so, laboratories will need to use FVIII and FIX assays which have been shown to be suitable on a product-by-product basis. For some products, there are marked differences between results obtained using one-stage or chromogenic assays and results obtained using different reagents in the one-stage assay. The laboratory should use an assay in which the recovery of the product closely aligns with the assay used by the pharmaceutical company to assign potency to the product, so that the units reported by the laboratory agree with those used to demonstrate efficacy of the product during clinical trials. Reported assay differences in relation to several of the EHL FVIII and FIX molecules will be reviewed in this article. Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Diet as prophylaxis and treatment for venous thromboembolism?

PubMed Central

2010-01-01

Background Both prophylaxis and treatment of venous thromboembolism (VTE: deep venous thrombosis (DVT) and pulmonary emboli (PE)) with anticoagulants are associated with significant risks of major and fatal hemorrhage. Anticoagulation treatment of VTE has been the standard of care in the USA since before 1962 when the U.S. Food and Drug Administration began requiring randomized controlled clinical trials (RCTs) showing efficacy, so efficacy trials were never required for FDA approval. In clinical trials of 'high VTE risk' surgical patients before the 1980s, anticoagulant prophylaxis was clearly beneficial (fatal pulmonary emboli (FPE) without anticoagulants = 0.99%, FPE with anticoagulants = 0.31%). However, observational studies and RCTs of 'high VTE risk' surgical patients from the 1980s until 2010 show that FPE deaths without anticoagulants are about one-fourth the rate that occurs during prophylaxis with anticoagulants (FPE without anticoagulants = 0.023%, FPE while receiving anticoagulant prophylaxis = 0.10%). Additionally, an FPE rate of about 0.012% (35/28,400) in patients receiving prophylactic anticoagulants can be attributed to 'rebound hypercoagulation' in the two months after stopping anticoagulants. Alternatives to anticoagulant prophylaxis should be explored. Methods and Findings The literature concerning dietary influences on VTE incidence was reviewed. Hypotheses concerning the etiology of VTE were critiqued in relationship to the rationale for dietary versus anticoagulant approaches to prophylaxis and treatment. Epidemiological evidence suggests that a diet with ample fruits and vegetables and little meat may substantially reduce the risk of VTE; vegetarian, vegan, or Mediterranean diets favorably affect serum markers of hemostasis and inflammation. The valve cusp hypoxia hypothesis of DVT/VTE etiology is consistent with the development of VTE being affected directly or indirectly by diet. However, it is less consistent with the rationale of using

The effect of V/III ratio on the morphology and structure of GaAs nanowires by MOCVD

NASA Astrophysics Data System (ADS)

Liu, Yan; Peng, Yan; Guo, Jingwei; La, Dongsheng; Xu, Zhaopeng

2018-05-01

In this paper, GaAs nanowires with different V/III ratios (70, 140, 280 and 560) were vertically grown from bottom to top on GaAs substrates by using metal organic chemical vapor deposition based on gold assisted vapor-liquid-solid mechanism. It is found that the growth rate of nanowires is inversely proportional to their V/III ratio. And the V/III ratio can also change nanowire growth type. For the nanowire with small V/III ratios (≤280), the reactants are most from those atoms merged in the catalyst. But, for the nanowire with V/III ratio 560, the contribution mainly comes from the diffusions of atoms pyrolyzed on the surface of the nanowire and the substrate. A shrunken neck under the catalyst is observed in TEM characterizations. These results will provide a theoretical basis for potential practical applications of nanowire-based devices.

Ciprofloxacin vs levofloxacin for prophylaxis during hematopoietic stem-cell transplantation.

PubMed

Copeland, Vanessa; McLaughlin, Milena; Trifilio, Steven

2018-01-01

The objective of the current retrospective study was to compare differences in rate of breakthrough infections for ciprofloxacin vs levofloxacin prophylaxis in autologous hematopoietic stem-cell transplant (HSCT) patients treated for multiple myeloma. This was a retrospective, cohort study comparing autologous HSCT recipients treated for multiple myeloma who received ciprofloxacin prophylaxis vs levofloxacin prophylaxis. A total of 297 patients, 143 levofloxacin- and 154 ciprofloxacin-treated were included. There was a significantly higher incidence of bloodstream infections in the ciprofloxacin group (24/154) compared to the levofloxacin group (10/143), P = .03, primarily caused by a statistically higher incidence of gram-positive bloodstream infections (ciprofloxacin [21/154] vs levofloxacin [8/143]; P < .01). Clinically relevant differences exist between fluoroquinolone agents used for prophylaxis. Levofloxacin prophylaxis was more effective than ciprofloxacin prophylaxis to reduce the incidence of bloodstream infections in this study. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Clinical Impact of Fluoroquinolone-Resistant Escherichia coli in the Fecal Flora of Hematological Patients with Neutropenia and Levofloxacin Prophylaxis

PubMed Central

Chong, Yong; Shimoda, Shinji; Yakushiji, Hiroko; Ito, Yoshikiyo; Aoki, Takatoshi; Miyamoto, Toshihiro; Kamimura, Tomohiko; Shimono, Nobuyuki; Akashi, Koichi

2014-01-01

Background Fluoroquinolone prophylaxis in patients with neutropenia and hematological malignancies is said to be effective on febrile netropenia (FN)-related infection and mortality; however, the emergence of antibiotic resistance has become a concern. Ciprofloxacin and levofloxacin prophylaxis are most commonly recommended. A significant increase in the rate of quinolone-resistant Escherichia coli in fecal flora has been reported following ciprofloxacin prophylaxis. The acquisition of quinolone-resistant E. coli after levofloxacin use has not been evaluated. Methods We prospectively examined the incidence of quinolone-resistant E. coli isolates recovered from stool cultures before and after levofloxacin prophylaxis in patients with neutropenia from August 2011 to May 2013. Some patients received chemotherapy multiple times. Results In this trial, 68 patients were registered. Levofloxacin-resistant E. coli isolates were detected from 11 and 13 of all patients before and after the prophylaxis, respectively. However, this was not statistically significant (P = 0.65). Multiple prophylaxis for sequential chemotherapy did not induce additional quinolone resistance among E. coli isolates. Interestingly, quinolone-resistant E. coli, most of which were extended-spectrum β-lactamase (ESBL) producers, were already detected in approximately 20% of all patients before the initiation of prophylaxis. FN-related bacteremia developed in 2 patients, accompanied by a good prognosis. Conclusions Levofloxacin prophylaxis for neutropenia did not result in a significant acquisition of quinolone-resistant E. coli. However, we detected previous colonization of quinolone-resistant E. coli before prophylaxis, which possibly reflects the spread of ESBL. The epidemic spread of resistant E. coli as a local factor may influence strategies toward the use of quinolone prophylaxis. PMID:24465506

Analysis of the Japanese subgroup in LEOPOLD II: a phase 2/3 study of BAY 81-8973, a new recombinant factor VIII product.

PubMed

Fujii, Teruhisa; Hanabusa, Hideji; Shima, Midori; Morinaga, Takeshi; Fukutake, Katsuyuki

2017-03-01

BAY 81-8973, a new full length recombinant FVIII product, has been developed for prophylaxis and on-demand therapy in patients with hemophilia A. LEOPOLD II was a phase 2/3 study comparing prophylaxis versus on-demand treatment with BAY 81-8973. The analysis herein evaluated the clinical profile in Japanese subjects enrolled in LEOPOLD II. The LEOPOLD II was an open-label randomized crossover study. Our analysis evaluated the efficacy using the annualized bleeding rate, safety, and pharmacokinetics in Japanese subjects with severe hemophilia A enrolled in LEOPOLD II. The median annualized bleeding rate was 59.9/year in the on-demand group and 1.9/year in the prophylaxis group for Japanese subjects. There were no study drug-related adverse events in the Japanese subjects. None of the subjects developed FVIII inhibitors. There were no apparent clinical differences in efficacy, safety, and pharmacokinetics between the Japanese and the non-Japanese subjects. Data for the Japanese subjects showed annualized bleeding rates to be remarkably lower in the prophylaxis group compared to the on-demand group and that BAY 81-8973 exhibited a good safety profile and tolerability. These results were similar for the non-Japanese subjects. The results support adoption of BAY 81-8973 for treatment of Japanese subjects with severe hemophilia A.

What is the place of pre-exposure prophylaxis in HIV prevention?

PubMed

De Man, Jeroen; Colebunders, Robert; Florence, Eric; Laga, Marie; Kenyon, Christopher

2013-01-01

New tools are needed to bring down ongoing high HIV incidence. This review aims to evaluate the place of one of these new tools (pre-exposure prophylaxis) in a comprehensive prevention strategy. Several trials have demonstrated the safety and the efficacy of pre-exposure prophylaxis in HIV prevention. Two large trials have, however, failed to show such efficacy. This was likely due to poor adherence in these trials. New forms of long-acting pre-exposure prophylaxis currently in trials may deal with these problems of low adherence. Pre-exposure prophylaxis has been demonstrated to be cost-effective within certain settings. The introduction of pre-exposure prophylaxis into prevention programs needs to be carefully thought through. For example, pre-exposure prophylaxis-induced risk compensation, at both an individual and population level, could undermine other aspects of a comprehensive HIV prevention program. In conclusion, pre-exposure prophylaxis could be a useful additional tool for the prevention of HIV in specific high-risk groups. It should be implemented in a way that deals with issues such as ensuring high adherence and ensuring that pre-exposure prophylaxis does not detract from, but complements, other more fundamental elements of HIV prevention programs.

[Perioperative antibiotic prophylaxis in cancer surgery].

PubMed

Vilar-Compte, Diana; García-Pasquel, María José

2011-01-01

The effectiveness of perioperative antibiotic prophylaxis in reducing surgical site infections has been demonstrated. Its utility is recognized for clean-contaminated procedures and some clean surgeries. Prophylactic antibiotics are used as intended to cover the most common germs in the surgical site; first and second generation cephalosporins are the most used. For optimal prophylaxis, an antibiotic with a targeted spectrum should be administered at sufficiently high concentrations in serum, tissue, and the surgical wound during the time that the incision is open and risk of bacterial contamination. The infusion of the first dose of antimicrobial should begin within 60 min before surgical incision and should be discontinued within 24 h after the end of surgery The prolonged use of antibiotic prophylaxis leads to emergence of bacterial resistance and high costs. The principles of antimicrobial prophylaxis in cancer surgery are the same as those described for general surgery; it is recommended to follow and comply with the standard criteria. In mastectomies and clean head and neck surgery there are specific recommendations that differ from non-cancer surgery. In the case of very extensive surgeries, such as pelvic surgery or bone surgery with reconstruction, extension of antibiotics for 48-72 h should be considered.

Pneumocystis jiroveci pneumonia in patients with inflammatory bowel disease: a survey of prophylaxis patterns among gastroenterology providers.

PubMed

Okafor, Philip N; Wasan, Sharmeel K; Farraye, Francis A

2013-01-01

. Additional studies are needed to determine PJP risk factors and risks and benefits of prophylaxis.

Henry VIII, McLeod syndrome and Jacquetta's curse.

PubMed

Stride, P; Lopes Floro, K

2013-01-01

The mental decline of King Henry VIII from being a jovial, charismatic and athletic young man into an increasingly paranoid, brutal tyrant in later life, ever more concerned at his lack of one or more male heirs, has attracted many medical diagnostic theories. Previous hypotheses have included diabetes, syphilis and hypothyroidism, among others. However, these inadequately explain Henry's failure to produce a male heir, despite multiple pairings. The latest postulated diagnoses for Henry are the coexistence of both Kell blood group antigenicity (possibly inherited from Jacquetta Woodville, Henry's maternal great grandmother) causing related impaired fertility, and McLeod syndrome, causing psychotic changes. As the mutated McLeod protein of the syndrome significantly reduces the expression, effectively inactivating the Kell antigen, we critically review this theory, examining in detail the pathophysiology of these conditions and assessing the genealogy of Henry VIII and its effect in subsequent generations.

Primary granulocyte colony-stimulating factor prophylaxis during the first two cycles only or throughout all chemotherapy cycles in patients with breast cancer at risk for febrile neutropenia.

PubMed

Aarts, Maureen J; Peters, Frank P; Mandigers, Caroline M; Dercksen, M Wouter; Stouthard, Jacqueline M; Nortier, Hans J; van Laarhoven, Hanneke W; van Warmerdam, Laurence J; van de Wouw, Agnes J; Jacobs, Esther M; Mattijssen, Vera; van der Rijt, Carin C; Smilde, Tineke J; van der Velden, Annette W; Temizkan, Mehmet; Batman, Erdogan; Muller, Erik W; van Gastel, Saskia M; Borm, George F; Tjan-Heijnen, Vivianne C G

2013-12-01

Early breast cancer is commonly treated with anthracyclines and taxanes. However, combining these drugs increases the risk of myelotoxicity and may require granulocyte colony-stimulating factor (G-CSF) support. The highest incidence of febrile neutropenia (FN) and largest benefit of G-CSF during the first cycles of chemotherapy lead to questions about the effectiveness of continued use of G-CSF throughout later cycles of chemotherapy. In a multicenter study, patients with breast cancer who were considered fit enough to receive 3-weekly polychemotherapy, but also had > 20% risk for FN, were randomly assigned to primary G-CSF prophylaxis during the first two chemotherapy cycles only (experimental arm) or to primary G-CSF prophylaxis throughout all chemotherapy cycles (standard arm). The noninferiority hypothesis was that the incidence of FN would be maximally 7.5% higher in the experimental compared with the standard arm. After inclusion of 167 eligible patients, the independent data monitoring committee advised premature study closure. Of 84 patients randomly assigned to G-CSF throughout all chemotherapy cycles, eight (10%) experienced an episode of FN. In contrast, of 83 patients randomly assigned to G-CSF during the first two cycles only, 30 (36%) had an FN episode (95% CI, 0.13 to 0.54), with a peak incidence of 24% in the third cycle (ie, first cycle without G-CSF prophylaxis). In patients with early breast cancer at high risk for FN, continued use of primary G-CSF prophylaxis during all chemotherapy cycles is of clinical relevance and thus cannot be abandoned.

Assessment of evidence-based dental prophylaxis education in postdoctoral pediatric dentistry programs.

PubMed

Redford-Badwal, Deborah A; Nainar, S M Hashim

2002-09-01

The objective of the study was to investigate various aspects of evidence-based dental prophylaxis education in postdoctoral pediatric dentistry training programs in the United States. An anonymous nationwide postal survey of fifty-two postdoctoral pediatric dentistry program directors was conducted in September 2001. The survey had a response rate of 75 percent with all geographic regions of the nation represented and with a preponderance of university-based programs (62 percent). Most of the training programs (74 percent) routinely recommended dental prophylaxis for all recall patients. The proportion of programs that recommended dental prophylaxis for the following indications were: plaque, stain and/or calculus removal--97 percent; caries prevention--59 percent; prior to topical fluoride application--67 percent; prior to sealant application--62 percent; and for behavioral modification--77 percent. Most training programs (77 percent) defined dental prophylaxis as both rubber cup pumice prophylaxis and toothbrush prophylaxis. However, only one-half of the training programs (51 percent) had modified their teaching to substitute toothbrush prophylaxis in lieu of rubber cup pumice prophylaxis. In conclusion, only one half of postdoctoral pediatric dentistry training programs in the United States teach evidence-based practice of dental prophylaxis for recall patients.

Reduction in surgical antibiotic prophylaxis expenditure and the rate of surgical site infection by means of a protocol that controls the use of prophylaxis.

PubMed

Gomez, Marisa I; Acosta-Gnass, Silvia I; Mosqueda-Barboza, Luisa; Basualdo, Juan A

2006-12-01

To evaluate the effectiveness of an intervention based on training and the use of a protocol with an automatic stop of antimicrobial prophylaxis to improve hospital compliance with surgical antibiotic prophylaxis guidelines. An interventional study with a before-after trial was conducted in 3 stages: a 3-year initial stage (January 1999 to December 2001), during which a descriptive-prospective survey was performed to evaluate surgical antimicrobial prophylaxis and surgical site infections; a 6-month second stage (January to June 2002), during which an educational intervention was performed regarding the routine use of a surgical antimicrobial prophylaxis request form that included an automatic stop of prophylaxis (the "automatic-stop prophylaxis form"); and a 3-year final stage (July 2002 to June 2005), during which a descriptive-prospective survey of surgical antimicrobial prophylaxis and surgical site infections was again performed. An 88-bed teaching hospital in Entre Ríos, Argentina. A total of 3,496 patients who underwent surgery were included in the first stage of the study and 3,982 were included in the final stage. Comparison of the first stage of the study with the final stage revealed that antimicrobial prophylaxis was given at the appropriate time to 55% and 88% of patients, respectively (relative risk [RR], 0.27 [95% confidence interval {CI}, 0.25-0.30]; P<.01); the antimicrobial regimen was adequate in 74% and 87% of patients, respectively (RR, 0.50 [95% CI, 0.45-0.55]; P<.01); duration of the prophylaxis was adequate in 44% and 55% of patients, respectively (RR, 0.80 [95% CI, 0.77-0.84]; P<.01); and the surgical site infection rates were 3.2% and 1.9%, respectively (RR, 0.59 [95% CI, 0.44-0.79]; P<.01). Antimicrobial expenditure was 10,678.66 US$ per 1,000 patient-days during the first stage and 7,686.05 US$ per 1,000 patient-days during the final stage (RR, 0.87 [95% CI, 0.86-0.89]; P<.01). The intervention based on training and application of a

Diagnostic and prognostic value of factor VIII binding antibodies in acquired hemophilia A: data from the GTH-AH 01/2010 study.

PubMed

Werwitzke, S; Geisen, U; Nowak-Göttl, U; Eichler, H; Stephan, B; Scholz, U; Holstein, K; Klamroth, R; Knöbl, P; Huth-Kühne, A; Bomke, B; Tiede, A

2016-05-01

Essentials Factor VIII (FVIII) binding IgG detected by ELISA could be an alternative to the Bethesda assay. We studied the performance of anti-FVIII IgG ELISA in patients with acquired hemophilia and controls. Anti-FVIII IgG > 99th percentile of controls was highly sensitive and specific. Patients with high anti-FVIII IgG have a lower chance of achieving remission. Background Acquired hemophilia A is a severe bleeding disorder that requires fast and accurate diagnosis as it occurs often unexpectedly in previously healthy men and women of every age. The Nijmegen-modified Bethesda assay is the diagnostic reference standard for detecting neutralizing autoantibodies against factor VIII (FVIII), but is not widely available, not ideal for quantifying the complex type 2 inhibitors seen in acquired hemophilia, and suffers from high inter-laboratory variability. Objectives To assess the diagnostic and prognostic value of FVIII-binding antibodies as detected by ELISA compared with the Nijmegen Bethesda assay. Methods Samples from the time of first diagnosis and clinical data were available from 102 patients with acquired hemophilia enrolled in the prospective GTH-AH 01/2010 study. Controls (n = 102) were matched for gender and age. Diagnostic cut-offs were determined by receiver-operator curve analysis. The prognostic value was assessed in 92 of the 102 patients by Cox regression analysis of time to partial remission. Results Anti-FVIII IgG above the 99th percentile (> 15 arbitrary units per mL) revealed high sensitivity and specificity (both 0.99; 95% confidence interval, 0.95-1.0) for diagnosing acquired hemophilia. The likelihood of achieving partial remission was related to anti-FVIII IgG concentration (< 300 arbitrary units, 1.0; 300-1050, 0.65; > 1050, 0.39). The Bethesda titer was only associated with the likelihood of partial remission when analyzed in the central laboratory, but not when data from local GTH study sites were used. Conclusion Although the Nijmegen

Post-discharge compliance to venous thromboembolism prophylaxis in high-risk orthopaedic surgery: results from the ETHOS registry.

PubMed

Bergqvist, David; Arcelus, Juan I; Felicissimo, Paulo

2012-02-01

Venous thromboembolism (VTE) risk persists for several weeks following high-risk orthopaedic surgery (HROS). The ETHOS registry evaluated post-operative VTE prophylaxis prescribed, and actual VTE prophylaxis received, compared with the 2004 American College of Chest Physicians (ACCP) guidelines in HROS patients. We performed a subanalysis of ETHOS to assess patient compliance with ACCP-adherent prophylaxis after discharge and the factors predicting poor compliance. Consecutive patients undergoing hip fracture surgery, total hip arthroplasty, or knee arthroplasty were enrolled at discharge from 161 centres in 17 European countries if they had received adequate in-hospital VTE prophylaxis. Data on prescribed and actual prophylaxis received were obtained from hospital charts and patient post-discharge diaries. Good compliance was defined as percentage treatment intake ≥80% with no more than two consecutive days without treatment. A total of 3,484 patients (79.4%) received ACCP-adherent anticoagulant prescription at discharge and 2,999 (86.0%) had an evaluable patient diary. In total, 87.7% of evaluable patients were compliant with prescribed treatment after discharge. The most common reason for non-compliance (33.4%) was "drug was not bought". Injection of treatment was not a barrier to good compliance. Main factors affecting compliance related to purchase of and access to treatment, patient education, the person responsible for administering injections, country, and type of hospital ward at discharge. Within our study population, patient compliance with ACCP-adherent thromboprophylaxis prescribed at discharge was good. Improvements in patient education and prescribing practices at discharge may be important in further raising compliance levels in high-risk orthopaedic surgery patients.

Secreted HSP Vaccine for Malaria Prophylaxis

DTIC Science & Technology

2016-10-26

AWARD NUMBER: W81XWH-13-2-0098 TITLE: Secreted HSP Vaccine for Malaria Prophylaxis PRINCIPAL INVESTIGATOR: Dr. Natasa Strbo CONTRACTING ORGANIZATION...Secreted HSP Vaccine for Malaria Prophylaxis 4. TITLE AND SUBTITLE NATASA STRBO, M.D., D.SC NAME(S) AND E-M tzA UNIVERS]TY OF MTAMI 1600 NW 1OTH AVENUE ROOM...Here we developed malaria vaccine that relies on secreted gp96-lg chaperon-ing Plasmodium falciparum antigenic sporozoite proteins CSP and AMA1. The

The genetic background of hypertensive, septic rats determines outcome improvement with antibiotic and G-CSF prophylaxis.

PubMed

Bauhofer, Artur; Tischer, Bjirn; Middeke, Martin; Plaul, Ulrike; Lorenz, Wilfried; Torossian, Alexander

2003-10-01

Hypertension is proposed as a risk factor among others (high age, diabetes mellitus, and pre- and intraoperative bleeding) for adverse outcomes, such as severe infections, leading to sepsis and to multiple organ failure as the most deleterious complication. Hypertension was modeled with spontaneous hypertensive rats (SHR) and Dahl salt-sensitive (DS) rats and the infective complication by polymicrobial, peritoneal contamination, and infection (PCI). The concept of clinic modeling randomized trials was used to simulate clinical complexity, including a relevant antibiotic prophylaxis in combination with granulocyte-colony stimulating factor (G-CSF) and clinical trial conditions. Outcome parameters were: survival, systemic cytokines (protein), and organ-specific cytokine levels (mRNA). With low complexity (no prophylaxis), 28% of the animals in the Wistar and 50% in the SHR group survived (P=0.17). Tumor necrosis factor-alpha levels were lower in the liver of SHR vs. Wistar rats with PCI (P<0.01). The anti-inflammatory cytokine interleukin (IL)-10 was expressed on a higher level in SHR with PCI compared with Wistar rats (P<0.01). With increased complexity (antibiotic and G-CSF prophylaxis) the survival rate was increased from 50% in Wistar rats to 89% in SHR (P<0.01) and the mRNA expression of IL-6 was decreased in the kidney of SHR (P<0.05). Survival rate was 44% in the DS rats vs. 67% of the Wistar rats (P=0.18). The mRNA expression of tumor necrosis factor-alpha and IL-10 was reduced (P<0.01) by pretreatment in the liver of DS rats with PCI. The hypertensive, genetically distinct SHR and DS rats express different patterns of pro- and anti-inflammatory cytokine levels after PCI. G-CSF and antibiotic prophylaxis increases only in SHR survival and decreases IL-6 mRNA expression in the kidney significantly.

Structural characterization of the novel aminoglycoside phosphotransferase AphVIII from Streptomyces rimosus with enzymatic activity modulated by phosphorylation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Boyko, Konstantin M., E-mail: kmb@inbi.ras.ru; National Research Center “Kurchatov Institute”, Kurchatov Complex of NBICS-technologies, Akad. Kurchatova sqr., 1, Moscow, 123182; Gorbacheva, Marina A.

2016-09-02

Aminoglycoside phosphotransferases represent a broad class of enzymes that promote bacterial resistance to aminoglycoside antibiotics via the phosphorylation of hydroxyl groups in the latter. Here we report the spatial structure of the 3′-aminoglycoside phosphotransferase of novel VIII class (AphVIII) solved by X-ray diffraction method with a resolution of 2.15 Å. Deep analysis of APHVIII structure and its comparison with known structures of aminoglycoside phosphotransferases of various types reveals that AphVIII has a typical two-domain fold and, however, possesses some unique characteristics that distinguish the enzyme from its known homologues. The most important difference is the presence of the activation loop withmore » unique Ser146 residue. We demonstrate that in the apo-state of the enzyme the activation loop does not interact with other parts of the enzyme and seems to adopt catalytically competent state only after substrate binding. - Highlights: • 3D structure of the novel aminoglycoside phosphotransferase AphVIII was obtained. • AphVIII activation loop is clearly identified in the electron density. • AphVIII has some unique structural features in its substrate C-ring binding pocket.« less

Long-term, low-dose prophylaxis against urinary tract infections in young children.

PubMed

Brandström, Per; Hansson, Sverker

2015-03-01

Urinary tract infection (UTI) affects about 2 % of boys and 8 % of girls during the first 6 years of life with Escherichia coli as the predominant pathogen. Symptomatic UTI causes discomfort and distress, and carries a risk of inducing renal damage. The strong correlation between febrile UTI, dilating vesicoureteral reflux (VUR), and renal scarring led to the introduction of antibiotic prophylaxis for children with VUR to reduce the rate of UTI recurrence. It became common practice to use prophylaxis for children with VUR and other urinary tract abnormalities. This policy has been challenged because of a lack of scientific support. Now, randomized controlled studies are available that compare prophylaxis to no treatment or placebo. They show that children with normal urinary tracts or non-dilating VUR do not benefit from prophylaxis. Dilating VUR may still be an indication for prophylaxis in young children. After the first year of life, boys have very few recurrences and do not benefit from prophylaxis. Girls with dilating VUR, on the other hand, are more prone to recurrences and benefit from prophylaxis. There has been a decline in the use of prophylaxis due to questioning of its efficacy, increasing bacterial resistance, and a propensity to low adherence to medication. Alternative measures to reduce UTI recurrences should be emphasized. However, in selected patients carefully followed, prophylaxis can protect from recurrent UTI and long-term sequelae. 1. There is a strong correlation between UTI, VUR, and renal scarring. 2. Children with normal urinary tracts or non-dilating VUR do not benefit from prophylaxis. 3. Young children, mainly girls, with dilating VUR are at risk of recurrent UTI and acquired renal scarring and seem to gain from antibiotic prophylaxis. 4. Increasing bacterial resistance and low adherence with prescribed medication is a major obstacle to successful antibiotic prophylaxis.

Observational cohort study of pediatric inpatients with central venous catheters at "intermediate risk" of thrombosis and eligible for anticoagulant prophylaxis.

PubMed

Harney, Kathy M; McCabe, Margaret; Branowicki, Patricia; Kalish, Leslie A; Neufeld, Ellis J

2010-01-01

The risk of deep vein thrombosis (DVT) among hospitalized children is rising.The optimal approach to DVT prophylaxis in children is unclear. This study set out to ascertain the prevalence of DVT among pediatric inpatients who neither have contraindications to nor absolute indications for prophylactic therapy. A prospective surveillance of at-risk children plus a retrospective chart review were conducted. Patients were considered to be at risk after the first 2 days of their admission. Of 1,637 patients reviewed, 198 patients met criteria; among these, 84% did not receive prophylaxis. Of 2,354 observed days at risk for nonprophylaxed patients (including days at risk prior to initiating prophylaxis among prophlyaxed patients), there were 9 DVT events, for a rate 3.82/1,000 days observed. A total of 31 patients received prophylaxis. Three of these patients experienced a DVT. One patient had a bleeding event, hematuria. These results describe patients who may be eligible for prophylaxis and should be screened for further risk factors.

Prophylaxis of thromboembolism in bariatric surgery with parnaparin.

PubMed

Forestieri, Pietro; Quarto, Gennaro; De Caterina, Maurizio; Cuocolo, Alberto; Pilone, Vincenzo; Formato, Antonio; Ruocco, Aldo; Ferrari, Patrizio

2007-12-01

There are limited data on appropriate dosing of low-molecular-weight heparins (LMWHs) for venous thromboembolism (VTE) prophylaxis in bariatric surgery. The primary objective of this preliminary study was to evaluate the preoperative effects of increasing doses of the LMWH parnaparin on coagulation in severely obese patients undergoing bariatric surgery. Severely obese patients (BMI > 50 kg/m(2)) were administered three increasing single doses of parnaparin (3200, 4250, and 6400 IU) on the three consecutive days leading up to biliointestinal bypass surgery. Activated partial thromboplastin time (APTT), anti-factor IIa and anti-factor Xa levels were measured 1 h before and 4 h after dosing. The highest dose (6400 IU/day) was continued from the day of surgery until day 30 (recovery period). Intermittent pneumatic compression and stockings were applied during surgery and the recovery period, respectively. Lower limb echoDoppler and phleboscintigraphy, and pulmonary scintigraphy were used for VTE detection. Ten patients (mean BMI 52.4 kg/m(2)) were recruited into this study. During the preoperative dosing phase, parnaparin dose-dependently prolonged APTT, with the 6400 IU dose significantly prolonging APTT versus the lower doses. Meanwhile, anti-factor Xa and anti-factor IIa activity was increased by the 4250 and 6400 IU doses. After surgery, one patient with heparin resistance experienced pulmonary embolization. No bleeding complications were observed. The dose-response data reported in this preliminary study suggest that parnaparin doses of 4250 and 6400 IU may provide effective prophylaxis for VTE in patients undergoing bariatric surgery. However, given the small number of patients, larger, well-controlled trials are required to confirm these findings.

Hepatitis B reactivation and timing for prophylaxis

PubMed Central

Tuna, Nazan; Karabay, Oguz

2015-01-01

It is known that immunotherapy and cancer chemotherapy may cause hepatitis B virus (HBV) reactivation in hepatitis B surface antigen carriers and inactive chronic hepatitis B patients. Guidelines recommend antiviral prophylaxis regardless of HBV DNA levels to prevent reactivation. We read from the article written by Liu et al that Lamivudine was given inadequate time for antiviral prophylaxis. PMID:25717269

Thromboelastography during coronary artery bypass grafting surgery of severe hemophilia A patient - the effect of heparin and protamine on factor VIII activity.

PubMed

Misgav, Mudi; Mandelbaum, Tal; Kassif, Yigal; Berkenstadt, Haim; Tamarin, Ilia; Kenet, Gili

2017-06-01

: Coronary artery bypass grafting surgery (CABG) in hemophilia patients is challenging. Thromboelastography (TEG) is useful to assess hemostasis perioperatively. A patient with severe hemophilia A underwent CABG with TEG studies. After factor VIII (FVIII) bolus dose, TEG was normalized. Following 'on-pump' heparinization, protamine administration revealed prolonged TEG-R and TEG-R with heparinase confirming it, whereas the activated clotting time was normal, suggesting low FVIII activity rather than excess of heparin. Another FVIII bolus yielded complete normalization of all TEG parameters. Data are compatible with in-vitro assays performed in our laboratory, showing that both heparin and protamine may impair measurable FVIII activity. The rational use of TEG measurements enabled more accurate hemostatic therapy application with regard to FVIII, heparin and protamine administration. Adopting this approach may lead to a better therapy tailoring for hemophilia patients undergoing CABG surgery.

Is LMWH Sufficient for Anticoagulant Prophylaxis in Bariatric Surgery? Prospective Study.

PubMed

Moaad, Farraj; Zakhar, Bramnik; Anton, Kvasha; Moner, Merie; Wisam, Sbeit; Safy, Farraj; Igor, Waksman

2017-09-01

The objective of this study was to evaluate the coagulation profile by thromboelastography in morbidly obese patients who undergo bariatric surgery. Morbid obesity entails increased risk for thromboembolic events. There is no clear protocol for thromboembolic prophylaxis, regarding timing and length of treatment, in bariatric surgery. Thromboelastography provides data on a coagulation process from creation of the clot until the fibrinolysis. Ninety-three morbidly obese patients were prospectively recruited within a 2-year period. Coagulation profile was measured by thromboelastography before surgery, in the immediate postoperative period, within 3 h from surgery, and in the late postoperative period, within 10-14 days after surgery. Venous thromboembolic prophylaxis was achieved by giving low molecular weight heparin (LMWH), once a day. Of the eligible patients, 67 underwent sleeve gastrectomy while 23 underwent Roux-en-Y gastric bypass. Normal values of coagulation factor function, clotting time, and fibrin function, as measured by R, K, and α (angle), were demonstrated in addition to higher maximal amplitude (MA) values, reflecting increased function of platelets. The average MA value before the surgery was above normal and continued rising consistently in the immediate postoperative as well as in the early postoperative period. Morbidly obese patients have a strong tendency toward thrombosis, as demonstrated by pathologically elevated MA values. Altered coagulation profiles were demonstrated 2 weeks postoperatively; thus, prophylaxis that continued at least for 2 weeks after bariatric surgery should be considered. Since LMW heparin is not sufficient alone as thromboembolic prophylaxis, we recommend adding antiplatelet therapy. Further evaluation of appropriate thromboprophylaxis is warranted.

Antiepileptic prophylaxis following severe traumatic brain injury within a military cohort.

PubMed

Cranley, Mark R; Craner, M; McGilloway, E

2016-04-01

Traumatic brain injury increases the risk of both early and late seizures. Antiepileptic prophylaxis reduces early seizures, but their use beyond 1 week does not prevent the development of post-traumatic epilepsy. Furthermore, prolonged prophylaxis exposes patients to side effects of the drugs and has occupational implications. The American Academy of Neurology recommends that antiepileptic prophylaxis should be started for patients with severe traumatic brain injury and discontinued after 1 week. An audit is presented here that investigates the use of prophylaxis in a cohort of military patients admitted to the UK Defence Medical Rehabilitation Centre (DMRC). Data were collected and analysed retrospectively from electronic and paper records between February 2009 and August 2012. The timing and duration of antiepileptic drug use and the incidence of seizures were recorded. During the study period, 52 patients with severe traumatic brain injury were admitted to the rehabilitation centre: 25 patients (48%) were commenced on prophylaxis during the first week following injury while 27 (52%) did not receive prophylaxis. Only one patient (2%) received prophylaxis for the recommended period of 1 week, 22 patients (42%) received prophylaxis for longer than 1 week with a mean duration of 6.2 months. Two patients (4%) had post-traumatic epilepsy and started on treatment at DMRC. The use of antiepileptic prophylaxis varies widely and is generally inconsistent with evidence-based guidance. This exposes some patients to a higher risk of early seizures and others to unnecessary use of antiepileptics. Better implementation of prophylaxis is required. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

Ehlers–Danlos syndrome type VIII is clinically heterogeneous disorder associated primarily with periodontal disease, and variable connective tissue features

PubMed Central

Reinstein, Eyal; DeLozier, Celia Dawn; Simon, Ziv; Bannykh, Serguei; Rimoin, David L; Curry, Cynthia J

2013-01-01

Ehlers–Danlos syndrome (EDS) type VIII (periodontitis type) is a distinct form of EDS characterized by periodontal disease leading to precocious dental loss and a spectrum of joint and skin manifestations. EDS type VIII is transmitted in an autosomal dominant pattern; however, the mutated gene has not been identified. There are insufficient data on the spectrum of clinical manifestations and natural history of the disorder, and only a limited number of patients and pedigrees with this condition have been reported. We present a four-generation EDS type VIII kindred and show that EDS VIII is clinically variable and although some cases lack the associated skin and joint manifestations, microscopic evidence of collagen disorganization is detectable. We further propose that the diagnosis of EDS type VIII should be considered in familial forms of periodontitis, even when the associated skin and joint manifestations are unconvincing for the diagnosis of a connective tissue disorder. This novel observation highlights the uncertainty of using connective tissue signs in clinical practice to diagnose EDS type VIII. PMID:22739343

Cytomegalovirus Hyper Immunoglobulin for CMV Prophylaxis in Thoracic Transplantation

PubMed Central

Rea, Federico; Potena, Luciano; Yonan, Nizar; Wagner, Florian; Calabrese, Fiorella

2016-01-01

Cytomegalovirus (CMV) infection negatively influences both short- and long-term outcomes after cardiothoracic transplantation. In heart transplantation, registry analyses have shown that CMV immunoglobulin (CMVIG) with or without virostatic prophylaxis is associated with a significant reduction in mortality and graft loss versus no prophylaxis, particularly in high-risk donor (D)+/recipient (R)− transplants. Randomized comparative trials are lacking but retrospective data suggest that addition of CMVIG to antiviral prophylaxis may reduce rates of CMV-related events after heart transplantation, including the incidence of acute rejection or chronic allograft vasculopathy. However, available data consistently indicate that when CMVIG is used, it should be administered with concomitant antiviral therapy, and that evidence concerning preemptive management with CMVIG is limited, but promising. In lung transplantation, CMVIG should again only be used with concomitant antiviral therapy. Retrospective studies have shown convincing evidence that addition of CMVIG to antiviral prophylaxis lowers CMV endpoints and mortality. The current balance of evidence suggests that CMVIG prophylaxis reduces the risk of bronchiolitis obliterans syndrome, but a controlled trial is awaited. Overall, the relatively limited current data set suggests that prophylaxis with CMVIG in combination with antiviral therapy appears effective in D+/R− heart transplant patients, whereas in lung transplantation, addition of CMVIG in recipients of a CMV-positive graft may offer an advantage in terms of CMV infection and disease. PMID:26900991

Post-Exposure Prophylaxis

MedlinePlus

... gov Reason Number 87 to Get an HIV Test Veterans #DoingItMyWay – Testing for HIV June 27th is National HIV Testing Day Ryan White and HIV Testing Day 2018 Additional Resources AIDSInfo – Occupational Post-exposure Prophylaxis (PEP) Guidelines AIDSInfo – Nonoccupational Post-exposure ...

Metabolic aspects and viability of heparin/CPDA-1-stored red cell concentrate as a by-product of a high-yield factor VIII production method.

PubMed

de Jonge, J; Smit Sibinga, C T; Das, P C

1983-01-01

As a by-product of a new high-yield method of production of freeze-dried factor VIII, red cell concentrate (RCC) containing a small amount of heparin besides CPDA-1 was studied. Compared to CPDA-1 stored RCC no difference was found in hematology parameters and 2,3-DPG levels during 28 days storage. Although still in the normal range for transfusion, ATP levels were significantly lower compared to CPDA-1-stored RCC after 30 days shelf life. A survival study with 51Cr-labelled red cells showed good recovery and normal red cell half-life. Rapid transfusion of heparin/CPDA-1 RCC in 6 volunteers did not have any effect on aPTT. Heparin could not be detected in posttransfusion plasma samples.

Comparative trial of the use of antiplatelet and oral anticoagulant in thrombosis prophylaxis in patients undergoing total cavopulmonary operation with extracardiac conduit: echocardiographic, tomographic, scintigraphic, clinical and laboratory analysis.

PubMed

Pessotti, Cristiane Felix Ximenes; Jatene, Marcelo Biscegli; Jatene, Ieda Biscegli; Oliveira, Patrícia Marques; Succi, Fabiana Moreira Passos; Moreira, Valeria de Melo; Lopes, Rafael Willain; Pedra, Simone Rolim Fernandes Fontes

2014-01-01

To compare the efficacy of aspirin and warfarin for prophylaxis of thrombosis in patients undergoing total cavopulmonary anastomosis. Evaluate whether coagulation factors (VII, VIII and protein C), clinical data, fenestration or hemodynamic factors, interfere with postoperative thrombosis. A prospective, randomized study of 30 patients, randomized into Group I (Warfarin) and Group II (AAS), underwent total cavopulmonary shunt with extracardiac conduit, between 2008 and 2011, with follow-up by clinical visits to evaluate side effects and adhesion. Performed transesophageal echocardiography in post operatory time, 3, 6,12 and 24 months; angiotomography at 6, 12 and 24 months to evaluate changes in the internal tube wall or thrombi and pulmonary scintigraphy to evaluate possible PTE. Two deaths in group I; 33.3% of patients had thrombus (46.7% in Group II). The previous occurrence of thrombus and low levels of coagulation protein C were the only factors that influenced the time free of thrombus (P=0.035 and 0.047). Angiotomographic evaluation: 35.7% in group II presented material accumulation greater than 2 mm (P=0.082). Scintigraphy: two patients had PTE in group II. Five patients had difficulty to comply with the treatment, 4 in group I with INR ranging from 1 to 6.4. The previous occurrence of thrombus is a risk factor for thrombosis in the postoperative period. Patients using AAS tend to deposit material in the tube wall. The small sample size did not allow to conclude which is the most effective drug in the prevention of thrombosis in this population.

Cost effectiveness of primary pegfilgrastim prophylaxis in patients with breast cancer at risk of febrile neutropenia.

PubMed

Aarts, Maureen J; Grutters, Janneke P; Peters, Frank P; Mandigers, Caroline M; Dercksen, M Wouter; Stouthard, Jacqueline M; Nortier, Hans J; van Laarhoven, Hanneke W; van Warmerdam, Laurence J; van de Wouw, Agnes J; Jacobs, Esther M; Mattijssen, Vera; van der Rijt, Carin C; Smilde, Tineke J; van der Velden, Annette W; Temizkan, Mehmet; Batman, Erdogan; Muller, Erik W; van Gastel, Saskia M; Joore, Manuela A; Borm, George F; Tjan-Heijnen, Vivianne C

2013-12-01

Guidelines advise primary granulocyte colony-stimulating factor (G-CSF) prophylaxis during chemotherapy if risk of febrile neutropenia (FN) is more than 20%, but this comes with considerable costs. We investigated the incremental costs and effects between two treatment strategies of primary pegfilgrastim prophylaxis. Our economic evaluation used a health care perspective and was based on a randomized study in patients with breast cancer with increased risk of FN, comparing primary G-CSF prophylaxis throughout all chemotherapy cycles (G-CSF 1-6 cycles) with prophylaxis during the first two cycles only (G-CSF 1-2 cycles). Primary outcome was cost effectiveness expressed as costs per patient with episodes of FN prevented. The incidence of FN increased from 10% in the G-CSF 1 to 6 cycles study arm (eight of 84 patients) to 36% in the G-CSF 1 to 2 cycles study arm (30 of 83 patients), whereas the mean total costs decreased from € 20,658 (95% CI, € 20,049 to € 21,247) to € 17,168 (95% CI € 16,239 to € 18,029) per patient, respectively. Chemotherapy and G-CSF determined 80% of the total costs. As expected, FN-related costs were higher in the G-CSF 1 to 2 cycles arm. The incremental cost effectiveness ratio for the G-CSF 1 to 6 cycles arm compared with the G-CSF 1 to 2 cycles arm was € 13,112 per patient with episodes of FN prevented. We conclude that G-CSF prophylaxis throughout all chemotherapy cycles is more effective, but more costly, compared with prophylaxis limited to the first two cycles. Whether G-CSF prophylaxis throughout all chemotherapy cycles is considered cost effective depends on the willingness to pay per patient with episodes of FN prevented.

Physical activity for prevention of osteoporosis in patients with severe haemophilia on long-term prophylaxis.

PubMed

Khawaji, M; Astermark, J; Akesson, K; Berntorp, E

2010-05-01

Physical activity has been considered as an important factor for bone density and as a factor facilitating prevention of osteoporosis. Bone density has been reported to be reduced in haemophilia. To examine the relation between different aspects of physical activity and bone mineral density (BMD) in patients with severe haemophilia on long-term prophylaxis. The study group consisted of 38 patients with severe haemophilia (mean age 30.5 years). All patients received long-term prophylaxis to prevent bleeding. The bone density (BMD g cm(-2)) of the total body, lumbar spine, total hip, femoral neck and trochanter was measured by dual energy X-ray absorptiometry. Physical activity was assessed using the self-report Modifiable Activity Questionnaire, an instrument which collects information about leisure and occupational activities for the prior 12 months. There was only significant correlation between duration and intensity of vigorous physical activity and bone density at lumber spine L1-L4; for duration (r = 0.429 and P = 0.020) and for intensity (r = 0.430 and P = 0.019); whereas no significant correlation between all aspects of physical activity and bone density at any other measured sites. With adequate long-term prophylaxis, adult patients with haemophilia are maintaining bone mass, whereas the level of physical activity in terms of intensity and duration play a minor role. These results may support the proposition that the responsiveness to mechanical strain is probably more important for bone mass development in children and during adolescence than in adults and underscores the importance of early onset prophylaxis.

Coagulation Factor Tests

MedlinePlus

... your coagulation factors. Coagulation factors are known by Roman numerals (I, II VIII, etc.) or by name ( ... need this test if you have a family history of bleeding disorders. Most bleeding disorders are inherited . ...

Assessment of 30-day mortality and complication rates associated with extended deep vein thrombosis prophylaxis following hip fracture surgery.

PubMed

Durand, Wesley M; Goodman, Avi D; Johnson, Joey P; Daniels, Alan H

2018-06-01

DVT is a common complication following lower extremity surgery, occurring in up to 60% of patients undergoing hip fracture surgery without postoperative anticoagulation. The risk of fatal PE continues well-beyond two weeks postoperatively, thus extended DVT prophylaxis beyond 14 days may be warranted. This investigation sought to examine the association between prescription of extended DVT prophylaxis and 30-day postoperative complications following hip fracture surgery. This study utilized the ACS NSQIP Hip Fracture Procedure Targeted dataset, a newly available set of patient variables for 2016. The outcome measures were death, occurrence of any postoperative complication, complication subtype, readmission or reoperation within 30-days postoperatively, and length of stay. The primary independent variable was medical DVT prophylaxis continued 28-days postoperatively ("extended DVT prophylaxis"). The control group contains both patients receiving no prophylaxis and those receiving short-duration prophylaxis. Multivariate stepwise logistic regression was employed to control for potential demographic, comorbidity, and procedural/medical confounding factors. In total, 7533 surgically treated hip fracture patients treated in 2016 were analyzed. Overall, 57.8% of patients (n = 4354) were prescribed extended DVT prophylaxis. On bivariate analysis, prescription of extended DVT prophylaxis was associated with significantly lower incidence of death (7.7% without vs. 2.7% with, p < 0.0001) and stroke/CVA (1.4% vs. 0.6%, p = 0.0016). In multivariate analysis, prescription of extended DVT prophylaxis was significantly associated with lower odds of death (OR 0.33, p < 0.0001), stroke/CVA (OR 0.44, p = 0.0010), and acute kidney injury (AKI) (OR 0.31, p = 0.0010). This retrospective cohort study of the 2016 ACS NSQIP found that hip fracture surgery patients prescribed ≥28 days of postoperative DVT prophylaxis exhibited 67% lower odds of death and

Detection of two intervening Ne viii absorbers probing warm gas at z ˜ 0.6

NASA Astrophysics Data System (ADS)

Pachat, Sachin; Narayanan, Anand; Khaire, Vikram; Savage, Blair D.; Muzahid, Sowgat; Wakker, Bart P.

2017-10-01

We report on the detection of two Ne viii absorbers, at z = 0.619 07 and 0.570 52 in the Hubble Space Telescope/Cosmic Origins Spectrograph spectrum of background quasars SDSS J080908.13 + 461925.6 and SBS 1122 + 594, respectively. The Ne viii 770 line is at ˜3σ significance. In both instances, the Ne viii is found to be tracing gas with T ≳ 105 K, predominantly collisionally ionized, with moderate densities of n_{H} ≲ 10^{-4} cm-3, sub-solar metallicities and total hydrogen column densities of N(H) ≳ 1019 cm-2. In the z = 0.619 07 absorber, the low, intermediate ions and O VI are consistent with origin in photoionized gas, with the O VI potentially having some contribution from the warm collisional phase traced by Ne viii. The z = 0.570 52 system has H I absorption in at least three kinematically distinct components, with one of them having b({H I}) = 49 {± } 11 km s-1. The intermediate-ionization lines, O VI and Ne viii, are coincident in velocity with this component. Their different line widths suggest warm temperatures of T = (0.5-1.5) × 105 K. Both absorbers are residing in regions where there are several luminous (≳L★) galaxies. The absorber at z = 0.570 52 is within the virial radius of a 2.6L★ galaxy, possibly associated with shock-heated circumgalactic material.

Deep Vein Thrombosis Prophylaxis: State of the Art.

PubMed

Lieberman, Jay R

2018-03-21

The selection of a prophylaxis regimen to prevent symptomatic pulmonary embolism and deep vein thrombosis is a balance between efficacy and safety. The latest American Academy of Orthopaedic Surgeons guideline recommended that either chemoprophylaxis or mechanical prophylaxis be used after total joint arthroplasty but did not recommend specific agents. However, the latest evidence-based American College of Chest Physicians guideline recommended a variety of chemoprophylaxis and mechanical agents for a minimum of 10 to 14 days after total joint arthroplasty. Risk stratification is the key to the selection of the appropriate prophylaxis regimen for the individual patient, but the optimal risk stratification protocol still needs to be developed. Copyright © 2018. Published by Elsevier Inc.

[Prophylaxis of alcoholic disease of the liver].

PubMed

Beliakin, S A

2009-08-01

Military doctors should have a uniform position to the use of alcohol. Now alcohol is the basic pathogenic factor in development of a lethal cirrhosis of a liver. The most known sayings justifying the use of alcohol, are insolvent. Useful doses of alcohol does not exist. The quantity of used alcohol has the great value. Only at achievement of age 21 year it is possible to use safe doses of alcohol. A safe dose of pure alcohol (ethanol) less than 30,0 in day. In a basis of prophylaxis of a cirrhosis of a liver there is a medical educational activity.

Risk factors for venous thromboembolic events in pediatric surgical patients: Defining indications for prophylaxis.

PubMed

Cairo, Sarah B; Lautz, Timothy B; Schaefer, Beverly A; Yu, Guan; Naseem, Hibbut-Ur-Rauf; Rothstein, David H

2017-12-27

Venous thromboembolism (VTE) in pediatric surgical patients is a rare event. The risk factors for VTE in pediatric general surgery patients undergoing abdominopelvic procedures are unknown. The American College of Surgeon's National Surgical Quality Improvement Program-Pediatric (NSQIP-P) database (2012-2015) was queried for patients with VTE after abdominopelvic general surgery procedures. Patient and operative variables were assessed to identify risk factors associated with VTE and develop a pediatric risk score. From 2012-2015, 68 of 34,813 (0.20%) patients who underwent abdominopelvic general surgery procedures were diagnosed with VTE. On multivariate analysis, there was no increased risk of VTE based on concomitant malignancy, chemotherapy, inflammatory bowel disease, or laparoscopic surgical approach, while a higher rate of VTE was identified among female patients. The odds of experiencing VTE were increased on stepwise regression for patients older than 15 years and those with preexisting renal failure or a diagnosis of septic shock, patients with American Society of Anesthesia (ASA) classification ≥ 2, and for anesthesia time longer than 2 h. The combination of age > 15 years, ASA classification ≥ 2, anesthesia time > 2 h, renal failure, and septic shock was included in a model for predicting risk of VTE (AUC = 0.907, sensitivity 84.4%, specificity 88.2%). VTE is rare in pediatric patients, but prediction modeling may help identify those patients at heightened risk. Additional studies are needed to validate the factors identified in this study in a risk assessment model as well as to assess the efficacy and cost-effectiveness of prophylaxis methods. Level III, retrospective comparative study. Copyright © 2018. Published by Elsevier Inc.

A national survey of antimicrobial prophylaxis in adult cardiac surgery across Canada

PubMed Central

Paradiso-Hardy, Fran L; Cornish, Patti; Pharand, Chantal; Fremes, Stephen E

2002-01-01

OBJECTIVE: To characterize national and regional patterns of antimicrobial prophylaxis in adult cardiac surgery across Canada. DESIGN: Retrospective, cross-sectional analysis. SETTING: Thirty-three adult cardiac surgical centres across Canada. INTERVENTIONS: A one-page questionnaire collecting information regarding institutional demographics and antimicrobial prophylaxis regimens for adult cardiac surgical procedures was mailed to all adult surgical centres across Canada. If a response was not received within one month, a second survey was mailed, followed by a telephone reminder within two weeks of the second mailing. MAIN RESULTS: The Overall response rate was 100%. Prophylactic antimicrobials were used in all the adult cardiac centres; single-agent prophylaxis was used in 97% (32 of 33) of centres; Single-dose antimicrobial prophylaxis was used in only 3% (one of 33) of centres. Preoperative and postoperative antimicrobial prophylaxis regimens varied both between provinces and within provinces across Canada. Cefazolin was the antimicrobial used in 88% (38 of 43) and 87% (33 of 38) of the reported pre-operative and post-operative prophylaxis regimens, respectively. Antimicrobial prophylaxis was initiated in the operating room 72% (26 of 36) of the time and intra-operative supplemental antimicrobial doses were administered for cardiac procedures longer than a median of 4 hours (range 4 to 8 hr). Overall, the median duration of antimicrobial prophylaxis was 36 hours (range 8 to 96 hr). CONCLUSIONS: Despite the availability of various published guidelines, our survey identified several areas for improvement with respect to antimicrobial prophylaxis in adult cardiac surgery across Canada. PMID:18159370

Clinical Prediction of Failure of Lamivudine Prophylaxis for Hepatitis B Virus-Infected Patients Undergoing Cytotoxic Chemotherapy for Malignancy

PubMed Central

Kim, In Kyoung; Kim, Byeong Gwan; Kim, Donghee; Kim, Yoon Jun; Yoon, Jung-Hwan; Lee, Hyo Suk

2012-01-01

Although lamivudine (LAM) prophylaxis is recommended for patients infected with hepatitis B virus (HBV) undergoing chemotherapy for malignant disease, HBV reactivation sometimes occurs during or after LAM administration. The aim of this study was to determine predictors of LAM prophylactic failure in patients with malignancies. Patients with malignancies were routinely screened for serum hepatitis B surface antigen (HBsAg) from June 2002 to August 2008. All consecutive, HBsAg-positive patients received LAM prophylaxis during and after completion of chemotherapy. We assessed risk factors for virologic breakthrough and withdrawal hepatitis. Death without HBV reactivation was regarded as a competing risk event, which was adjusted by Fine and Gray's model. A total of 110 patients were included in this study. They received LAM prophylaxis for a median of 9.2 months. Virologic breakthrough occurred in 15 patients at a median of 10.9 months from the initiation of LAM prophylaxis. Withdrawal hepatitis occurred in 15 patients at a median of 2.4 months after cessation of LAM prophylaxis. Multivariable analysis showed that high baseline HBV DNA titer (≥2,000 IU/ml) (hazard ratio [HR], 9.94; P = 0.0063) and the use of rituximab (HR, 3.19; P = 0.027) were significant predictors of virologic breakthrough and that high baseline HBV DNA titer (HR, 5.90; P = 0.007), liver cirrhosis (HR, 10.4; P = 0.002), and distant metastasis (HR, 5.14; P = 0.008) were independent risk factors for withdrawal hepatitis. Patients with high viremia, liver cirrhosis, rituximab treatment, and distant metastasis are at high risk of prophylactic failure and need antiviral agents with a greater barrier to resistance. PMID:22890764

Failure to Redose Antibiotic Prophylaxis in Long Surgery Increases Risk of Surgical Site Infection.

PubMed

Kasatpibal, Nongyao; Whitney, Joanne D; Dellinger, E Patchen; Nair, Bala G; Pike, Kenneth C

Antibiotic prophylaxis is a key component of the prevention of surgical site infection (SSI). Failure to manage antibiotic prophylaxis effectively may increase the risk of SSI. This study aimed to examine the effects of antibiotic prophylaxis on SSI risk. A retrospective cohort study was conducted among patients having general surgery between May 2012 and June 2015 at the University of Washington Medical Center. Peri-operative data extracted from hospital databases included patient and operation characteristics, intra-operative medication and fluid administration, and survival outcome. The effects of antibiotic prophylaxis and potential factors on SSI risk were estimated using multiple logistic regression and were expressed as risk ratios (RRs). A total of 4,078 patients were eligible for analysis. Of these, 180 had an SSI. Mortality rates within and after 30 days were 0.8% and 0.3%, respectively. Improper antibiotic redosing increased the risk of SSI (RR 4.61; 95% confidence interval [CI] 1.33-15.91). Other risk factors were in-patient status (RR 4.05; 95% CI 1.69-9.66), smoking (RR 1.63; 95% CI 1.03-2.55), emergency surgery (RR 1.97; 95% CI 1.26-3.08), colectomy (RR 3.31; 95% CI 1.19-9.23), pancreatectomy (RR 4.52; 95% CI 1.53-13.39), proctectomy (RR 5.02; 95% CI 1.72-14.67), small bowel surgery (RR 6.16; 95% CI 2.13-17.79), intra-operative blood transfusion >500 mL (RR 2.76; 95% CI 1.45-5.26), and multiple procedures (RR 1.40; 95% CI 1.01-1.95). These data demonstrate that failure to redose prophylactic antibiotic during long operations increases the risk of SSI. Strengthening a collaborative surgical quality improvement program may help to eradicate this risk.

Increased risk of RSV infection in children with Down's syndrome: clinical implementation of prophylaxis in the European Union.

PubMed

van Beek, Dianne; Paes, Bosco; Bont, Louis

2013-01-01

Prospective cohort studies show that Down's syndrome (DS) is an independent risk factor for hospitalization for RSV bronchiolitis. It is unknown whether this observation has been translated into specific management for DS children. The primary goal was to assess the knowledge of healthcare providers in the European Union about RSV infection in DS children and to determine whether it influenced the implementation of prophylaxis. DS caregivers were surveyed using a standardized questionnaire, and country-specific guidelines were obtained. Fifty-three caregivers participated. Thirty-nine (86.7%) had knowledge of the increased risk of severe RSV infection in DS children, and 30 (71.4%) graded that it was important to have a statement on the use of RSV prophylaxis in existing guidelines. Twenty-eight participants had a local DS guideline; hard copies of twelve unique guidelines were obtained. Only one (8.3%) contained a statement on RSV prophylaxis for DS, and five considered such a statement for the next version. Conclusion. Most pediatricians had knowledge that DS children have an increased risk of severe RSV infection. Despite the lack of a specific RSV prophylaxis trial in DS, they felt that a statement on RSV prophylaxis in DS guidelines was important, but this was rarely present in current guidelines.

Increased Risk of RSV Infection in Children with Down's Syndrome: Clinical Implementation of Prophylaxis in the European Union

PubMed Central

Paes, Bosco; Bont, Louis

2013-01-01

Prospective cohort studies show that Down's syndrome (DS) is an independent risk factor for hospitalization for RSV bronchiolitis. It is unknown whether this observation has been translated into specific management for DS children. The primary goal was to assess the knowledge of healthcare providers in the European Union about RSV infection in DS children and to determine whether it influenced the implementation of prophylaxis. DS caregivers were surveyed using a standardized questionnaire, and country-specific guidelines were obtained. Fifty-three caregivers participated. Thirty-nine (86.7%) had knowledge of the increased risk of severe RSV infection in DS children, and 30 (71.4%) graded that it was important to have a statement on the use of RSV prophylaxis in existing guidelines. Twenty-eight participants had a local DS guideline; hard copies of twelve unique guidelines were obtained. Only one (8.3%) contained a statement on RSV prophylaxis for DS, and five considered such a statement for the next version. Conclusion. Most pediatricians had knowledge that DS children have an increased risk of severe RSV infection. Despite the lack of a specific RSV prophylaxis trial in DS, they felt that a statement on RSV prophylaxis in DS guidelines was important, but this was rarely present in current guidelines. PMID:23878586

Role of vaccinations and prophylaxis in rheumatic diseases.

PubMed

Papadopoulou, Despoina; Tsoulas, Christos; Tragiannidis, Athanassios; Sipsas, Nikolaos V

2015-04-01

Targeted strategies for reducing the increased risk of infection in patients with autoimmune rheumatic diseases include vaccinations as well as antibiotic prophylaxis in selected patients. However, there are still issues under debate: Is vaccination in patients with rheumatic diseases immunogenic? Is it safe? What is the impact of immunosuppressive drugs on vaccine immunogenicity and safety? Does vaccination cause disease flares? In which cases is prophylaxis against Pneumocystis jirovecii required? This review addresses these important questions to which clinicians and researchers still do not have definite answers. The first part includes immunization recommendations and reviews current data on vaccine efficacy and safety in patients with rheumatic diseases. The second part discusses prophylaxis for Pneumocystis pneumonia. Copyright © 2015 Elsevier Ltd. All rights reserved.

Antibiotic prophylaxis for operative vaginal delivery.

PubMed

Liabsuetrakul, Tippawan; Choobun, Thanapan; Peeyananjarassri, Krantarat; Islam, Q Monir

2017-08-05

Vacuum and forceps assisted vaginal deliveries are reported to increase the incidence of postpartum infections and maternal readmission to hospital compared to spontaneous vaginal delivery. Prophylactic antibiotics may be prescribed to prevent these infections. However, the benefit of antibiotic prophylaxis for operative vaginal deliveries is still unclear. To assess the effectiveness and safety of antibiotic prophylaxis in reducing infectious puerperal morbidities in women undergoing operative vaginal deliveries including vacuum or forceps deliveries, or both. We searched Cochrane Pregnancy and Childbirth's Trials Register (12 July 2017), ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform (ICTRP) (12 July 2017) and reference lists of retrieved studies. All randomised trials comparing any prophylactic antibiotic regimens with placebo or no treatment in women undergoing vacuum or forceps deliveries were eligible. Participants were all pregnant women without evidence of infections or other indications for antibiotics of any gestational age undergoing vacuum or forceps delivery for any indications. Interventions were any antibiotic prophylaxis (any dosage regimen, any route of administration or at any time during delivery or the puerperium) compared with either placebo or no treatment. Two review authors assessed trial eligibility and methodological quality. Two review authors extracted the data independently using prepared data extraction forms. Any discrepancies were resolved by discussion and a consensus reached through discussion with all review authors. We assessed methodological quality of the one included trial using the GRADE approach. One trial, involving 393 women undergoing either vacuum or forceps deliveries, was included. The trial compared the antibiotic intravenous cefotetan after cord clamping compared with no treatment. This trial reported only two out of the nine outcomes specified in this review. Seven women in the group

Cost-effectiveness of adding granulocyte colony-stimulating factor to primary prophylaxis with antibiotics in small-cell lung cancer.

PubMed

Timmer-Bonte, Johanna N H; Adang, Eddy M M; Smit, Hans J M; Biesma, Bonne; Wilschut, Frank A; Bootsma, Gerben P; de Boo, Theo M; Tjan-Heijnen, Vivianne C G

2006-07-01

Recently, a Dutch, randomized, phase III trial demonstrated that, in small-cell lung cancer patients at risk of chemotherapy-induced febrile neutropenia (FN), the addition of granulocyte colony-stimulating factor (GCSF) to prophylactic antibiotics significantly reduced the incidence of FN in cycle 1 (24% v 10%; P = .01). We hypothesized that selecting patients at risk of FN might increase the cost-effectiveness of GCSF prophylaxis. Economic analysis was conducted alongside the clinical trial and was focused on the health care perspective. Primary outcome was the difference in mean total costs per patient in cycle 1 between both prophylactic strategies. Cost-effectiveness was expressed as costs per percent-FN-prevented. For the first cycle, the mean incremental costs of adding GCSF amounted to 681 euro (95% CI, -36 to 1,397 euro) per patient. For the entire treatment period, the mean incremental costs were substantial (5,123 euro; 95% CI, 3,908 to 6,337 euro), despite a significant reduction in the incidence of FN and related savings in medical care consumption. The incremental cost-effectiveness ratio was 50 euro per percent decrease of the probability of FN (95% CI, -2 to 433 euro) in cycle 1, and the acceptability for this willingness to pay was approximately 50%. Despite the selection of patients at risk of FN, the addition of GCSF to primary antibiotic prophylaxis did not result in cost savings. If policy makers are willing to pay 240 euro for each percent gain in effect (ie, 3,360 euro for a 14% reduction in FN), the addition of GCSF can be considered cost effective.

Antibiotic prophylaxis and risk of Clostridium difficile infection after coronary artery bypass graft surgery.

PubMed

Poeran, Jashvant; Mazumdar, Madhu; Rasul, Rehana; Meyer, Joanne; Sacks, Henry S; Koll, Brian S; Wallach, Frances R; Moskowitz, Alan; Gelijns, Annetine C

2016-02-01

Antibiotic use, particularly type and duration, is a crucial modifiable risk factor for Clostridium difficile. Cardiac surgery is of particular interest because prophylactic antibiotics are recommended for 48 hours or less (vs ≤24 hours for noncardiac surgery), with increasing vancomycin use. We aimed to study associations between antibiotic prophylaxis (duration/vancomycin use) and C difficile among patients undergoing coronary artery bypass grafting. We extracted data on coronary artery bypass grafting procedures from the national Premier Perspective claims database (2006-2013, n = 154,200, 233 hospitals). Multilevel multivariable logistic regressions measured associations between (1) duration (<2 days, "standard" vs ≥2 days, "extended") and (2) type of antibiotic used ("cephalosporin," "cephalosporin + vancomycin," "vancomycin") and C difficile as outcome. Overall C difficile prevalence was 0.21% (n = 329). Most patients (59.7%) received a cephalosporin only; in 33.1% vancomycin was added, whereas 7.2% received vancomycin only. Extended prophylaxis was used in 20.9%. In adjusted analyses, extended prophylaxis (vs standard) was associated with significantly increased C difficile risk (odds ratio, 1.43; confidence interval, 1.07-1.92), whereas no significant associations existed for vancomycin use as adjuvant or primary prophylactic compared with the use of cephalosporins (odds ratio, 1.21; confidence interval, 0.92-1.60, and odds ratio, 1.39; confidence interval, 0.94-2.05, respectively). Substantial inter-hospital variation exists in the percentage of extended antibiotic prophylaxis (interquartile range, 2.5-35.7), use of adjuvant vancomycin (interquartile range, 4.2-61.1), and vancomycin alone (interquartile range, 2.3-10.4). Although extended use of antibiotic prophylaxis was associated with increased C difficile risk after coronary artery bypass grafting, vancomycin use was not. The observed hospital variation in antibiotic prophylaxis

Iron prophylaxis in pregnancy--general or individual and in which dose?

PubMed

Milman, Nils

2006-12-01

Iron is mandatory for normal fetal development, including the brain. Iron deficiency may have deleterious effects for intelligence and behavioral development. It is important to prevent iron deficiency in the fetus by preventing iron deficiency in the pregnant woman. Iron deficiency anemia during pregnancy is a risk factor for preterm delivery and low birth weight. In the Western countries there is no consensus on iron prophylaxis to pregnant women. An adequate iron balance during pregnancy implies body iron reserves of >or=500 mg at conception. The physiologic iron requirements in the second half of gestation cannot be fulfilled solely through dietary iron. Iron supplements during gestation consistently increase serum ferritin and hemoglobin and reduce the prevalence of iron deficiency anemia. Iron has a negative influence on absorption of other divalent metals and increases oxidative stress in pregnancy, for which reason minimum effective iron dose should be advised. From a physiologic point of view, individual iron prophylaxis according to serum ferritin concentration should be preferred to general prophylaxis. Suggested guidelines are (1) ferritin>70 microg/l: no iron supplements; (2) ferritin 30-70 microg/l: 40 mg ferrous iron daily; and (3) ferritin<30 microg/l: 80-100 mg ferrous iron daily. In controlled studies, there are no documented side effects of iron supplements below 100 mg/day. Iron supplements should be taken at bedtime or between meals to ensure optimum absorption.

Impact of antiviral prophylaxis in adults Epstein-Barr Virus-seronegative kidney recipients on early and late post-transplantation lymphoproliferative disorder onset: a retrospective cohort study.

PubMed

Ville, Simon; Imbert-Marcille, Berthe-Marie; Coste-Burel, Marianne; Garandeau, Claire; Meurette, Aurélie; Cantarovitch, Diego; Giral, Magali; Hourmant, Maryvonne; Blancho, Gilles; Dantal, Jacques

2018-05-01

Post-transplantation lymphoproliferative disorder (PTLD) pathogenesis is related to EBV infection. Mismatch with the donor (EBV D+/R-) is the main risk factor for both early PTLD (<1 year post-transplantation) and late (>1 year). In these at-risk patients, the role of antiviral prophylaxis for preventing PTLD remains controversial. We analyzed the impact of antiviral drugs given to prevent CMV disease in a monocentric retrospective cohort of 73 adult kidney or kidney-pancreas EBV-seronegative recipients, transplanted between 01/01/2000 and 01/01/2016. Thirty-seven (50.7%, prophylaxis group) received (val-)aciclovir or (val-)ganciclovir for 3-6 months and 36 (49.3%, no-prophylaxis group) received no-prophylaxis. Mean follow-up was 69 ± 7.2 months in the prophylaxis group and 91 ± 10.3 months in the no-prophylaxis group. Monitoring of EBV PCR revealed that prophylaxis delayed primary infection at 100 days (43% vs. 84%, P = 0.02). Early PTLD incidence was not different between groups (4/37 vs. 4/36, P = 0.99). Concerning late events, EBV-related neoplasia incidence was significantly lower in treated patients among whom no cases were observed, while in the no-prophylaxis group 6 cases were reported (P = 0.02). Despite a weak level of evidence our study suggests that antiviral prophylaxis could prevent late onset PTLD. © 2017 Steunstichting ESOT.

D-dimer, factor VIII and von Willebrand factor predict a non-dipping pattern of blood pressure in hypertensive patients.

PubMed

Agorasti, Athanasia; Trivellas, Theodoros; Mourvati, Efthimia; Papadopoulos, Vasilios; Tsatalas, Konstantinos; Vargemezis, Vasilios; Passadakis, Ploumis

2013-06-01

The aim of this study is to assess whether the haemostatic markers D-dimer, factor VIII (FVIII) and von Willebrand factor (VWF) are predictive of non-dipping status in treated hypertensive patients; so, as easy available laboratory data can predict non-dipping pattern and help with the selection of the patients whom circadian blood pressure should be re-examined. Forty treated hypertensive patients with essential hypertension were included in the study. Twenty-four-hour ambulatory blood pressure monitoring was performed in all patients. Daytime and nocturnal average systolic, diastolic and mean blood pressures were calculated. Patients were characterised as "non-dippers" on the basis of a less than 10 % decline in nocturnal blood pressure (BP); either systolic or diastolic or mean (MAP). D-dimer as marker of fibrinolytic function, FVIII activity and VWF antigen as marker of endothelial dysfunction were measured on plasma. The predictive efficiency was analysed by receiver operating characteristic (ROC) curves. Youden index was used for the estimation of the cut-off points and the associated values for sensitivity and 1-specificity. Plasma levels of D-dimer, FVIII and VWF were significantly higher in non-dippers as compared with dippers, irrespective of the classification used (BP index); all P < 0.05. The ROC curves indicated a good diagnostic efficiency for D-dimer (AUC(ROC) = 0.697, 0.715 and 0.774), FVIII (AUC(ROC) = 0.714, 0.692 and 0.755) and VWF (AUC(ROC) = 0.706, 0.740 and 0.708) in distinguishing non-dipping pattern (systolic, diastolic or mean) in the study population; all P < 0.05. Among the three haemostatic markers, D-dimer presents the most satisfactory sensitivity/1-specificity for the differentiation of non-dippers, with a cut-off point >168 ng/ml (sensitivity/1-specificity for systolic BP non-dippers of 0.789/0.381, for diastolic BP non-dippers 0.923/0.444 and for MAP non-dippers 0.875/0.375). In conclusion, D-dimer has a good predictive value for

[Estimation of efficacy of the ozone-quant therapy in prophylaxis and treatment of the purulent-necrotic complications of pancreatic pseudocysts].

PubMed

Hazdiuk, P V

2009-01-01

There were analyzed the tactics and the results of 132 patients complex surgical treatment , suffering pancreatic gland pseudocysts (PGP). The original method of the ozone-quant therapy (OQTH), using biophysical factors, such as the ozonized solution of sodium chloride and low-intensity laser irradiation, was applied for prophylaxis and treatment of PGP purulent-necrotic complications (PNC). The data obtained, witness about efficacy of the proposed OQTH method in prophylaxis and treatment of PGP PNC.

[Non-antibiotic prophylaxis for recurrent urinary-tract infections].

PubMed

Beerepoot, M A J; ter Riet, G; Verbon, A; Nys, S; de Reijke, T M; Geerlings, S E

2006-03-11

Urinary-tract infections (UTIs) occur frequently and hence have significant financial implications. Antibiotic prophylaxis can be considered in women with recurrent UTIs. However, frequent exposure to antibiotics can lead to antimicrobial resistance and side effects. The most important steps in the pathogenesis of UTIs are the colonisation and adherence of uropathogens. Lactobacilli impede intravaginal colonisation by competing with uropathogens. Cranberries interfere with the adherence of uropathogens to uroepithelial cells. Therefore, cranberries and lactobacilli are potential alternatives in the prophylaxis of UTIs. Randomised clinical trials comparing these compounds with long-term, low-dose antibiotics for the prevention of recurrent UTIs in women have not yet been conducted. Such a trial has recently been started in The Netherlands: the 'Non-antibiotic versus antibiotic prophylaxis for recurrent urinary-tract infections' (NAPRUTI) study.

Microbiological changes associated with dental prophylaxis.

PubMed

Goodson, J Max; Palys, Michael D; Carpino, Elizabeth; Regan, Elizabeth O; Sweeney, Michael; Socransky, Sigmund S

2004-11-01

Despite the common application of dental prophylaxis as part of patient therapy, there is little reported that describes the microbiological impact of this treatment. The authors gave 20 healthy college-aged subjects three dental prophylaxes with a fluoride-containing prophylaxis paste during a two-week period and instructed them in oral hygiene. They evaluated the microbiological composition of dental plaque samples collected before and after treatment using DNA probe analysis. They analyzed 40 representative bacterial species in seven bacterial complexes by checkerboard DNA-DNA hybridization assay techniques. After three dental prophylaxes, the patients' mean Gingival Index score decreased from 0.82 to 0.77, the mean Plaque Index score decreased from 0.72 to zero, and the total number of bacteria per tooth decreased to approximately one-third of the original number. The authors computed two different measures of bacterial presence. The reduction in bacterial numbers was statistically significant and occurred in many species. Bacterial proportion (DNA percentage or percentage of the bacteria per tooth) did not change significantly. Greater reductions in bacterial count occurred in species that showed high numbers before treatment. The total bacterial count decreased by approximately 72 percent of its original level before prophylaxis was initiated. Professional dental prophylaxis did not target any particular bacteria or bacterial groups but removed bacteria nonspecifically and in proportion to their initial numbers. Repeated dental prophylaxes effect a reduction in bacterial amount that is commensurate with the initial amount, but they do does not alter composition. This suggests that mild gingivitis may be a bacterially nonspecific effect of plaque accumulation and emphasizes the need for regular plaque removal to maintain optimal gingival health.

Recombinant factor VIIa (eptacog alfa): a pharmacoeconomic review of its use in haemophilia in patients with inhibitors to clotting factors VIII or IX.

PubMed

Lyseng-Williamson, Katherine A; Plosker, Greg L

2007-01-01

Recombinant factor VIIa (NovoSeven; also known as recombinant activated factor VII or eptacog alfa) is indicated as an intravenous haemostatic agent in haemophilia patients with inhibitors to clotting factors VIII or IX. In noncomparative trials in haemophilia patients with inhibitors, on-demand home treatment with recombinant factor VIIa was effective in controlling episodes of mild to moderate bleeding and well tolerated, with early treatment being associated with a greater rate of success and the need for fewer doses than delayed treatment. Prophylactic treatment with recombinant factor VIIa was also effective in maintaining haemostasis in patients with this indication undergoing surgery. Relative to prior treatment with plasma-derived agents, treatment with recombinant factor VIIa was associated with improvements in health-related quality of life in a cost-utility study in haemophilia patients with inhibitors in Australia. In well designed decision-model cost analyses conducted from a healthcare payer perspective in several countries, on-demand treatment with recombinant factor VIIa to control mild to moderate bleeding episodes in this patient population was predicted to be cost saving or cost neutral relative to on-demand treatment with intravenous activated prothrombin complex concentrate (aPCC). Although the acquisition cost of recombinant factor VIIa was greater than that of aPCC in some studies, the greater initial efficacy of recombinant factor VIIa than aPCC resulted in lower predicted total medical costs. Results were generally robust to plausible changes in key parameters. Orthopaedic surgery with recombinant factor VIIa to maintain haemostasis in haemophilia patients with inhibitors was generally predicted to be cost saving, relative to not having surgery, over the medium to long term in modelled cost analyses from a healthcare payer perspective in the UK and US. The initial cost of surgery was high, but the difference in costs between patients

75 FR 1333 - Notice of New Fee Site; Federal Lands Recreation Enhancement Act (Title VIII, Pub. L. 108-447)

Federal Register 2010, 2011, 2012, 2013, 2014

2010-01-11

... New Fee Site; Federal Lands Recreation Enhancement Act (Title VIII, Pub. L. 108-447) AGENCY: Forest... Recreation Enhancement Act (Title VIII, Pub. L. 108-447) directed the Secretary of Agriculture to publish a...

Haemorrhagic Complications and Symptomatic Venous Thromboembolism in Interventional Tumour Ablations: The Impact of Peri-interventional Thrombosis Prophylaxis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Mohnike, Konrad, E-mail: konrad.mohnike@med.ovgu.de; Sauerland, Hanna; Seidensticker, Max

AimThe aim of this study was to assess the rates of haemorrhagic and thrombotic complications in patients undergoing interventional tumour ablation with and without peri-interventional low-molecular-weight heparin (LMWH) thrombosis prophylaxis.MethodsPatients presented with primary and secondary neoplastic lesions in the liver, lung, kidney, lymph nodes and other locations. A total of 781 tumour ablations (radiofrequency ablation, n = 112; interstitial brachytherapy, n = 669) were performed in 446 patients over 22 months; 260 were conducted under peri-interventional thrombosis prophylaxis with LMWH (H-group;) and 521 without this (NH-group, in 143 of these, LMWH was given post-interventionally).ResultsSixty-three bleeding events occurred. There were significantly more bleedings in the H-groupmore » than in the NH-group (all interventions, 11.66 and 6.26 %, p = 0.0127; liver ablations, 12.73 and 7.1 %, p = 0.0416). The rate of bleeding events Grade ≥ III in all procedures was greater by a factor of >2.6 in the H-group than in the NH-group (4.64 and 1.73 %, p = 0.0243). In liver tumour ablations, the corresponding factor was about 3.3 (5.23 and 1.54 %, p = 0.028). In uni- and multivariate analyses including covariates, the only factor constantly and significantly associated with the rate of haemorrhage events was peri-interventional LMWH prophylaxis. Only one symptomatic lung embolism occurred in the entire cohort (NH-group). The 30- and 90-day mortalities were significantly greater in the H-group than in the NH-group.ConclusionsPeri-interventional LMWH thrombosis prophylaxis should be considered with caution. The rate of clinically relevant thrombotic events was extremely low.« less

HIV post exposure prophylaxis induced bicytopenia: a case report

PubMed Central

2014-01-01

Long and short term side effects of antiretroviral drugs are not fully understood yet. Here a case of reversible blood count changes following post exposure prophylaxis with tenofovir/emtricitabin and lopinavir/ritonavir is reported. We propose that antiretroviral drugs used in post exposure prophylaxis may have a significant impact on hematopoiesis. PMID:24506969

Atovaquone for Prophylaxis of Toxoplasmosis after Allogeneic Hematopoietic Stem Cell Transplantation.

PubMed

Mendorf, Alexander; Klyuchnikov, Evgeny; Langebrake, Claudia; Rohde, Holger; Ayuk, Francis; Regier, Marc; Christopeit, Maximilian; Zabelina, Tatjana; Bacher, Adelbert; Stübig, Thomas; Wolschke, Christine; Bacher, Ulrike; Kröger, Nicolaus

2015-01-01

Toxoplasmosis and infections by other opportunistic agents such as Pneumocystis jirovecii constitute life-threatening risks for patients after allogeneic hematopoietic stem cell transplantation. Trimethoprim/sulfamethoxazole (TMP-SMX) has been well established for post-transplant toxoplasmosis and pneumocystis prophylaxis, but treatment may be limited due to toxicity. We explored atovaquone as an alternative and compared it with TMP-SMX regarding toxicity and efficacy during the first 100 days after transplantation in 155 consecutive adult stem cell recipients. Eight patients with a prior history of TMP-SMX intolerance received atovaquone as first-line prophylaxis. TMP-SMX was used for 141 patients as first-line strategy, but 13 patients (9.2%) were later switched to atovaquone due to TMP-SMX toxicity or gastrointestinal symptoms. No active toxoplasmosis or active P. jirovecii infection developed under continued prophylaxis with either TMP-SMX or atovaquone. However, for reasons of TMP-SMX and/or atovaquone toxicity, 7 patients were unable to tolerate any efficacious toxoplasmosis prophylaxis and therefore obtained inhalative pentamidine as P. jirovecii prophylaxis but no toxoplasmosis prophylaxis. Importantly, 2 of these patients developed severe toxoplasmosis. In summary, atovaquone appears as a valid alternative for at least some post-transplant patients who cannot tolerate TMP-SMX. This should be further confirmed by multicenter trials. © 2015 S. Karger AG, Basel.

Risk of thrombosis and thromboembolic prophylaxis in obesity surgery: data analysis from the German Bariatric Surgery Registry.

PubMed

Stroh, C; Michel, N; Luderer, D; Wolff, S; Lange, V; Köckerling, F; Knoll, C; Manger, T

2016-11-01

Evidence-based data on optimal approach for prophylaxis of deep venous thrombosis (VTE) and pulmonary embolism (PE) in bariatric operations is discussed. Using antithrombotic prophylaxis, weight adjusted the risk of VTE and its complications have to be balanced with the increased bleeding risk. Since 2005, the current situation for bariatric surgery has been examined by quality assurance study in Germany. As a prospective multicenter observational study, data on the type, regimen, and time course of VTE prophylaxis were documented. The incidences of clinically diagnosed VTE or PE were derived during the in-hospital course and follow up. Overall, 31,668 primary bariatric procedures were performed between January 2005 and December 2013. Most performed operations were 3999 gastric banding (GB); 13,722 Roux-en-Y-gastric bypass (RYGBP); and 11,840 sleeve gastrectomies (SG). Gender (p = 0.945), surgical procedure (p = 0.666), or administration of thromboembolic prophylaxis (p = 0.272) had no statistical impact on the DVT incidence. By contrast, BMI (p = 0.116) and the duration of thromboembolic prophylaxis (p = 0.127) did impact the frequency of onset of DVT. Age, BMI, male gender, and a previous history of VTE are the most important risk factors. The drug of choice for VTE is heparin. LMWH should be given preference over unfractionated heparins due to their improved pharmacological properties, i.e., better bioavailability and longer half-life as well as ease of use. Despite the low incidence of VTE and PE, there is a lack of evidence. Therefore, prospective randomized studies are necessary to determine the optimal VTE prophylaxis for bariatric surgical patients.

Risk factors for human rabies in China.

PubMed

Gong, Z; He, F; Chen, Z

2012-02-01

In China, we have witnessed an increasing incidence of rabies in recent years and the number of deaths ranked first among the 39 notifiable infectious diseases. We conducted a case-control study to identify risk factors for human rabies infection and disease to recommend prevention and treatment among people exposed to rabies. Exposure site, pre-exposure prophylaxis and post-exposure prophylaxis were significantly associated with rabies infection. Exposure site at upper limb and trunk or at lower limb were at lower risk as compared with head-exposed patients. The OR was 0.09(95% CI: 0.009-0.93) and 0.01(95% CI: 0.001-0.115) respectively. Pre-exposure prophylaxis (OR = 0.05, 95% CI: 0.03-0.11) and post-exposure prophylaxis (OR = 0.02, 95% CI: 0.01-0.40) were both protective factors as compared with no prophylaxis. For patients who had post-exposure prophylaxis, dose for the first injection and immunity procedure were significantly associated with rabies infection. © 2011 Blackwell Verlag GmbH.

Antibiotic prophylaxis for bacterial infections in afebrile neutropenic patients following chemotherapy.

PubMed

Gafter-Gvili, Anat; Fraser, Abigail; Paul, Mical; Vidal, Liat; Lawrie, Theresa A; van de Wetering, Marianne D; Kremer, Leontien C M; Leibovici, Leonard

2012-01-18

Bacterial infections are a major cause of morbidity and mortality in patients who are neutropenic following chemotherapy for malignancy. Trials have shown the efficacy of antibiotic prophylaxis in reducing the incidence of bacterial infections but not in reducing mortality rates. Our systematic review from 2006 also showed a reduction in mortality. This updated review aimed to evaluate whether there is still a benefit of reduction in mortality when compared to placebo or no intervention. We searched the Cochrane Cancer Network Register of Trials (2011), Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library Issue 2, 2011), MEDLINE (1966 to March 2011), EMBASE (1980 to March 2011), abstracts of conference proceedings and the references of identified studies. Randomised controlled trials (RCTs) or quasi-RCTs comparing different types of antibiotic prophylaxis with placebo or no intervention, or another antibiotic, to prevent bacterial infections in afebrile neutropenic patients. Two authors independently appraised the quality of each trial and extracted data from the included trials. Analyses were performed using RevMan 5.1 software. One-hundred and nine trials (involving 13,579 patients) that were conducted between the years 1973 to 2010 met the inclusion criteria. When compared with placebo or no intervention, antibiotic prophylaxis significantly reduced the risk of death from all causes (46 trials, 5635 participants; risk ratio (RR) 0.66, 95% CI 0.55 to 0.79) and the risk of infection-related death (43 trials, 5777 participants; RR 0.61, 95% CI 0.48 to 0.77). The estimated number needed to treat (NNT) to prevent one death was 34 (all-cause mortality) and 48 (infection-related mortality).Prophylaxis also significantly reduced the occurrence of fever (54 trials, 6658 participants; RR 0.80, 95% CI 0.74 to 0.87), clinically documented infection (48 trials, 5758 participants; RR 0.65, 95% CI 0.56 to 0.76), microbiologically documented infection

Antibiotic prophylaxis for bacterial infections in afebrile neutropenic patients following chemotherapy

PubMed Central

Gafter-Gvili, Anat; Fraser, Abigail; Paul, Mical; Vidal, Liat; Lawrie, Theresa A; van de Wetering, Marianne D; Kremer, Leontien CM; Leibovici, Leonard

2014-01-01

Background Bacterial infections are a major cause of morbidity and mortality in patients who are neutropenic following chemotherapy for malignancy. Trials have shown the efficacy of antibiotic prophylaxis in reducing the incidence of bacterial infections but not in reducing mortality rates. Our systematic review from 2006 also showed a reduction in mortality. Objectives This updated review aimed to evaluate whether there is still a benefit of reduction in mortality when compared to placebo or no intervention. Search methods We searched the Cochrane Cancer Network Register of Trials (2011), Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library Issue 2, 2011), MEDLINE (1966 to March 2011), EMBASE (1980 to March 2011), abstracts of conference proceedings and the references of identified studies. Selection criteria Randomised controlled trials (RCTs) or quasi-RCTs comparing different types of antibiotic prophylaxis with placebo or no intervention, or another antibiotic, to prevent bacterial infections in afebrile neutropenic patients. Data collection and analysis Two authors independently appraised the quality of each trial and extracted data from the included trials. Analyses were performed using RevMan 5.1 software. Main results One-hundred and nine trials (involving 13,579 patients) that were conducted between the years 1973 to 2010 met the inclusion criteria. When compared with placebo or no intervention, antibiotic prophylaxis significantly reduced the risk of death from all causes (46 trials, 5635 participants; risk ratio (RR) 0.66, 95% CI 0.55 to 0.79) and the risk of infection-related death (43 trials, 5777 participants; RR 0.61, 95% CI 0.48 to 0.77). The estimated number needed to treat (NNT) to prevent one death was 34 (all-cause mortality) and 48 (infection-related mortality). Prophylaxis also significantly reduced the occurrence of fever (54 trials, 6658 participants; RR 0.80, 95% CI 0.74 to 0.87), clinically documented infection

Descriptive analysis of malaria prophylaxis for travellers from Greece visiting malaria-endemic countries.

PubMed

Pavli, Androula; Smeti, Paraskevi; Spilioti, Athina; Vakali, Annita; Katerelos, Panagiotis; Maltezou, Helena C

2011-11-01

International travel is changing the epidemiology of imported malaria. Our aim was to study malaria prophylaxis administered to travellers from Greece. The study was conducted during 2008-2009. Data were collected using a standardized form. A total of 2337 travellers were studied; prophylaxis was recommended to 60.2% of them. Of the 2337 travellers, 32.6% travelled to sub-Saharan Africa, 25.5% to South America, 11.8% to Indian subcontinent, 11.7% to Middle East, and 4.4% to Southeast Asia; prophylaxis was recommended to 77.4%, 64%, 80.6%, 4.8% and 73.5% of them, respectively. According to the purpose of travel, prophylaxis was recommended to 85.4% of those travelling for work, 75.2% of those visiting friends and relatives, and 62% of those travelling for recreation. Prophylaxis advised was provided to 68.5%, 66.2%, 61.5%, and 18.9% to those staying at a residence of local people, camping, hotels, and cruise ships, respectively. Regarding long-term travellers, malaria prophylaxis was recommended to 42.6%. Recommendation of malaria prophylaxis was significantly statistically in association with destination countries, purpose of travel, type of residence in endemic areas There is a need to improve recommendations for malaria prophylaxis for travellers from Greece, and to increase awareness and education of professionals providing travel health services in Greece. Copyright © 2011 Elsevier Ltd. All rights reserved.

Pre-Exposure Prophylaxis (PrEP)

MedlinePlus

... VA – HIV Pre-Exposure Prophylaxis HIV.gov on Twitter 22 hours 47 min ago. HIV.gov @HIVGov # ... routine. #HIVTestingDay Reply Retweet Favorite HIV.gov on Twitter Search Find HIV Testing Sites & Care Services Connect ...

Evaluation of the duration of thromboembolic prophylaxis after high-risk orthopaedic surgery: the ETHOS observational study.

PubMed

Bergqvist, David; Arcelus, Juan I; Felicissimo, Paulo

2012-02-01

Real-life data on post-discharge venous thromboembolism (VTE) prophylaxis practices and treatments are lacking. We assessed post-operative VTE prophylaxis prescribed and received in a prospective registry, compared with the 2004 American College of Chest Physicians (ACCP) guidelines in high-risk orthopaedic surgery patients. Consecutive patients undergoing total hip arthroplasty (THA), hip fracture surgery (HFS), or knee arthroplasty (KA) were enrolled at discharge from 161 centres in 17 European countries if they had received in-hospital VTE prophylaxis that was considered in accordance with the ACCP guidelines by the treating physician. Data on prescribed and actual prophylaxis were obtained from hospital charts and patient post-discharge diaries. Post-operative prophylaxis prescribed and actual prophylaxis received were considered adherent or adequate, respectively, if recommended therapies were used for ≥28 days (HFS and THA) or ≥10 days (KA). Among 4,388 patients, 69.9% were prescribed ACCP-adherent VTE prophylaxis (THA: 1,411/2,217 [63.6%]; HFS: 701/1,112 [63.0%]; KA: 955/1,059 [90.2%]). Actual prophylaxis received was described in 3,939 patients with an available diary after discharge (non-evaluability rate of 10%). Mean actual durations of pharmacological prophylaxis from surgery were: 28.4 ± 13.7 (THA), 29.3 ± 13.9 (HFS), and 28.7 ± 14.1 days (KA). ACCP-adequate VTE prophylaxis was received by 66.5% of patients (60.9% THA, 55.4% HFS, and 88.7% KA). Prophylaxis inadequacies were mainly due to inadequate prescription, non-recommended prophylaxis prescription at discharge, or too short prophylaxis prescribed. In high-risk orthopaedic surgery patients with hospital-initiated prophylaxis, there is a gap between ACCP recommendations, prescribed and actual prophylaxis received, mainly due to inadequate prescription at discharge.

Hybrid stochastic framework predicts efficacy of prophylaxis against HIV: An example with different dolutegravir prophylaxis schemes.

PubMed

Duwal, Sulav; Dickinson, Laura; Khoo, Saye; von Kleist, Max

2018-06-01

To achieve the 90-90-90 goals set by UNAIDS, the number of new HIV infections needs to decrease to approximately 500,000 by 2020. One of the 'five pillars' to achieve this goal is pre-exposure prophylaxis (PrEP). Truvada (emtricitabine-tenofovir) is currently the only medication approved for PrEP. Despite its advantages, Truvada is costly and requires individuals to adhere to the once-daily regimen. To improve PrEP, many next-generation regimen, including long-acting formulations, are currently investigated. However, pre-clinical testing may not guide candidate selection, since it often fails to translate into clinical efficacy. On the other hand, quantifying prophylactic efficacy in the clinic is ethically problematic and requires to conduct long (years) and large (N>1000 individuals) trials, precluding systematic evaluation of candidates and deployment strategies. To prioritize- and help design PrEP regimen, tools are urgently needed that integrate pharmacological-, viral- and host factors determining prophylactic efficacy. Integrating the aforementioned factors, we developed an efficient and exact stochastic simulation approach to predict prophylactic efficacy, as an example for dolutegravir (DTG). Combining the population pharmacokinetics of DTG with the stochastic framework, we predicted that plasma concentrations of 145.18 and 722.23nM prevent 50- and 90% sexual transmissions respectively. We then predicted the reduction in HIV infection when DTG was used in PrEP, PrEP 'on demand' and post-exposure prophylaxis (PEP) before/after virus exposure. Once daily PrEP with 50mg oral DTG prevented 99-100% infections, and 85% of infections when 50% of dosing events were missed. PrEP 'on demand' prevented 79-84% infections and PEP >80% when initiated within 6 hours after virus exposure and continued for as long as possible. While the simulation framework can easily be adapted to other PrEP candidates, our simulations indicated that oral 50mg DTG is non-inferior to

Antibiotic prophylaxis for skin toxicity induced by antiepidermal growth factor receptor agents: a systematic review and meta-analysis.

PubMed

Petrelli, F; Borgonovo, K; Cabiddu, M; Coinu, A; Ghilardi, M; Lonati, V; Barni, S

2016-12-01

Topical and systemic prophylactic measures, which are administered before the development of epidermal growth factor receptor (EGFR)-related acneiform rash, are appropriate interventions to mitigate the intensity of skin toxicity. We have performed a systematic review and meta-analysis to evaluate whether prophylactic antibiotics may reduce the occurrence and severity of anti-EGFR drug-related skin rashes. A systematic review was performed by searching Medline, Scopus, Embase, CINAHL, LILACS, Web of Science and the Cochrane Library from inception until March 2016 for publications regarding the pre-emptive role of antibiotics for EGFR-induced skin rashes. Fixed- or random-effects meta-analyses, according to heterogeneity, were used to summarize odds ratios of skin toxicity with antibiotic use. Of the 827 citations found in the search, 13 studies comprising 1073 patients were included in the analysis. In 12 studies, patients in the prophylactic antibiotic arms had a lower risk of developing a skin rash (odds ratio 0·53, 95% confidence interval 0·39-0·72, P < 0·01) than patients without antibiotic prophylaxis. In particular, moderate-to-severe toxicities (grades 2-4) were reduced by nearly two-thirds (odds ratio 0·36, 95% confidence interval 0·22-0·60, P < 0·01) in 13 studies. This translated to a 26% absolute difference of high-grade skin rash compared with the control arms (from 50% to 24%). The results of this meta-analysis show that the risk of skin rash after treatment with anti-EGFR agents for solid tumours was significantly lower in patients taking prophylaxis with antibiotics than in those who were not. Therefore, taking pre-emptive tetracyclines for several weeks at the start of anti-EGFR treatment can significantly reduce the incidence and severity of cutaneous acneiform rash. © 2016 British Association of Dermatologists.

Enhanced Prophylaxis plus Antiretroviral Therapy for Advanced HIV Infection in Africa.

PubMed

Hakim, James; Musiime, Victor; Szubert, Alex J; Mallewa, Jane; Siika, Abraham; Agutu, Clara; Walker, Simon; Pett, Sarah L; Bwakura-Dangarembizi, Mutsa; Lugemwa, Abbas; Kaunda, Symon; Karoney, Mercy; Musoro, Godfrey; Kabahenda, Sheila; Nathoo, Kusum; Maitland, Kathryn; Griffiths, Anna; Thomason, Margaret J; Kityo, Cissy; Mugyenyi, Peter; Prendergast, Andrew J; Walker, A Sarah; Gibb, Diana M

2017-07-20

In sub-Saharan Africa, among patients with advanced human immunodeficiency virus (HIV) infection, the rate of death from infection (including tuberculosis and cryptococcus) shortly after the initiation of antiretroviral therapy (ART) is approximately 10%. In this factorial open-label trial conducted in Uganda, Zimbabwe, Malawi, and Kenya, we enrolled HIV-infected adults and children 5 years of age or older who had not received previous ART and were starting ART with a CD4+ count of fewer than 100 cells per cubic millimeter. They underwent simultaneous randomization to receive enhanced antimicrobial prophylaxis or standard prophylaxis, adjunctive raltegravir or no raltegravir, and supplementary food or no supplementary food. Here, we report on the effects of enhanced antimicrobial prophylaxis, which consisted of continuous trimethoprim-sulfamethoxazole plus at least 12 weeks of isoniazid-pyridoxine (coformulated with trimethoprim-sulfamethoxazole in a single fixed-dose combination tablet), 12 weeks of fluconazole, 5 days of azithromycin, and a single dose of albendazole, as compared with standard prophylaxis (trimethoprim-sulfamethoxazole alone). The primary end point was 24-week mortality. A total of 1805 patients (1733 adults and 72 children or adolescents) underwent randomization to receive either enhanced prophylaxis (906 patients) or standard prophylaxis (899 patients) and were followed for 48 weeks (loss to follow-up, 3.1%). The median baseline CD4+ count was 37 cells per cubic millimeter, but 854 patients (47.3%) were asymptomatic or mildly symptomatic. In the Kaplan-Meier analysis at 24 weeks, the rate of death with enhanced prophylaxis was lower than that with standard prophylaxis (80 patients [8.9% vs. 108 [12.2%]; hazard ratio, 0.73; 95% confidence interval [CI], 0.55 to 0.98; P=0.03); 98 patients (11.0%) and 127 (14.4%), respectively, had died by 48 weeks (hazard ratio, 0.76; 95% CI, 0.58 to 0.99; P=0.04). Patients in the enhanced-prophylaxis group had

Prophylaxis for infective endocarditis. Who needs it? How effective is it?

PubMed Central

Press, N.; Montessori, V.

2000-01-01

OBJECTIVE: To review guidelines for using antibiotic prophylaxis to prevent infective endocarditis, and to present recent changes and controversies regarding these guidelines. QUALITY OF EVIDENCE: Data are from physiologic and in vitro studies, as well as studies of animal models, and from retrospective analyses of human endocarditis cases. Systematic reviews and guidelines are also examined. As no randomized clinical trials have examined prophylaxis for bacterial endocarditis, many recommendations presented are based on consensus guidelines. MAIN MESSAGE: Antibiotic prophylaxis to prevent bacterial endocarditis should be used in high- and moderate-risk patients with cardiac disease. It should be given before procedures in which bacteremias are likely with organisms that cause endocarditis, such as viridans streptococci. For most procedures, a single dose of amoxicillin (2 g by mouth 1 hour before the procedure) is sufficient to ensure adequate serum levels before and after the procedure. CONCLUSION: Infective endocarditis continues to have high rates of morbidity and mortality. Antibiotic prophylaxis, therefore, is important to combat this preventable disease. For high- and moderate-risk patients with cardiac disease, the cost-benefit ratio favours prophylaxis. PMID:11143584

Prophylaxis for infective endocarditis. Who needs it? How effective is it?

PubMed

Press, N; Montessori, V

2000-11-01

To review guidelines for using antibiotic prophylaxis to prevent infective endocarditis, and to present recent changes and controversies regarding these guidelines. Data are from physiologic and in vitro studies, as well as studies of animal models, and from retrospective analyses of human endocarditis cases. Systematic reviews and guidelines are also examined. As no randomized clinical trials have examined prophylaxis for bacterial endocarditis, many recommendations presented are based on consensus guidelines. Antibiotic prophylaxis to prevent bacterial endocarditis should be used in high- and moderate-risk patients with cardiac disease. It should be given before procedures in which bacteremias are likely with organisms that cause endocarditis, such as viridans streptococci. For most procedures, a single dose of amoxicillin (2 g by mouth 1 hour before the procedure) is sufficient to ensure adequate serum levels before and after the procedure. Infective endocarditis continues to have high rates of morbidity and mortality. Antibiotic prophylaxis, therefore, is important to combat this preventable disease. For high- and moderate-risk patients with cardiac disease, the cost-benefit ratio favours prophylaxis.

Social, structural, behavioral and clinical factors influencing retention in Pre-Exposure Prophylaxis (PrEP) care in Mississippi.

PubMed

Arnold, Trisha; Brinkley-Rubinstein, Lauren; Chan, Philip A; Perez-Brumer, Amaya; Bologna, Estefany S; Beauchamps, Laura; Johnson, Kendra; Mena, Leandro; Nunn, Amy

2017-01-01

Pre-exposure prophylaxis (PrEP) is a biomedical intervention that can reduce rates of HIV transmission when taken once daily by HIV-negative individuals. Little is understood about PrEP uptake and retention in care among the populations most heavily impacted by the HIV epidemic, particularly among young men who have sex with men (YMSM) in the Deep South. Therefore, this study explored the structural, social, behavioral, and clinical factors that affect PrEP use and retention in care among YMSM in Jackson, Mississippi. Thirty MSM who were prescribed PrEP at an outpatient primary care clinic were interviewed and included 23 men who had been retained in PrEP care and seven who had not been retained. The mean age of participants was 26.6 years. Most (23) participants were African American. Major factors affecting PrEP use and retention in PrEP care included 1) structural factors such as cost and access to financial assistance for medications and clinical services; 2) social factors such as stigma and relationship status; 3) behavioral factors including sexual risk behaviors; and 4) clinical factors such as perceived and actual side effects. Many participants also discussed the positive spillover effects of PrEP use and reported that PrEP had a positive impact on their health. Four of the seven individuals who had not been retained re-enrolled in PrEP care after completing their interviews, suggesting that case management and ongoing outreach can enhance retention in PrEP care. Interventions to enhance retention in PrEP care among MSM in the Deep South will be most effective if they address the complex structural, social, clinical, and behavioral factors that influence PrEP uptake and retention in PrEP care.

77 FR 10740 - Lock+ Hydro Friends Fund VIII, FFP Project 92, LLC, Riverbank Hydro No. 24, LLC; Notice...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-02-23

... DEPARTMENT OF ENERGY Federal Energy Regulatory Commission [Project Nos. 14262-000, 14276-000, 14280-000] Lock+ Hydro Friends Fund VIII, FFP Project 92, LLC, Riverbank Hydro No. 24, LLC; Notice... Counties, Kentucky. The applications were filed by Lock+ Hydro Friends Fund VIII for Project No. 14262-000...

The benefit of low dose prophylaxis in the treatment of hemophilia: a focus on China.

PubMed

Wu, Runhui; Luke, Koon Hung

2017-11-01

Currently full dose prophylaxis is the standard of care in the treatment of hemophilia (World Federation of Hemophilia). However, the high costs prevent the use of standard or intermediate dose prophylaxis in China and other developing countries. Low dose prophylaxis would be a viable alternative treatment. At present global research data on the use of low dose prophylaxis is limited. Areas covered: Since 2007, China has been developing low dose prophylaxis as a high priority (90 % of moderate and severe hemophilia boys suffer joint disease by age 6 - 9). 11 studies were successfully conducted and published results showing evidence of the benefits of low dose prophylaxis to reduce joint bleeding. This new knowledge has been implemented into clinical practice in China. However the long-term outcome of arthropathy remains unclear and obstacles in execution exist. Expert commentary: In 2016, the first phenotype-based individualized prophylaxis study using four escalating low dose regimens on severe Chinese hemophilia A boys (China Individualized Prophylaxis Study (CHIP China)) launched. Using the previously published and imminent CHIP data, the goal for China is to establish an effective escalating low dose prophylaxis protocol for use in China as a standard of care.

Parents' knowledge and perceptions regarding vitamin K prophylaxis in newborns.

PubMed

Eventov-Friedman, Smadar; Vinograd, Orit; Ben-Haim, Maggie; Penso, Sara; Bar-Oz, Benjamin; Zisk-Rony, Rachel Y

2013-07-01

There is an increasing trend of parents refusing vitamin K (VK) prophylaxis in newborns. We examined the knowledge, perceptions, cultural and religious barriers of expecting parents regarding VK prophylaxis. Questionnaires were completed by 217 participants: 151 female participants and 85% were expecting their first child. Two thirds had academic degrees, yet were ignorant regarding recommendation to provide VK (22.5%), source (15.5%), action (34%), and provision options (29%). Moreover, first-time parents had not yet decided to provide VK after birth (P<0.05). There is a need to provide expecting parents with information regarding safety, utility, and benefits of VK prophylaxis.

Venous thromboembolism in women undergoing pelvic reconstructive surgery with mechanical prophylaxis alone.

PubMed

Montoya, T Ignacio; Leclaire, Edgar L; Oakley, Susan H; Crane, Andrea K; Mcpencow, Alexandra; Cichowski, Sara; Rahn, David D

2014-07-01

The objective of this study was determine the frequency of symptomatic perioperative venous thromboembolism (VTE) and risk factor(s) associated with VTE occurrence in women undergoing elective pelvic reconstructive surgery using only intermittent pneumatic compression (IPC) for VTE prophylaxis. A multi-center case-cohort retrospective review was conducted at six clinical sites over a 66-month period. All sites utilize IPC as standard VTE prophylaxis for urogynecological surgery. VTE cases occurring during the same hospitalization and up to 6 weeks postoperatively were identified by ICD9 code query. Four controls were temporally matched to each case. Information collected included demographics, medical history, route of surgery, operative time, and intraoperative characteristics. Univariate and multivariate backward stepwise logistic regression analyses were performed to identify potential risk factors for VTE. Symptomatic perioperative VTE was diagnosed in 27 subjects from a cohort of 10,627 women who underwent elective urogynecological surgery (0.25 %). Univariate analysis identified surgical route (laparotomy vs others), type of surgery ("major" vs "minor"), history of gynecological cancer, surgery time, and patient age as risk factors for VTE (P < 0.05). Multivariate analysis identified increased frequency of VTE with laparotomy, age ≥ 70, and surgery duration ≥ 5 h. In our study cohort, the frequency of symptomatic perioperative VTE was low. Laparotomy, age ≥ 70 years, and surgery duration ≥ 5 h were associated with VTE occurrence.

10. Historic American Buildings Survey Photocopy of Plate VIII (dated ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

10. Historic American Buildings Survey Photocopy of Plate VIII (dated 1889) in John Calvin Stevens and Albert Winslow Cobb, Examples of American Domestic Architecture, New York, William T. Comstock, 1889 PLANS AND INTERIOR DETAILS, 1889 - John Calvin Stevens House, 52 Bowdoin Street, Portland, Cumberland County, ME

Clinicians-related Determinants of Anticoagulation Therapy and Prophylaxis in Nigeria

PubMed Central

Anakwue, Raphael; Nwagha, Theresa; Ukpabi, Ogba J.; Obeka, Ndudim; Onwubuya, Emmanuel; Onwuchekwa, Uwa; Azubuike, Benjamin; Okoye, Innocent

2017-01-01

Background: Thromboembolic and hypercoagulable diseases are common life-threatening but treatable problems in hospital practice. Fortunately, anticoagulation is an efficacious management practice indicated for arterial, venous, and intracardiac thromboembolism. Clinicians in developing countries may have gaps in their knowledge of anticoagulation therapy/prophylaxis which could affect their clinical decision. Objectives: The study examined the knowledge and attitude of clinicians to anticoagulation therapy/prophylaxis in some tertiary hospitals in Nigeria. Methodology: The study was a multicenter survey. A pretested questionnaire was administered to clinicians in six tertiary hospitals in Southeast Nigeria. Results: A total of 528 questionnaires were returned by 419 (79.4%) residents and 109 (20.6%) consultants. We observed significant abysmal knowledge and lack of awareness of direct oral anticoagulants (DOACs) among most respondents irrespective of their job grades (P = 0.02, odds ratio [OR] 0.59, 95% confidence interval [CI] 0.38–0.90). Their knowledge of anti-Xa assay as laboratory monitoring tool was also significantly inadequate (P = 0.001, OR 0.23, 95% CI 0.10–0.51). On statement analysis on their attitude to anticoagulation therapy/prophylaxis, “Do you think anticoagulation therapy/prophylaxis is clinically relevant” had the highest mean of 4.60, P = 0.01, and a high degree of agreement; while “Should hospital inpatient with > 3 days admission routinely receive anticoagulation/prophylaxis?” had the lowest mean of 2.27, P = 0.02, and a low degree of agreement. Conclusion: There is the need to upscale knowledge of anticoagulation agents and an attitude change to anticoagulation therapy/prophylaxis, especially on the DOACs through continuing medical education activities in emerging countries such as Nigeria. PMID:29063899

Risk of infection among patients with non-metastatic solid tumors or non-Hodgkin's lymphoma receiving myelosuppressive chemotherapy and antimicrobial prophylaxis in US clinical practice.

PubMed

Weycker, Derek; Chandler, David; Barron, Rich; Xu, Hairong; Wu, Hongsheng; Edelsberg, John; Lyman, Gary H

2017-01-01

Purpose Guidelines generally do not recommend oral antimicrobials for prophylaxis against chemotherapy-related infections in patients with solid tumors. Evidence on antimicrobial prophylaxis use, and associated chemotherapy-related infection risk, in US clinical practice is limited. Methods A retrospective cohort design and data from two US private healthcare claims repositories (2008-2011) were employed. Study population included adults who received myelosuppressive chemotherapy for non-metastatic cancer of the breast, colon/rectum, or lung, or for non-Hodgkin's lymphoma. For each subject, the first chemotherapy course was characterized, and within the first course, each chemotherapy cycle and chemotherapy-related infection episode was identified. Use of prophylaxis with oral antimicrobials and colony-stimulating factors in each cycle also was identified. Results A total of 7116 (22% of all) non-metastatic breast cancer, 1833 (15%) non-metastatic colorectal cancer, 1999 (15%) non-metastatic lung cancer, and 1949 (21%) non-Hodgkin's lymphoma patients received antimicrobial prophylaxis in ≥1 cycle. Mean number of antimicrobial prophylaxis cycles during the course among these patients was typically <2, with little difference across cancers and chemotherapy regimens. Fluoroquinolones were the most commonly received class of antimicrobials, accounting for 20%-50% all antimicrobials administered. Among subjects who received first-cycle antimicrobial prophylaxis, chemotherapy-related infection risk in that cycle ranged from 3% to 6% across cancer types. Among patients who received first-cycle antimicrobial prophylaxis and developed chemotherapy-related infections, 38%-67% required inpatient care. Chemotherapy-related infection risk in subsequent cycles with antimicrobial prophylaxis was comparable. Conclusion The results of this study suggest that use of antimicrobial prophylaxis during myelosuppressive chemotherapy is far from uncommon in clinical practice. The

Dominant von Willebrand disease type 2A groups I and II due to missense mutations in the A2 domain of the von Willebrand factor gene: diagnosis and management.

PubMed

Michiels, Jan Jacques; van Vliet, Huub H D M

2009-01-01

Pertinent findings in patients with von Willebrand disease (VWD) type 2A include prolonged bleeding time (BT), consistently low von Willebrand factor (VWF):ristocetin cofactor activity (RCo)/antigen concentration (Ag) and VWF:collagen binding (CB)/Ag ratios, absence of high, and (depending on severity) intermediate and large VWF multimers, the presence of pronounced triplet structure of individual bands and increased VWF degradation products due to increased proteolysis caused by mutations in the A2 domain of VWF. Two categories of VWD type 2A can be distinguished: group I with severe and group II with mild VWD. A minority of VWD type 2A have mild VWD characterized by near normal to prolonged BT, normal factor VIII coagulant activity and VWF:Ag, low VWF:RCo and VWF:CB, a normal ristocetin-induced platelet aggregation and complete but transient correction of BT and functional VWF parameters to normal levels for only a few hours due to short half-lives for VWF:RCo and CWF:CB. Such transient complete responses to desmopressin (DDAVP) lasting only a few hours may facilitate treatment and prophylaxis of minor bleedings, but may not be able to prevent bleeding during minor and major surgery. Most VWD type 2A patients have pronounced VWD with very low VWF:RCo, prolonged BT, PFA-100 closure times >250 s, and response to DDAVP is only transient, minor, poor or absent, with no correction of the BT despite some increase in VWF:RCo, thus being candidates for factor VIII-VWF concentrate substitution for the acute and prophylactic treatment of bleeding symptoms. Copyright (c) 2009 S. Karger AG, Basel.

Mechanical Prophylaxis after Lower Extremity Total Joint Arthroplasty: A Review.

PubMed

Chughtai, Morad; Newman, Jared M; Solow, Max; Davidson, Iyooh U; Sodhi, Nipun; Gaal, Benjamin; Khlopas, Anton; Sultan, Assem A; Mont, Michael A

2017-12-22

Venous thromboembolism (VTE) is a serious complication that can occur after total hip and knee arthroplasty, and can potentially lead to significant morbidity and even mortality. While various modalities have been used to prevent VTE development, the medications can be associated with a number of adverse events. Therefore, mechanical prophylaxis with pumps and compressive devices has been used more frequently alone, or in combination, with medications. Therefore, the purpose of this study was to review the current literature on mechanical prophylaxis for VTEs after lower extremity total joint arthroplasty. Specifically, we reviewed mechanical prophylaxis after: 1) total hip arthroplasty and 2) total knee arthroplasty.

[Preoperative preparation, antibiotic prophylaxis and surgical wound infection in breast surgery].

PubMed

Rodríguez-Caravaca, Gil; de las Casas-Cámara, Gonzalo; Pita-López, María José; Robustillo-Rodela, Ana; Díaz-Agero, Cristina; Monge-Jodrá, Vicente; Fereres, José

2011-01-01

The impact of surgical wound infection on public health justifies its surveillance and prevention. Our objectives were to estimate the incidence of surgical wound infection in breast procedures and assess its protocol of antibiotic prophylaxis and preoperative preparation. Observational multicentre prospective cohort study of incidence of surgical wound infection. Incidence was evaluated, stratified by National Nosocomial Infection Surveillance (NNIS) risk index and we calculated the standardized incidence ratio (SIR). The SIR was compared with Spanish rates and U.S. rates. The compliance and performance of the antibiotic prophylaxis and preoperative preparation protocol were assessed and their influence in the incidence of infection with the relative risk. Ten hospitals from the Comunidad de Madrid were included, providing 592 procedures. The cumulative incidence of surgical wound infection was 3.89% (95% CI: 2.3-5.5). The SIR was 1.82 on the Spanish rate and 2.16 on the American. Antibiotic prophylaxis was applied in 97.81% of cases, when indicated. The overall performance of antibiotic prophylaxis was 75%, and 53% for preoperative preparation. No association was found between infection and performance of prophylaxis or preoperative preparation (P>.05). Our incidence is within those seen in the literature although it is somewhat higher than the national surveillance programs. The performance of prophylaxis antibiotic must be improved, as well as the recording of preoperative preparation data. Copyright © 2010 Elsevier España, S.L. All rights reserved.

Comparison of the two-year outcomes and costs of prophylaxis in medical patients at risk of venous thromboembolism.

PubMed

Deitelzweig, Steven B; Becker, Russ; Lin, Jay; Benner, Josh

2008-11-01

A decision-analytic model incorporating a Markov process to assess the incremental cost and effectiveness of venous thromboembolism (VTE) prevention strategies was used. Modeling was carried out using a hypothetical cohort of medical patients at risk of VTE. The model compared clinical effectiveness (primary and recurrent VTE, death), safety (adverse events), and direct medical costs between patients receiving enoxaparin prophylaxis, unfractionated heparin (UFH) prophylaxis, and no prophylaxis (n = 10,000 for each arm). Monte Carlo simulation was performed to identify changes in inputs that would affect the results. The estimated incidence ofVTE at two years (including recurrent VTE) was 6.8% with enoxaparin prophylaxis, 7.9% with UFH prophylaxis, and 17.9% with no prophylaxis. Two-year mortality occurred in 15.7% of enoxaparin patients and 16.0% of UFH patients, with the incidences of major bleeding in these groups being 0.7% and 1.2%, respectively. However, both enoxaparin and UFH prophylaxis were associated with higher rates of major bleeds than no prophylaxis (0.6%). Total average costs per patient were (US dollars) $1,264 (for enoxaparin prophylaxis, $1,585 for UFH prophylaxis, and $2,245 for no prophylaxis). No realistic parameter changes resulted in enoxaparin prophylaxis being more costly than UFH prophylaxis. For the healthcare payer, considering all direct medical costs associated with VTE up to two years after an admission for acute illness, prophylaxis with enoxaparin was more effective and less costly than UFH. This identifies enoxaparin as a potentially favorable VTE prophylaxis regimen compared with UFH and no prophylaxis in at-risk medical patients.

Resistance pattern of breakthrough urinary tract infections in children on antibiotic prophylaxis.

PubMed

Nateghian, Ali Reza; Robinson, Joan L; Mohandessi, Shahab; Hooman, Nakysa

2009-01-01

Prophylactic antibiotics are commonly used for prevention of urinary tract infections (UTIs) in children. It was postulated that the organisms and resistance patterns of breakthrough infections would differ with the choice of antimicrobial prophylaxis. This was a retrospective descriptive study of all breakthroughs UTI from 2000 to 2006 in children over 1 month of age discharged from a referral children's hospital in Tehran, Iran on continuous antibiotic prophylaxis for UTIs. Fifty-seven children discharged on prophylaxis had breakthrough UTIs of which 32 (56%) had a previously diagnosed urinary tract anomaly. Escherichia coli was responsible for the majority of infections irrespective of choice of prophylaxis. Thirty-three of 56 breakthrough UTIs (59%) were with organisms that were resistant to the prophylactic antibiotic. There was an increased incidence of resistance to prophylaxis in children on cefixime (16 of 22; 78%) when compared with children on cephalexin (7 of 19; 37%; p=0.02) and a trend toward increased resistance when compared with children on trimethoprim-sulfamethoxasole (3 of 8; 37%) (p=0.10). In conclusion, the resistance pattern of organisms causing breakthrough UTIs varies with the choice of prophylaxis which should be taken into consideration in chosing empiric therapy for such infections.

Identification of a Chemical Probe for Family VIII Bromodomains through Optimization of a Fragment Hit.

PubMed

Gerstenberger, Brian S; Trzupek, John D; Tallant, Cynthia; Fedorov, Oleg; Filippakopoulos, Panagis; Brennan, Paul E; Fedele, Vita; Martin, Sarah; Picaud, Sarah; Rogers, Catherine; Parikh, Mihir; Taylor, Alexandria; Samas, Brian; O'Mahony, Alison; Berg, Ellen; Pallares, Gabriel; Torrey, Adam D; Treiber, Daniel K; Samardjiev, Ivan J; Nasipak, Brian T; Padilla-Benavides, Teresita; Wu, Qiong; Imbalzano, Anthony N; Nickerson, Jeffrey A; Bunnage, Mark E; Müller, Susanne; Knapp, Stefan; Owen, Dafydd R

2016-05-26

The acetyl post-translational modification of chromatin at selected histone lysine residues is interpreted by an acetyl-lysine specific interaction with bromodomain reader modules. Here we report the discovery of the potent, acetyl-lysine-competitive, and cell active inhibitor PFI-3 that binds to certain family VIII bromodomains while displaying significant, broader bromodomain family selectivity. The high specificity of PFI-3 for family VIII was achieved through a novel bromodomain binding mode of a phenolic headgroup that led to the unusual displacement of water molecules that are generally retained by most other bromodomain inhibitors reported to date. The medicinal chemistry program that led to PFI-3 from an initial fragment screening hit is described in detail, and additional analogues with differing family VIII bromodomain selectivity profiles are also reported. We also describe the full pharmacological characterization of PFI-3 as a chemical probe, along with phenotypic data on adipocyte and myoblast cell differentiation assays.

Spotlight on the human factor: building a foundation for the future of haemophilia A management: report from a symposium on human recombinant FVIII at the World Federation of Hemophilia World Congress, Melbourne, Australia on 12 May 2014.

PubMed

Kessler, C; Oldenburg, J; Ettingshausen, C Escuriola; Tiede, A; Khair, K; Négrier, C; Klamroth, R

2015-01-01

Inhibitor development is the most serious and challenging complication in the treatment of severe haemophilia A. Up to 38% of such patients develop inhibitors with current recombinant factor VIII (rFVIII) products produced in hamster cell lines. Human-cl rhFVIII is a new generation fully sulfated B-domain-deleted FVIII coagulant glycoprotein, which is generated from a human cell line. Thus, there are no non-human epitopes which would be potentially immunogenic. This molecule has significantly higher VWF-binding affinity compared with existing full-length rFVIII produced in hamster cell lines. The development aim of Human-cl rhFVIII is to address the challenges of FVIII inhibitors and frequent infusions during prophylaxis. Human-cl rhFVIII's mean half-life is very comparable to some of the newer products which involve modification of the FVIII molecule to extend the circulating half-life. There are promising data concerning the use of a personalized prophylaxis regimen with Human-cl rhFVIII. Preliminary data indicate a median dosing interval of 3.5 days with 66.7% of the patients on a twice per week or fewer infusions schedule combined with a low bleeding rate and no increased FVIII consumption when compared to standard prophylaxis. No product-specific laboratory assay is required to monitor the coagulation activity for Human-cl rhFVIII. The results of registration clinical trials with Human-cl rhFVIII as well as the ongoing studies in previously untreated patients (NuProtect) and personalized prophylaxis study in previously treated patients (NuPreviq), will be discussed. The manufacturer has received marketing authorization for Human-cl rhFVIII in Europe and Canada under the name Nuwiq(®) and plans to launch it in the USA and globally in 2015. © 2014 John Wiley & Sons Ltd.

HST/COS detection of a Ne VIII absorber towards PG 1407+265: an unambiguous tracer of collisionally ionized hot gas?

NASA Astrophysics Data System (ADS)

Hussain, T.; Muzahid, S.; Narayanan, A.; Srianand, R.; Wakker, B. P.; Charlton, J. C.; Pathak, A.

2015-01-01

We report the detection of Ne VIII in a zabs = 0.599 61 absorber towards the QSO PG1407+265 (zem= 0.94). Besides Ne VIII, absorption from H I Lyman series lines (H I λ1025-λ915), several other low (C II, N II, O II and S II), intermediate (C III, N III, N IV, O III, S IV and S V) and high (S VI, O VI and Ne VIII) ionization metal lines are detected. Disparity in the absorption line kinematics between different ions implies that the absorbing gas comprises of multiple ionization phases. The low and the intermediate ions (except S V) trace a compact (˜410 pc), metal-rich (Z ˜ Z⊙) and overdense (log nH ˜ -2.6) photoionized region that sustained star formation for a prolonged period. The high ions, Ne VIII and O VI, can be explained as arising in a low density (-5.3 ≤ log nH ≤ -5.0), metal-rich (Z ≳ Z⊙) and diffuse (˜180 kpc) photoionized gas. The S V, S VI and C IV [detected in the Faint Object Spectrograph (FOS) spectrum] require an intermediate photoionization phase with -4.2 < log nH < -3.5. Alternatively, a pure collisional ionization model, as used to explain the previous known Ne VIII absorbers, with 5.65 < log T < 5.72, can reproduce the S VI, O VI and Ne VIII column densities simultaneously in a single phase. However, even such models require an intermediate phase to reproduce any observable S V and/or C IV. Therefore, we conclude that when multiple phases are present, the presence of Ne VIII is not necessarily an unambiguous indication of collisionally ionized hot gas.

Effect of antibiotic prophylaxis on Coagulase-negative Staphylococcus virulence factor profiles in patients undergoing cataract surgery.

PubMed

López, Yolanda; Samudio, Margarita; Fariña, Norma; Castillo, Verónica; Abente, Sonia; Nentwich, Martin M; González-Britez, Nilsa; Laspina, Florentina; Carron, Agustín; Cibils, Diógenes; de Kaspar, Herminia Miño

2017-08-01

In this prospective study, multiplex polymerase chain reaction (PCR) was used to identify genes encoding virulence factors (ica, atlE and mecA) in Coagulase-negative Staphylococcus (CNS) isolates from the ocular microbiota of patients undergoing cataract surgery and to investigate possible changes in the CNS profile due to antibiotic prophylaxis. Between 09/2011 and 08/2013, patients undergoing cataract surgery were recruited at the Department of Ophthalmology, National University of Asuncion, Paraguay. In the eye to be operated on, patients received moxifloxacin 0.5 % eye drops four times at the day before surgery and a last drop 1 hour before surgery (T1). The other eye remained as control (T0). Conjunctival swabs were taken from both eyes 1 hour after the last drop. The presence of genes encoding biofilm formation (ica and atlE) and methicillin resistance (mecA) was detected by a multiplex PCR. Of the 162 patients (162 study eyes, 162 fellow eye as control group), 87 (53.7 %) eyes were positive for CNS at T0 yielding 96 CNS isolates; 70 eyes (43.2 %) were positive at T1 yielding 77 CNS isolates. For this study, 43 CNS isolates (44.8 %) from T0 and 45 (64.3 %) from T1 were used. Of the total isolates, 81.8 % (72/88) had at least one virulence factor gene (37/43 from T0 and 35/45 from T1) (p = 0.314). Simultaneous detection of ica and atlE genes was higher in T0 (58.0 %) than T1 (46.7 %), but the difference was not significant (p = 0.28). A high frequency of genes encoding virulence factors was observed in the coagulase-negative Staphylococcus isolates. The use of moxifloxacin did not significantly modify the CNS virulence factor profiles.

Effects of antimicrobial prophylaxis and blood stream infections in patients with acute liver failure: a retrospective cohort study.

PubMed

Karvellas, Constantine J; Cavazos, Jorge; Battenhouse, Holly; Durkalski, Valerie; Balko, Jody; Sanders, Corron; Lee, William M

2014-11-01

We investigated whether antimicrobial prophylaxis alters the incidence of bloodstream infection in patients with acute liver failure (ALF), and whether bloodstream infections affect overall mortality within 21 days after development of ALF. We performed a retrospective cohort analysis of 1551 patients with ALF enrolled by the US Acute Liver Failure Study Group from January 1998 through November 2009. We analyzed data on infections in the first 7 days after admission and the effects of prophylaxis with antimicrobial drugs on the development of bloodstream infections and 21-day mortality. In our study population, 600 patients (39%) received antimicrobial prophylaxis and 226 patients (14.6%) developed at least 1 bloodstream infection. Exposure to antimicrobial drugs did not affect the proportion of patients who developed bloodstream infections (12.8% in patients with prophylaxis vs 15.7% in nonprophylaxed patients; P = .12), but a greater percentage of patients who received prophylaxis received liver transplants (28% vs 22%; P = .01). After adjusting for confounding factors, overall mortality within 21 days was associated independently with age (odds ratio [OR], 1.014), Model for End-stage Liver Disease score at admission (OR, 1.078), and vasopressor administration at admission (OR, 2.499). Low grade of coma (OR, 0.47) and liver transplantation (OR, 0.101) reduced mortality. Although bloodstream infection was associated significantly with 21-day mortality (P = .004), an interaction between bloodstream infection and etiology was detected: blood stream infection affected mortality to a greater extent in nonacetaminophen ALF patients (OR, 2.03) than in acetaminophen ALF patients (OR, 1.14). Based on a large, observational study, antimicrobial prophylaxis does not reduce the incidence of bloodstream infection or mortality within 21 days of ALF. However, bloodstream infections were associated with increased 21-day mortality in patients with ALF-to a greater extent in

Prophylaxis usage, bleeding rates, and joint outcomes of hemophilia, 1999 to 2010: a surveillance project

PubMed Central

Soucie, J. Michael; Gill, Joan Cox

2017-01-01

This analysis of the US Hemophilia Treatment Center Network and the Centers for Disease Control and Prevention surveillance registry assessed trends in prophylaxis use and its impact on key indicators of arthropathy across the life-span among participants with severe hemophilia A. Data on demographics, clinical characteristics, and outcomes were collected prospectively between 1999 and 2010 at annual clinical visits to 134 hemophilia treatment centers. Trends in treatment and outcomes were evaluated using cross-sectional and longitudinal analyses. Data analyzed included 26 614 visits for 6196 males; mean age at first registry visit was 17.7 years; and median was 14 (range, 2 to 69). During this time, prophylaxis use increased from 31% to 59% overall, and by 2010, 75% of children and youths <20 years were on prophylaxis. On cross-sectional analysis, bleeding rates decreased dramatically for the entire population (P < .001) in parallel with increased prophylaxis usage, possibly because frequent bleeders adopted prophylaxis. Joint bleeding decreased proportionately with prophylaxis (22%) and nonprophylaxis (23%), and target joints decreased more with prophylaxis (80% vs 61%). Joint, total, and target joint bleeding on prophylaxis were 33%, 41%, and 27%, respectively, compared with nonprophylaxis. On longitudinal analysis of individuals over time, prophylaxis predicted decreased bleeding at any age (P < .001), but only prophylaxis initiation prior to age 4 years and nonobesity predicted preservation of joint motion (P < .001 for each). Using a national registry, care providers in a specialized health care network for a rare disorder were able to detect and track trends in outcomes over time. PMID:28183693

Antiviral prophylaxis during chemotherapy or immunosuppressive drug therapy to prevent HBV reactivation in patients with resolved HBV infection: a systematic review and meta-analysis.

PubMed

Su, Yi-Chia; Lin, Pei-Chin; Yu, Hsien-Chung; Wu, Chih-Chien

2018-05-29

Until recently, the role of antiviral prophylaxis in preventing hepatitis B virus (HBV) reactivation during immunosuppressive therapy or chemotherapy in patients with resolved HBV infection was unclear. The aim of the study reported here was to compare the efficacy of antiviral prophylaxis versus that of non-prophylaxis in resolved HBV-infected patients undergoing chemotherapy or immunosuppressive therapy. PubMed, the Cochrane library, and the ClinicalTrials.gov website were searched from inception until December 2017. Studies comparing reactivation in prophylaxis versus non-prophylaxis in patients undergoing immunosuppressive therapy or chemotherapy were included. The meta-analysis was performed to calculate the relative risk (RR) and the pooled estimates. A meta-analysis was conducted of 13 studies (2 randomized controlled trials [RCTs] and 11 cohort studies). The summary RR for HBV reactivation was 0.47 (95% confidence interval [CI] 0.13-1.69) for antiviral prophylaxis versus non-prophylaxis. Both of the RCTs included in the meta-analysis enrolled patients treated with rituximab. Subgroup analyses showed that the two RCTs ± high-quality cohort studies showed a decreased risk of HBV reactivation among the antiviral prophylaxis groups (RCT 1: RR 0.13, 95% CI 0.02-0.70; P = 0.02; RCT 2: 0.28, 95% CI 0.08-0.98; P = 0.05). Subgroup analyses further showed that the cohort studies did not support an association between the antiviral prophylaxis groups and HBV reactivation (RR 0.62, 95% CI 0.14-2.83; P = 0.54); adjusting for confounding factors, such as detectable anti-HBs antibodies, failed to produce a significant association (RR,0.29, 95% CI 0.07-1.28; P = 0.10). Our meta-analyses did not show an association between antiviral prophylaxis use and risk of HBV reactivation. As using only the RCTs ± high-quality cohort studies data rendered this association significant, clinicians can consider providing antiviral prophylaxis to patients with resolved

Cost-effectiveness of filgrastim and pegfilgrastim as primary prophylaxis against febrile neutropenia in lymphoma patients.

PubMed

Lathia, Nina; Isogai, Pierre K; De Angelis, Carlo; Smith, Thomas J; Cheung, Matthew; Mittmann, Nicole; Hoch, Jeffrey S; Walker, Scott

2013-08-07

Febrile neutropenia is a serious toxicity of cancer chemotherapy that is usually treated in hospital. We assessed the cost-effectiveness of filgrastim and pegfilgrastim as primary prophylaxis against febrile neutropenia in diffuse large B-cell lymphoma (DLBCL) patients undergoing chemotherapy. We used a Markov model that followed patients through induction chemotherapy to compare the three prophylaxis strategies: 1) no primary prophylaxis against febrile neutropenia; 2) primary prophylaxis with 10 days of filgrastim therapy; and 3) primary prophylaxis with a single dose of pegfilgrastim. The target population was a hypothetical cohort of 64-year-old men and women with DLBCL. Data sources included published literature and current clinical practice. The analysis was conducted from a publicly funded health-care system perspective. The main outcome measures included costs, quality-adjusted life years (QALYs), and incremental cost-effectiveness ratios (ICERs). In the base-case analysis, costs associated with no primary prophylaxis, primary prophylaxis with 10 days of filgrastim, and primary prophylaxis with pegfilgrastim were CaD $7314, CaD $13947, and CaD $16290, respectively. The QALYs associated with the three strategies were 0.2004, 0.2015, and 0.2024, respectively. The ICER for the filgrastim vs no primary prophylaxis strategy was CaD $5796000 per QALY. The ICER for the pegfilgrastim vs filgrastim primary prophylaxis strategy was CaD $2611000 per QALY. All one-way sensitivity analyses yielded ICERs greater than CaD $400000 per QALY. Cost-effectiveness acceptability curves show that 20.0% of iterations are cost-effective at a willingness-to-pay threshold of CaD $1595000 for the filgrastim strategy and CaD $561000 for the pegfilgrastim strategy. Primary prophylaxis against febrile neutropenia with either filgrastim or pegfilgrastim is not cost-effective in DLBCL patients.

Extended antiretroviral prophylaxis to reduce breast-milk HIV-1 transmission.

PubMed

Kumwenda, Newton I; Hoover, Donald R; Mofenson, Lynne M; Thigpen, Michael C; Kafulafula, George; Li, Qing; Mipando, Linda; Nkanaunena, Kondwani; Mebrahtu, Tsedal; Bulterys, Marc; Fowler, Mary Glenn; Taha, Taha E

2008-07-10

Effective strategies are urgently needed to reduce mother-to-child transmission of human immunodeficiency virus type 1 (HIV-1) through breast-feeding in resource-limited settings. Women with HIV-1 infection who were breast-feeding infants were enrolled in a randomized, phase 3 trial in Blantyre, Malawi. At birth, the infants were randomly assigned to one of three regimens: single-dose nevirapine plus 1 week of zidovudine (control regimen) or the control regimen plus daily extended prophylaxis either with nevirapine (extended nevirapine) or with nevirapine plus zidovudine (extended dual prophylaxis) until the age of 14 weeks. Using Kaplan-Meier analyses, we assessed the risk of HIV-1 infection among infants who were HIV-1-negative on DNA polymerase-chain-reaction assay at birth. Among 3016 infants in the study, the control group had consistently higher rates of HIV-1 infection from the age of 6 weeks through 18 months. At 9 months, the estimated rate of HIV-1 infection (the primary end point) was 10.6% in the control group, as compared with 5.2% in the extended-nevirapine group (P<0.001) and 6.4% in the extended-dual-prophylaxis group (P=0.002). There were no significant differences between the two extended-prophylaxis groups. The frequency of breast-feeding did not differ significantly among the study groups. Infants receiving extended dual prophylaxis had a significant increase in the number of adverse events (primarily neutropenia) that were deemed to be possibly related to a study drug. Extended prophylaxis with nevirapine or with nevirapine and zidovudine for the first 14 weeks of life significantly reduced postnatal HIV-1 infection in 9-month-old infants. (ClinicalTrials.gov number, NCT00115648.) 2008 Massachusetts Medical Society

American Indian Tribal Programs in Child Welfare in Region VIII.

ERIC Educational Resources Information Center

Goodluck, Charlotte; Elpers, Jenny

Designed to develop and to share information and resources on child abuse and neglect, child welfare, and youth services in Region VIII (Colorado, Utah, Wyoming, North Dakota, South Dakota, and Montana), the Family Resource Center, a federally funded two year program, has developed a directory containing names, addresses, phone numbers and…

Glioneuronal Heterotopia Presenting As a Cerebellopontine angle Tumor of the cranial Nerve VIII, Case Report.

PubMed

Peris-Celda, M; Giannini, C; Diehn, F E; Eckel, L J; Neff, B A; Van Gompel, J J

2018-04-03

Vestibular schwannomas and meningiomas account for the great majority of lesions arising in the cerebellopontine angle (CPA). In this report, we present a case of glioneuronal heterotopia, also known as glioneuronal hamartoma, arising from the VIII cranial nerve, which is an extremely uncommon lesion. Important radiologic and surgical aspects are reviewed, which may help in early recognition and intraoperative decision making when these lesions are encountered. A healthy 29-year-old female presented with intermittent right facial numbness. Magnetic resonance imaging (MRI) showed an incidental minimally enhancing cerebellopontine angle lesion on the right VII-VIII cranial nerve complex. The patient declined serial observation and opted for operative intervention for resection. Intraoperatively, the lesion resembled neural tissue and was continuous with the VIII cranial nerve. Pathological analysis demonstrated mature glioneuronal tissue consistent with hamartomatous brain tissue. The patient maintained normal hearing and facial nerve function after surgery. Radiologic, surgical and pathological characteristics are described. Ectopic glioneuronal tissue of the VIII cranial nerve is a rare non-neoplastic lesion, and should be considered in the differential diagnosis of unusual appearing intracanalicular and cerebellopontine angle lesions. The congenital and benign nature of this entity makes observation a valid option for these cases, although they are so infrequent that they are often presumptively managed as vestibular schwannomas. Attempts to radically resect these lesions may result in higher rates of hearing loss or facial palsy due to their continuity with the cranial nerves. Copyright © 2018 Elsevier Inc. All rights reserved.

Aspirin for Prophylaxis Against Venous Thromboembolism After Orthopaedic Oncologic Surgery.

PubMed

Mendez, Gregory M; Patel, Yash M; Ricketti, Daniel A; Gaughan, John P; Lackman, Richard D; Kim, Tae Won B

2017-12-06

Patients who undergo orthopaedic oncologic surgical procedures are at increased risk of developing a venous thromboembolism (VTE). Guidelines from surgical societies are shifting to include aspirin as a postoperative VTE prophylactic agent. The purpose of this study was to review our experience using aspirin as postoperative VTE prophylaxis for orthopaedic oncologic surgical procedures. This study was a retrospective review of patients diagnosed with a primary malignant soft-tissue or bone tumor or metastatic carcinoma. Demographic information, histopathologic diagnosis, VTE history, surgical procedure, and VTE prophylaxis were analyzed. VTE rates in the overall and prophylactic-specific cohorts were recorded and compared. A total of 142 distinct surgical procedures in 130 patients were included. VTE prophylaxis with aspirin was used after 103 procedures, and non-aspirin prophylaxis was used after 39. In 33 cases, imaging was used to investigate for VTE because of clinical signs and symptoms. VTE developed after 7 (4.9%) of the 142 procedures. There were 6 deep venous thromboses (DVTs) and 1 pulmonary embolism, and 2 of the VTEs presented in patients with a VTE history. VTE developed in 2.9% (3) of the 103 aspirin cases and 10.3% (4) of the 39 non-aspirin cases. No patient in the aspirin group who had been diagnosed with metastatic carcinoma, malignant soft-tissue sarcoma, lymphoma, or multiple myeloma developed a VTE. Risk factors for VTE development included diabetes mellitus (odds ratio [OR] = 10.40, 95% confidence interval [CI] = 1.61 to 67.30), a history of VTE (OR = 7.26, 95% CI = 1.19 to 44.25), postoperative transfusion (OR = 34.50, 95% CI = 3.94 to 302.01), and estimated blood losses of 250 mL (OR = 1.50, 95% CI = 1.11 to 2.03), 500 mL (OR = 2.26, 95% CI = 1.23 to 4.13), and 1,000 mL (OR = 5.10, 95% CI = 1.52 to 17.04). Aspirin may be a suitable and effective option for VTE chemoprophylaxis in patients treated with orthopaedic oncologic surgery, especially

Cardiac surgery antibiotic prophylaxis and calculated empiric antibiotic therapy.

PubMed

Gorski, Armin; Hamouda, Khaled; Özkur, Mehmet; Leistner, Markus; Sommer, Sebastian-Patrick; Leyh, Rainer; Schimmer, Christoph

2015-03-01

Ongoing debate exists concerning the optimal choice and duration of antibiotic prophylaxis as well as the reasonable calculated empiric antibiotic therapy for hospital-acquired infections in critically ill cardiac surgery patients. A nationwide questionnaire was distributed to all German heart surgery centers concerning antibiotic prophylaxis and the calculated empiric antibiotic therapy. The response to the questionnaire was 87.3%. All clinics that responded use antibiotic prophylaxis, 79% perform it not longer than 24 h (single-shot: 23%; 2 doses: 29%; 3 doses: 27%; 4 doses: 13%; and >5 doses: 8%). Cephalosporin was used in 89% of clinics (46% second-generation, 43% first-generation cephalosporin). If sepsis is suspected, the following diagnostics are performed routinely: wound inspection 100%; white blood cell count 100%; radiography 99%; C-reactive protein 97%; microbiological testing of urine 91%, blood 81%, and bronchial secretion 81%; procalcitonin 74%; and echocardiography 75%. The calculated empiric antibiotic therapy (depending on the suspected focus) consists of a multidrug combination with broad-spectrum agents. This survey shows that existing national guidelines and recommendations concerning perioperative antibiotic prophylaxis and calculated empiric antibiotic therapy are well applied in almost all German heart centers. © The Author(s) 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.

Endocarditis prophylaxis and congenital heart defects in the Norwegian Public Dental Service.

PubMed

Sivertsen, Tine B; Astrøm, Anne N; Greve, Gottfried; Aßmus, Jörg; Skeie, Marit S

2013-01-01

The aims of this study are (i) to assess how dental health workers of the Public Dental Service, PDS, carry out endocarditis prophylaxis related to dental treatment for children and adolescents with congenital heart defects (CHD) and to identify factors influencing their appropriate use of guidelines and (ii) to assess how dental health workers perceive any characteristics of patients with CHD. This cross-sectional study was based on self-administered questionnaires mailed to all dentists and hygienists in the PDS in three Norwegian counties. The response rates among dentists (n = 130) and dental hygienists (n = 54) were, respectively, 63% and 68%. The findings revealed an over-prescription of endocarditis antibiotics to patients with CHD. Most of the background variables investigated did not influence the responders' prescription decision for appropriate use of the current guidelines on the topic. The only significant factor was whether or not the respondent considered that the endocarditis prophylaxis guidelines were consistent and easy to follow. Compared with healthy children, dental healthcare workers felt less confident when providing dental treatment to children with CHD. There is room for improved education about children with CHD in dentistry and dental education. ©2012 The Author(s)/Acta Paediatrica ©2012 Foundation Acta Paediatrica.

[Prophylaxis of thrombosis induced by chemotherapy or central venous catheters].

PubMed

Voog, Eric; Lazard, Eric; Juhel, Laurence

2007-02-01

Deep venous thrombosis and pulmonary embolism are well-recognized complications of cancer, especially in patients with a venous access device or receiving chemotherapy. The pathogenic mechanisms of thrombosis in cancer patients involve a complex interaction between the patient's tumor cells and hemostatic system. Chemotherapy and central venous catheters increase the risk of thromboembolism. Prophylactic treatment for these patients remains controversial. We conducted a systematic literature review using the Medline database and abstract books for meetings of the American Society of Clinical Oncology and the American Society of Hematology since 2000. Our search focused on clinical trials of primary prevention of venous catheter-related thrombosis or prevention of chemotherapy-related venous thromboembolism in cancer patients. Ten studies evaluating primary prevention of patients with central catheters were identified, and their results are contradictory. Currently only one study has examined prevention of chemotherapy-related venous thromboembolism, in women with metastatic breast cancer. Its results cannot be extrapolated to other tumors. Systematic prophylaxis cannot yet be recommended. In the near future we must improve our knowledge of the risk factors of these complications. Prophylaxis should be individualized for each patient. New anticoagulant drugs should be tested in cancer patients.

Use of antibacterial prophylaxis for patients with neutropenia. Australian Consensus Guidelines 2011 Steering Committee.

PubMed

Slavin, M A; Lingaratnam, S; Mileshkin, L; Booth, D L; Cain, M J; Ritchie, D S; Wei, A; Thursky, K A

2011-01-01

The use of oral prophylactic antibiotics in patients with neutropenia is controversial and not recommended by this group because of a lack of evidence showing a reduction in mortality and concerns that such practice promotes antimicrobial resistance. Recent evidence has demonstrated non-significant but consistent, improvement in all-cause mortality when fluoroquinolones (FQs) are used as primary prophylaxis. However, the consensus was that this evidence was not strong enough to recommend prophylaxis. The evidence base for FQ prophylaxis is presented alongside current consensus opinion to guide the appropriate and judicious use of these agents. Due consideration is given to patient risk, as it pertains to specific patient populations, as well as the net effect on selective pressure from antibiotics if FQ prophylaxis is routinely used in a target population. The potential costs and consequences of emerging FQ resistance, particularly among Escherichia coli, Clostridium difficile and Gram-positive organisms, are considered. As FQ prophylaxis has been advocated in some chemotherapy protocols, specific regard is given to whether FQ prophylaxis should be used to support these regimens. The group also provides recommendations for monitoring and surveillance of emerging resistance in those centres that have adopted FQ prophylaxis. © 2011 The Authors. Internal Medicine Journal © 2011 Royal Australasian College of Physicians.

Thromboembolism prophylaxis in patients with Philadelphia-negative myeloproliferative neoplasms-Clinical practice among Nordic specialists.

PubMed

Bjerrum, Ole Weis; Samuelsson, Jan; Ghanima, Waleed; Kauppila, Marjut; Andersen, Christen Lykkegaard

2018-05-01

Patients with Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs) have higher risks of developing thromboembolisms compared to the general population. International guidelines on the management of MPNs therefore include recommendations concerning thromboembolism prophylaxis. In clinical practice, strict adherence to guidelines may be challenging and dependent on factors such as physician experience, outpatient clinic setting, and access to therapy; however, no data exist on physician adherence or patient compliance to thromboembolism prophylaxis in MPNs. The Nordic Myeloproliferative Neoplasm Study Group (NMPN) performed a survey among Nordic hematology specialists with the aim of documenting the implementation of international recommendations in a region of Northern Europe with similar healthcare systems. The study showed that Nordic specialists managed their patients in accordance with international guidelines concerning medical intervention, but to a lesser degree regarding the management of additional cardiovascular risk factors. The survey also drew attention to the common clinical dilemma of combining antiaggregatory agents with vitamin K antagonists (VKA), or novel oral anticoagulants (NOAC), as well as phlebotomy limits in female polycythemia vera patients. The results of this study highlight the importance of considering all risk factors for thrombosis and an optimal collaboration with the primary healthcare sector. © 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Extended Venous Thromboembolism Prophylaxis after Radical Cystectomy: A Call for Adherence to Current Guidelines.

PubMed

Klaassen, Zachary; Arora, Karan; Goldberg, Hanan; Chandrasekar, Thenappan; Wallis, Christopher J D; Sayyid, Rashid K; Fleshner, Neil E; Finelli, Antonio; Kutikov, Alexander; Violette, Philippe D; Kulkarni, Girish S

2018-04-01

Radical cystectomy is inherently associated with morbidity. We assess the timing and incidence of venous thromboembolism, review current guideline recommendations and provide evidence for considering extended venous thromboembolism prophylaxis in all patients undergoing radical cystectomy. We searched PubMed® for available literature on radical cystectomy and venous thromboembolism, focusing on incidence and timing, evidence supporting extended venous thromboembolism prophylaxis in patients undergoing radical cystectomy or abdominal oncologic surgery, current guideline recommendations, safety considerations and direct oral anticoagulants. Search terms included "radical cystectomy," "venous thromboembolism," "prophylaxis," and "extended oral anticoagulants" and "direct oral anticoagulants" alone and in combination. Relevant articles were reviewed, including original research, reviews and clinical guidelines. References from review articles and guidelines were also assessed to develop a narrative review. The incidence of symptomatic venous thromboembolism in short-term followup after radical cystectomy is 3% to 11.6%, of which more than 50% of cases will occur after hospital discharge. Meta-analyses of clinical trials in patients undergoing major abdominal oncologic operations suggest a decreased risk of venous thromboembolisms for patients receiving extended (4 weeks) venous thromboembolism prophylaxis. Extended prophylaxis should be considered in all radical cystectomy cases. Although the relative risk of bleeding also increases, the overall net benefit of extended prophylaxis clearly favors use for at least 28 days postoperatively. Extrarenal eliminated prophylaxis agents are preferred given the risk of renal insufficiency in radical cystectomy cases, with newer oral anticoagulants providing an alternative route of administration. Patients undergoing radical cystectomy are at high risk for venous thromboembolism after hospital discharge. There is strong evidence

Information Technology: Making It All Fit. Track VIII: Academic Computing Strategy.

ERIC Educational Resources Information Center

CAUSE, Boulder, CO.

Six papers from the 1988 CAUSE conference's Track VIII, Academic Computing Strategy, are presented. They include: "Achieving Institution-Wide Computer Fluency: A Five-Year Retrospective" (Paul J. Plourde); "A Methodology and a Policy for Building and Implementing a Strategic Computer Plan" (Frank B. Thomas); "Aligning…

[Spanish Society for Pediatric Infectious Diseases guidelines on tuberculosis in pregnant women and neonates (ii): Prophylaxis and treatment].

PubMed

Baquero-Artigao, F; Mellado Peña, M J; del Rosal Rabes, T; Noguera Julián, A; Goncé Mellgren, A; de la Calle Fernández-Miranda, M; Navarro Gómez, M L

2015-10-01

In pregnant women who have been exposed to tuberculosis (TB), primary isoniazid prophylaxis is only recommended in cases of immunosuppression, chronic medical conditions or obstetric risk factors, and close and sustained contact with a patient with infectious TB. Isoniazid prophylaxis for latent tuberculosis infection (LTBI) is recommended in women who have close contact with an infectious TB patient or have risk factors for progression to active disease. Otherwise, it should be delayed until at least three weeks after delivery. Treatment of TB disease during pregnancy is the same as for the general adult population. Infants born to mothers with disseminated or extrapulmonary TB in pregnancy, with active TB at delivery, or with postnatal exposure to TB, should undergo a complete diagnostic evaluation. Primary isoniazid prophylaxis for at least 12 weeks is recommended for those with negative diagnostic tests and no evidence of disease. Repeated negative diagnostic tests are mandatory before interrupting prophylaxis. Isoniazid for 9 months is recommended in LTBI. Treatment of neonatal TB disease is similar to that of older children, but should be maintained for at least 9 months. Respiratory isolation is recommended in congenital TB, and in postnatal TB with positive gastric or bronchial aspirate acid-fast smears. Separation of mother and infant is only necessary when the mother has received treatment for less than 2 weeks, is sputum smear-positive, or has drug-resistant TB. Breastfeeding is not contraindicated, and in case of mother-infant separation expressed breast milk feeding is recommended. Copyright © 2014 Asociación Española de Pediatría. Published by Elsevier España, S.L.U. All rights reserved.

Clinical experience with Optivate®, high-purity factor VIII (FVIII) product with von Willebrand factor (VWF) in young children with haemophilia A.

PubMed

Matysiak, M; Bobrowska, H; Balwierz, W; Chybicka, A; Kowalczyk, J R; Shaikh-Zaidi, R; Gillanders, K; Dash, C H

2011-09-01

Optivate® is a high-purity FVIII/VWF product. Its safety, tolerability and efficacy in subjects ≥ 12 years have been demonstrated. This study was undertaken to assess Optivate® in children with haemophilia A. Twenty-five children, including one PUP (previously untreated patient), aged 1-6 years (mean 4.67 years) were treated with Optivate® for 26 weeks. Inhibitors were assessed every 3 months and viral status at the study start and end. Prophylaxis was used by five boys and on demand by twenty. The mean number of bleeds in the study was lower compared to the same period pre-study (12.0/child vs. 16.2/child), with fewer bleeds (P < 0.05) in the prophylactic subgroup (8.0/child) compared with the on-demand sub-group (13.4/child). Fourteen major bleeds were reported, all by the on-demand sub-group. Children on prophylaxis were administered a mean of 59.4 infusions; on-demand group 35.1 infusions. A total of 998 infusions were used with a mean dose of 29.1 IU kg⁻¹, and a mean of 38.6 exposure days (ED). Children < 4 years used higher doses, and reported fewer bleeds than older children. Children's Parents/Guardians rated Optivate® as helpful or very helpful in controlling 97.5% of bleeds by the prophylactic group, and in 98.5% of the bleeds in the on-demand group. Only 5 of 101 ADRs were treatment-related events (5%), all were mild and non-serious. There were no clinically significant changes in vital signs, viral transmissions or inhibitors. In young children Optivate® was well tolerated, safe and efficacious. © 2011 Blackwell Publishing Ltd.

Effect of V/III ratio on the surface morphology and electrical properties of m-plane (10 1 bar 0) GaN homoepitaxial layers

NASA Astrophysics Data System (ADS)

Barry, Ousmane I.; Tanaka, Atsushi; Nagamatsu, Kentaro; Bae, Si-Young; Lekhal, Kaddour; Matsushita, Junya; Deki, Manato; Nitta, Shugo; Honda, Yoshio; Amano, Hiroshi

2017-06-01

We have investigated the effect of V/III ratio on the surface morphology, impurity concentration and electrical properties of m-plane (10 1 bar 0) Gallium Nitride (GaN) homoepitaxial layers. Four-sided pyramidal hillocks are observed on the nominally on-axis m-plane GaN films. Hillocks sizes relatively increase by increasing the V/III ratio. All facets of pyramidal hillocks exhibit well-defined step-terrace features. Secondary ion mass spectrometry depth profiles reveal that carbon impurities decrease by increasing the V/III ratio while the lowest oxygen content is found at an optimized V/III ratio of 900. Vertical Schottky barrier diodes fabricated on the m-GaN samples were characterized. Low leakage current densities of the order of 10-10 A/cm2 at -5 V are obtained at the optimum V/III ratio. Oxygen impurities and screw-component dislocations around hillocks are found to have more detrimental impact on the leakage current mechanism.

Antibiotic prophylaxis is not indicated prior to dental procedures for prevention of periprosthetic joint infections.

PubMed

Rademacher, Willem M H; Walenkamp, Geert H I M; Moojen, Dirk Jan F; Hendriks, Johannes G E; Goedendorp, Theo A; Rozema, Frederik R

2017-10-01

Background and purpose - To minimize the risk of hematogenous periprosthetic joint infection (HPJI), international and Dutch guidelines recommended antibiotic prophylaxis prior to dental procedures. Unclear definitions and contradictory recommendations in these guidelines have led to unnecessary antibiotic prescriptions. To formulate new guidelines, a joint committee of the Dutch Orthopaedic and Dental Societies conducted a systematic literature review to answer the following question: can antibiotic prophylaxis be recommended for patients (with joint prostheses) undergoing dental procedures in order to prevent dental HPJI? Methods - The Medline, Embase, and Cochrane databases were searched for randomized controlled trials (RCTs), reviews, and observational studies up to July 2015. Studies were included if they involved patients with joint implants undergoing dental procedures, and either considered HPJI as an outcome measure or described a correlation between HPJI and prophylactic antibiotics. A guideline was formulated using the GRADE method and AGREE II guidelines. Results - 9 studies were included in this systematic review. All were rated "very low quality of evidence". Additional literature was therefore consulted to address clinical questions that provide further insight into pathophysiology and risk factors. The 9 studies did not provide evidence that use of antibiotic prophylaxis reduces the incidence of dental HPJI, and the additional literature supported the conclusion that antibiotic prophylaxis should be discouraged in dental procedures. Interpretation - Prophylactic antibiotics in order to prevent dental HPJI should not be prescribed to patients with a normal or an impaired immune system function. Patients are recommended to maintain good oral hygiene and visit the dentist regularly.

Duration of antimicrobial prophylaxis in patients undergoing hepatectomy: a prospective randomized controlled trial using flomoxef.

PubMed

Togo, Shinji; Tanaka, Kuniya; Matsuo, Kenichi; Nagano, Yasuhiko; Ueda, Michio; Morioka, Daisuke; Endo, Itaru; Shimada, Hiroshi

2007-05-01

Although the usefulness of antimicrobial prophylaxis for clean-contaminated surgery has been recognized, only a few randomized controlled studies on the duration of administration after hepatectomy have been performed. We investigated the duration of antimicrobial prophylaxis after hepatectomy. The subjects were 180 patients who underwent hepatectomy without reconstruction of the biliary or intestinal tract between April 2003 and March 2006 at our department. The patients were randomly allocated to groups to be treated with flomoxef sodium as antimicrobial prophylaxis for 2 days (89 patients) or 5 days (91 patients), including the operation day. The presence or absence of systemic inflammatory response syndrome (SIRS) and infections was investigated. No significant differences were noted in patient background between the two groups. Infections occurred in seven and six patients in the 2 day and 5 day treatment groups (7.9% and 6.6%), respectively, showing no significant difference between the two groups. No significant difference was noted when the cases were divided into surgical site infections and remote infections. The positive rate of SIRS was significantly higher in the 2 day treatment group than in the 5 day treatment group on days 2 and 3 after surgery. The risk factors in patients who developed infections were blood loss, operation time and the complication of biliary fistula. Two day administration of flomoxef sodium may be sufficient for antimicrobial prophylaxis after hepatectomy. However, when SIRS is positive on post-operative day 2, and induction of liver failure is of concern, it may be safer to continue antimicrobial drug administration until SIRS is eliminated.

76 FR 73616 - Lock Hydro Friends Fund VIII, FFP Project 92 LLC, Riverbank Hydro No. 24 LLC; Notice of Competing...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-11-29

... DEPARTMENT OF ENERGY Federal Energy Regulatory Commission [Project Nos. 14262-000; 14276-000; 14280-000] Lock Hydro Friends Fund VIII, FFP Project 92 LLC, Riverbank Hydro No. 24 LLC; Notice of..., and Competing Applications On September 1, 2011, Lock Hydro Friends Fund VIII (Lock Hydro), FFP...

Randomized study of surgical prophylaxis in immunocompromised hosts.

PubMed

Lopes, D R; Peres, M P S M; Levin, A S

2011-02-01

Although prophylaxis is current practice, there are no randomized controlled studies evaluating preoperative antimicrobial prophylaxis in dental procedures in patients immunocompromised by chemotherapy or organ transplants. To evaluate prophylaxis in dental-invasive procedures in patients with cancer or solid organ transplants, 414 patients were randomized to receive one oral 500-mg dose 2 hours before the procedure (1-dose group) or a 500-mg dose 2 hours before the procedure and an additional dose 8 hours later (2-dose group). Procedures were exodontia or periodontal scaling/root planing. Follow-up was 4 weeks. No deaths or surgical site infections occurred. Six patients (1.4%) presented with use of pain medication > 3 days or hospitalization during follow-up: 4 of 207 (2%) in the 1-dose group and 2 of 207 (1%) in the 2-dose group (relative risk, 2.02; 95% confidence interval, 0.37-11.15). In conclusion, no statistically significant difference occurred in outcome using 1 or 2 doses of prophylactic amoxicillin for invasive dental procedures in immunocompromised patients.

Advantages of Reduced Prophylaxis after Tubularized Incised Plate Repair of Hypospadias.

PubMed

Zeiai, Said; Nordenskjöld, Agneta; Fossum, Magdalena

2016-10-01

Concerns about antibiotic resistance, adverse drug reactions and questionable medical benefits have led to changes in prophylactic antibiotic management in hypospadias repair at our clinic. In March 2010 our guidelines were changed from continuous prophylaxis for 14 days to 1 dose preoperatively and another at removal of the stent. We analyze the effects of this new regimen. We performed a prospective journal cohort study of all our hypospadias operations from June 2008 to December 2011. We collected data from consecutive patients undergoing primary tubularized incised plate repair and postoperative stent. Patients operated on before March 2010 were compared to those operated on later. End points were postoperative infection requiring antibiotics and any complication that required redo surgery. The study included 113 primary tubularized incised plate repairs with postoperative stents. Patient distribution was the same in both groups. Of 58 patients in the group receiving continuous antibiotic prophylaxis 17 had a complication and/or infection, compared to 9 of 55 patients receiving 2-dose prophylaxis. The infection rate was 5% in the continuous prophylaxis group and 4% in the 2-dose group. In contrast to our expectations, a lower complication rate was observed in the group with lower antibiotic dose without an increased risk of infection. There is little documented evidence concerning benefits of antibiotic prophylaxis for postoperative complications, which gives rise to large variations in clinical practice. In our study lower antibiotic dose did not increase the number of infections, but rather decreased complication rates. We advocate antibiotic prophylaxis with only a 2-dose regimen. Copyright © 2016 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.

Effects of Mg/Ga and V/III source ratios on hole concentration of N-polar (000\\bar{1}) p-type GaN grown by metalorganic vapor phase epitaxy

NASA Astrophysics Data System (ADS)

Nonoda, Ryohei; Shojiki, Kanako; Tanikawa, Tomoyuki; Kuboya, Shigeyuki; Katayama, Ryuji; Matsuoka, Takashi

2016-05-01

The effects of growth conditions such as Mg/Ga and V/III ratios on the properties of N-polar (000\\bar{1}) p-type GaN grown by metalorganic vapor phase epitaxy were studied. Photoluminescence spectra from Mg-doped GaN depended on Mg/Ga and V/III ratios. For the lightly doped samples, the band-to-acceptor emission was observed at 3.3 eV and its relative intensity decreased with increasing V/III ratio. For the heavily doped samples, the donor-acceptor pair emission was observed at 2.8 eV and its peak intensity monotonically decreased with V/III ratio. The hole concentration was maximum for the Mg/Ga ratio. This is the same tendency as in group-III polar (0001) growth. The V/III ratio also reduced the hole concentration. The higher V/III ratio reduced the concentration of residual donors such as oxygen by substituting nitrogen atoms. The surface became rougher with increasing V/III ratio and the hillock density increased.

What Is the Safety and Efficacy of Chemical Venous Thromboembolism Prophylaxis Following Vestibular Schwannoma Surgery?

PubMed

Casazza, Geoffrey C; Bowers, Christian A; MacDonald, Joel D; Couldwell, William T; Shelton, Clough; Gurgel, Richard K

2018-02-01

The benefit of routine chemical prophylaxis use for venous thromboembolism (VTE) prevention in skull base surgery is controversial. Chemical prophylaxis can prevent undue morbidity and mortality, however there are risks for hemorrhagic complications. Retrospective case-control. A retrospective chart review of patients who underwent surgery for vestibular schwannoma from 2011 to 2016 was performed. Patients were divided by receipt of chemical VTE prophylaxis. Number of VTEs and hemorrhagic complications (intracranial hemorrhage, abdominal hematoma, and postauricular hematoma) were recorded. One hundred twenty-six patients were identified, 55 received chemical prophylaxis, and 71 did not. All the patients received mechanical prophylaxis. Two patients developed a deep vein thrombosis (DVT) and one patient developed a pulmonary embolism (PE). All patients who developed a DVT or PE received chemical prophylaxis. There was no difference in DVT (p = 0.1886) or PE (p = 0.4365) between those who received chemical prophylaxis and those who did not. Five patients developed a hemorrhagic complication, two intracranial hemorrhage, three abdominal hematoma, and zero postauricular hematoma. All five patients with a complication received chemical prophylaxis (p = 0.00142). The relative risk of a hemorrhagic complication was 14.14 (95% CI = 0.7987-250.4307; p = 0.0778). There was a significant difference between the number of hemorrhagic complications but not between numbers of DVT or PE. Mechanical and chemical prophylaxis may lower the risk of VTE but in our series, hemorrhagic complications were observed. These measures should be used selectively in conjunction with early ambulation.

Effectiveness of the iodine prophylaxis model adopted in Poland.

PubMed

Szybinski, Z; Golkowski, F; Buziak-Bereza, M; Trofimiuk, M; Przybylik-Mazurek, E; Huszno, B; Bandurska-Stankiewicz, E; Bar-Andziak, E; Dorant, B; Kinalska, I; Lewinski, A; Klencki, M; Rybakowa, M; Sowinski, J; Szewczyk, L; Szponar, L; Wasik, R

2008-04-01

Most of the Polish territory has been classified as an iodine-deficient and endemic goiter area according to the International Council for Control of Iodine Deficiency (ICCIDD) criteria. In 1997 the obligatory model of iodine prophylaxis was implemented. Our investigations were aimed at the effectiveness of iodine prophylaxis in Poland. We assessed urinary iodine excretion and goiter prevalence in 5663 children aged 6-12 yr. The population of children from the same 27 schools was investigated from 1992 to 1994 (1406 girls and 1244 boys) and from 1999 to 2005 (1563 girls and 1450 boys) using identical laboratory and ultrasound methods. We found significant increase in iodine urinary concentration (median 52 microg/l vs 93 microg/l, p<0.001) with accompanying drop in goiter prevalence (29.6% vs 5.2%, p<0.001) after implementation of iodine prophylaxis. Iodine excretion distribution changed significantly after 1997 with an increase in the percentage of children with iodine urinary concentration above 100 microg/l from 10.8% to 45.4%, respectively. A significantly higher iodine urinary concentration was observed in lowlands compared to uplands both before and after implementation of iodine prophylaxis (median, 50 microg/l vs 57 microg/l and 86 microg/l vs 114 microg/l, respectively, p<0.001). The goiter prevalence did not differ between girls and boys from 1992 to 1994 (28.8% vs 30.5%, p=0.35) and 1999 to 2005 (5.5% vs 4.9%, p=0.45). Implementation of the new model of iodine prophylaxis in Poland in 1997 has led to significant increase in iodine urinary concentration and decrease in goiter prevalence among Polish schoolchildren. In the youngest group of children (6-8 yr olds), prevalence of goiter decreased to 3.2%--i.e. below endemic levels.

Intraoperative retinal detachment prophylaxis in vitrectomy for retained cataract fragments.

PubMed

Morris, Robert E; Shere, Jeffrey L; Witherspoon, C Douglas; Segal, Zachary K; Tehranchi, Linda; Kuhn, Ferenc; Sapp, Mathew

2009-03-01

To assess the safety and efficacy of peripheral 360-degree laser retinopexy as prophylaxis against rhegmatogenous retinal detachment (RRD) in eyes having pars plana vitrectomy (PPV) for the removal of retained cataract fragments. Private practice, Callahan Eye Foundation Hospital, University of Alabama at Birmingham, and Helen Keller Foundation for Research and Education, Birmingham, Alabama, USA. This retrospective analysis comprised a consecutive series of patients who had PPV with 360-degree laser retinopexy for retained cataract fragment removal between January 1, 1995, and December 31, 2000. All laser treatments were applied with indirect ophthalmoscope delivery. In 78 eyes of 78 patients, the mean interval between cataract surgery and PPV with 360-degree laser retinopexy prophylaxis was 14 days. One (1.3%) of 78 eyes had postoperative RRD during a mean follow-up of 6 years. No laser-related complications occurred. The incidence of RRD after PPV with 360-degree laser retinopexy prophylaxis was 1.3%, a significant reduction from the average 8.2% RRD rate in the literature (P = .024). Although future prospective trials are indicated, the results suggest that 360-degree laser retinopexy prophylaxis could significantly reduce the incidence of this visually disabling complication.

Evaluation of postoperative antibiotic prophylaxis after liver resection: a randomized controlled trial.

PubMed

Hirokawa, Fumitoshi; Hayashi, Michihiro; Miyamoto, Yoshiharu; Asakuma, Mitsuhiro; Shimizu, Tetsunosuke; Komeda, Koji; Inoue, Yoshihiro; Uchiyama, Kazuhisa; Nishimura, Yasuichiro

2013-07-01

Antibiotic prophylaxis is frequently administered after liver resection to prevent postoperative infections. However, very few studies have examined the usefulness of antibiotic prophylaxis after liver resection. A randomized controlled trial was conducted to evaluate the postoperative antibiotic prophylaxis in patients after liver resection. A total of 241 patients scheduled to undergo liver resection were randomly assigned to the non-postoperative antibiotic group (n = 95) or the antibiotic group (n = 95). The antibiotic group was given flomoxef sodium every 12 hours for 3 days after the operation. The end point was signs of infection, surgical site infection, or infectious complications. There were no significant differences between the 2 groups in signs of infection (21.3% vs 25.5%, P = .606), the incidence of systemic inflammatory response syndrome (11.7% vs 17.0%, P = .406), infectious complications (7.5% vs 17.0%, P = .073), surgical site infection (10.6% vs 13.8%, P = .657), and remote site infection (2.1% vs 8.5%, P = .100). Postoperative antibiotic prophylaxis cannot prevent postoperative infections after liver resection, and it is thought that antibiotic prophylaxis is unnecessary and costly. Copyright © 2013 Elsevier Inc. All rights reserved.

Solid State Surfaces and Interfaces VIII

NASA Astrophysics Data System (ADS)

Pincik, Emil

2014-09-01

The conference SSSI VIII (November 25-28, 2013) was the 8th continuation of the series of the Solid State Surfaces and Interfaces conferences taking place usually in the Smolenice castle in the western part of the Slovak Republic. The event was organized by the following institutions of Slovak Republic: Institute of Physics of SAS Bratislava, Institute of Aurel Stodola of University of Žilina, and Faculty of Mathematics, Physics and Informatics of Comenius University Bratislava. More than 150 scientists of the three continents (Europe, Asia and Africa) participated on the event with almost 100 poster presentations. The representatives of all organizing institutions consider this event as very important for Middle Europe region.

A decision model to estimate a risk threshold for venous thromboembolism prophylaxis in hospitalized medical patients.

PubMed

Le, P; Martinez, K A; Pappas, M A; Rothberg, M B

2017-06-01

Essentials Low risk patients don't require venous thromboembolism (VTE) prophylaxis; low risk is unquantified. We used a Markov model to estimate the risk threshold for VTE prophylaxis in medical inpatients. Prophylaxis was cost-effective for an average medical patient with a VTE risk of ≥ 1.0%. VTE prophylaxis can be personalized based on patient risk and age/life expectancy. Background Venous thromboembolism (VTE) is a common preventable condition in medical inpatients. Thromboprophylaxis is recommended for inpatients who are not at low risk of VTE, but no specific risk threshold for prophylaxis has been defined. Objective To determine a threshold for prophylaxis based on risk of VTE. Patients/Methods We constructed a decision model with a decision-tree following patients for 3 months after hospitalization, and a lifetime Markov model with 3-month cycles. The model tracked symptomatic deep vein thromboses and pulmonary emboli, bleeding events and heparin-induced thrombocytopenia. Long-term complications included recurrent VTE, post-thrombotic syndrome and pulmonary hypertension. For the base case, we considered medical inpatients aged 66 years, having a life expectancy of 13.5 years, VTE risk of 1.4% and bleeding risk of 2.7%. Patients received enoxaparin 40 mg day -1 for prophylaxis. Results Assuming a willingness-to-pay (WTP) threshold of $100 000/ quality-adjusted life year (QALY), prophylaxis was indicated for an average medical inpatient with a VTE risk of ≥ 1.0% up to 3 months after hospitalization. For the average patient, prophylaxis was not indicated when the bleeding risk was > 8.1%, the patient's age was > 73.4 years or the cost of enoxaparin exceeded $60/dose. If VTE risk was < 0.26% or bleeding risk was > 19%, the risks of prophylaxis outweighed benefits. The prophylaxis threshold was relatively insensitive to low-molecular-weight heparin cost and bleeding risk, but very sensitive to patient age and life expectancy. Conclusions The decision to

Antibiotic prophylaxis in hematopoietic stem cell transplantation. A meta-analysis of randomized controlled trials.

PubMed

Kimura, Shun-ichi; Akahoshi, Yu; Nakano, Hirofumi; Ugai, Tomotaka; Wada, Hidenori; Yamasaki, Ryoko; Ishihara, Yuko; Kawamura, Koji; Sakamoto, Kana; Ashizawa, Masahiro; Sato, Miki; Terasako-Saito, Kiriko; Nakasone, Hideki; Kikuchi, Misato; Yamazaki, Rie; Kako, Shinichi; Kanda, Junya; Tanihara, Aki; Nishida, Junji; Kanda, Yoshinobu

2014-07-01

We performed a meta-analysis to evaluate the impact of systemic antibiotic prophylaxis in hematopoietic stem cell transplantation (HSCT) recipients. We collected reports from PubMed, the Cochrane Library, EMBASE, CINAHL, and Web of Science, along with references cited therein. We included prospective, randomized studies on systemic antibiotic prophylaxis in HSCT recipients. Seventeen trials with 1453 autologous and allogeneic HSCT recipients were included. Systemic antibiotic prophylaxis was compared with placebo or no prophylaxis in 10 trials and with non-absorbable antibiotics in two trials. Systemic antibiotics other than fluoroquinolones were evaluated in five of these 12 trials. Four trials evaluated the effect of the addition of antibiotics for gram-positive bacteria to fluoroquinolones. One trial compared two different systemic antibiotic regimens: fluoroquinolones versus trimethoprim-sulfamethoxazole. As a result, systemic antibiotic prophylaxis reduced the incidence of febrile episodes (OR 0.16; 95%CI 0.09-0.30), clinically or microbiologically documented infection (OR 0.38; 95%CI 0.22-0.63) and bacteremia (OR 0.31; 95%CI 0.16-0.59) without significantly affecting all-cause mortality or infection-related mortality. Systemic antibiotic prophylaxis successfully reduced the incidence of infection. However, there was no significant impact on mortality. The clinical benefits of prophylaxis with fluoroquinolones were inconclusive because of the small number of clinical trials evaluated. Copyright © 2014 The British Infection Association. Published by Elsevier Ltd. All rights reserved.

Budget Impact Analysis of Prolonged Half-Life Recombinant FVIII Therapy for Hemophilia in the United States.

PubMed

McMullen, Suzanne; Buckley, Brieana; Hall, Eric; Kendter, Jon; Johnston, Karissa

2017-01-01

Hemophilia A is a factor VIII deficiency, associated with spontaneous, recurrent bleeding episodes. This may lead to comorbidities such as arthropathy and joint replacement, which contribute to morbidity and increased health care expenditure. Recombinant factor VIII Fc fusion protein (rFVIIIFc), a prolonged half-life factor therapy, requires fewer infusions, resulting in reduced treatment burden. Use a budget impact analysis to assess the potential economic impact of introducing rFVIIIFc to a formulary from the perspective of a private payer in the United States. The budget impact model was developed to estimate the potential economic impact of adding rFVIIIFc to a private payer formulary across a 2-year time period. The eligible patient population consisted of inhibitor-free adults with severe hemophilia A, receiving recombinant-based episodic or prophylaxis treatment regimens. Patients were assumed to switch from conventional recombinant factor treatment to rFVIIIFc. Only medication costs were included in the model. The introduction of rFVIIIFc is estimated to have a budget impact of 1.4% ($0.12 per member per month) across 2 years for a private payer population of 1,000,000 (estimated 19.7 individuals receiving treatment for hemophilia A). The introduction of rFVIIIFc is estimated to prevent 124 bleeds across 2 years at a cost of $1891 per bleed avoided. Hemophilia A is a rare disease with a low prevalence; therefore, the overall cost to society of introducing rFVIIIFc is small. Considerations for comprehensively assessing the budget impact of introducing rFVIIIFc should include episodic and prophylaxis regimens, bleed avoidance, and annual factor consumption required under alternative scenarios. Copyright © 2017 International Society for Pharmacoeconomics and Outcomes Research (ISPOR). Published by Elsevier Inc. All rights reserved.

The effect of different methods of leucoreduction on plasma coagulation factors.

PubMed

Aboul Enein, Azza A; Abdel Rahman, Hala A; Abdel Maged, Mohamed M M; El Sissy, Maha H

2017-03-01

Removal of leucocytes from blood products, namely leucoreduction, improves the safety of blood transfusion by reducing adverse events associated with the incidental transfusion of leucocytes. Coagulation factors might be compromised during leucoreduction because of exposure of plasma to a variety of filter materials. The aim of the current study was to assess the effect of different methods of prestorage leucofiltration (apheresis and whole blood filters) on prothrombin time, international normalized ratio, partial thromboplastin time and factors V and VIII. There was a significant prolongation of prothrombin time as well as elevation of international normalized ratio in plasma after leucoreduction (14.5 ± 0.7 s vs. 13.9 ± 0.7 s, P = 0.008 and 1.14 ± 0.07 vs. 1.09 ± 0.07, P = 0.005, respectively). Also, there was a statistically significant prolongation of activated partial thromboplastin time in nonleucoreduced plasma (55.6 ± 9.9 s vs. 43.2 ± 12.8 s, P = 0.001). There was no significant filtration effect on factors V and VIII levels. Furthermore, there was no significant difference in factors V and VIII levels between plasma filtered by inline whole blood filters and apheresis machine. Leucodepleted plasma originating from both inline whole blood filter and apheresis machine maintained satisfactory levels of factors V and VIII.

Inhibitor development in patients receiving recombinant factor VIII (Recombinate rAHF/Bioclate): a prospective pharmacovigilance study.

PubMed

Ewenstein, B M; Gomperts, E D; Pearson, S; O'Banion, M E

2004-09-01

Clinical trials to date have not been adequately powered to assess comparatively infrequent events such as inhibitor development in previously treated patients (PTPs). Comprehensive large-scale pharmacovigilance studies can be useful for this purpose. We prospectively collected inhibitor development reports worldwide among recipients of Recombinate rAHF recombinant factor VIII (rFVIII), also formerly distributed under the product name Bioclate, for the entire postlicensure period from 1993 through 2002. To determine level of exposure to rFVIII we also compiled the Recombinate rAHF/Bioclate International Units (IU) distributed annually. To estimate inhibitor incidence separately for previously untreated or minimally treated patients (PUPs) with 1-50 exposure days and PTPs with >50 exposure days, we used haemophilia A incidence and prevalence data and pooled mean annual rFVIII consumption per PUP and PTP from international multicentre prospective clinical trials. Documented inhibitor cases totalled 89, and the total quantity of Recombinate rAHF/Bioclate rFVIII distributed was 6.48 x10(9) IU. No lot association or other clustering of inhibitor events was evident in PTPs. The incidence of all reported inhibitors, expressed as a percentage of patients treated, was 11.9% (CI: 5.05-28.0%) for PUPs when compared with 0.123% (CI: 0.030-0.512%) for PTPs. The rates for high-titre inhibitors (>5 BU) only were 5.96% (CI: 3.00-11.8%) for PUPs and 0.0554% (CI: 0.0113-0.271%) for PTPs. Thus, incidence rates for both all inhibitors and high-titre inhibitors in PTPs were 1% of the corresponding rates in PUPs. Data from prospective PUP clinical trials involving intensive active monitoring suggest that true inhibitor incidence may be approximately twice that estimated in this pharmacovigilance study. Nevertheless, inhibitor development in PTPs receiving Recombinate rAHF/Bioclate is infrequent.

Rheumatic Heart Disease Prophylaxis in Older Patients: A Register-Based Audit of Adherence to Guidelines

PubMed Central

Holland, James V; Hardie, Kate; de Dassel, Jessica; Ralph, Anna P

2018-01-01

Abstract Background Prevention of rheumatic heart disease (RHD) remains challenging in high-burden settings globally. After acute rheumatic fever (ARF), secondary antibiotic prophylaxis is required to prevent RHD. International guidelines on recommended durations of secondary prophylaxis differ, with scope for clinician discretion. Because ARF risk decreases with age, ongoing prophylaxis is generally considered unnecessary beyond approximately the third decade. Concordance with guidelines on timely cessation of prophylaxis is unknown. Methods We undertook a register-based audit to determine the appropriateness of antibiotic prophylaxis among clients aged ≥35 years in Australia’s Northern Territory. Data on demographics, ARF episode(s), RHD severity, prophylaxis type, and relevant clinical notes were extracted. The determination of guideline concordance was based on whether (1) national guidelines were followed; (2) a reason for departure from guidelines was documented; (3) lifelong continuation was considered appropriate in all cases of severe RHD. Results We identified 343 clients aged ≥35 years prescribed secondary prophylaxis. Guideline concordance was 39% according to national guidelines, 68% when documented reasons for departures from guidelines were included and 82% if patients with severe RHD were deemed to need lifelong prophylaxis. Shorter times since last echocardiogram or cardiologist review were associated with greater likelihood of guideline concordance (P < .001). The median time since last ARF was 5.9 years in the guideline-concordant group and 24.0 years in the nonconcordant group (P < .001). Thirty-two people had an ARF episode after age 40 years. Conclusions In this setting, appropriate discontinuation of RHD prophylaxis could be improved through timely specialist review to reduce unnecessary burden on clients and health systems.

Retrospective review of intravenous pentamidine for Pneumocystis pneumonia prophylaxis in allogeneic hematopoietic stem cell transplantation.

PubMed

Diri, R; Anwer, F; Yeager, A; Krishnadasan, R; McBride, A

2016-02-01

Patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT) are at risk of numerous opportunistic infections. Pneumocystis jirovecii pneumonia (PJP) is a potentially life-threatening infection that can develop in immunocompromised individuals. Current prophylaxis for PJP includes trimethoprim-sulfamethoxazole (TMP-SMX), dapsone, atovaquone, or inhaled pentamidine (PEN), often with varying breakthrough rates. The use of intravenous (IV) PEN for PJP prophylaxis has been evaluated in pediatric patients. A single-institution retrospective review of electronic medical records was conducted for patients who underwent allo-HSCT between January 2001 and May 2013 and who had received at least 1 dose of IV PEN for PJP prophylaxis. Data collected included patient demographics, diagnosis, previous chemotherapy, pre-transplant conditioning regimen, other medications, microbiology test results, and clinical outcomes. A total of 113 patients were included in the study. The median number of PEN doses administered per patient was 3 (range 1-23). IV PEN was primary PJP prophylaxis in 74 of the patients (65%) and second-line prophylaxis in 39 (35%) post transplant, with the majority switching from oral TMP-SMX. Side effects of IV PEN administration were minimal. No patients who received IV PEN prophylaxis developed PJP infection. No case of PJP was seen in patients who received other agents for PJP prophylaxis. This retrospective study showed that IV PEN is very effective and well-tolerated prophylaxis for PJP; IV PEN can be considered a favorable alternative for PJP in situations where other agents might be contraindicated. Our findings provide strong support for prospective studies of IV PEN for PJP prophylaxis in adult HSCT recipients. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Antibiotic Prophylaxis after Immediate Breast Reconstruction: The Reality of Its Efficacy.

PubMed

Ranganathan, Kavitha; Sears, Erika D; Zhong, Lin; Chung, Ting-Ting; Chung, Kevin C; Kozlow, Jeffrey H; Momoh, Adeyiza O; Waljee, Jennifer F

2018-04-01

Numerous techniques are used to prevent infection after immediate implant-based breast reconstruction. Postoperative antibiotic prophylaxis is commonly prescribed to decrease the risk of reconstructive failure, despite conflicting evidence regarding its effectiveness. The authors studied whether postoperative antibiotic prophylaxis decreases the risk of infection-related explantation in the setting of immediate prosthesis-based breast reconstruction. Using Truven MarketScan databases, the authors identified all patients who underwent immediate implant reconstruction between January of 2010 and June of 2014 with at least 6 months of follow-up. Postoperative antibiotic prophylaxis was defined as any oral antibiotic course to be taken postoperatively based on prescriptions filled within 14 days preoperatively through 24 hours after discharge. Reconstructive failure, defined as explantation because of infection, was the primary outcome. Secondary outcomes of interest included wound complications, infection, and readmission for infection. Multivariable regression analyses controlled for demographic variables/comorbidities. Of the 7443 patients, 6049 (81 percent) filled prescriptions for postoperative antibiotic prophylaxis. These patients were equally likely to develop a wound complication (OR, 0.93; 95 percent CI, 0.71 to 1.23) or infection (OR, 0.89; 95 percent CI, 0.70 to 1.14), undergo explantation because of infection (OR, 0.82; 95 percent CI, 0.57 to 1.18), or require readmission for infection (OR, 1.21; 95 percent CI, 0.82 to 1.78) compared with those who did not receive antibiotics. There was no significant difference in the risk of infection-related outcomes based on postoperative antibiotic prophylaxis duration. Postoperative antibiotic prophylaxis was not associated with a reduced risk of infection or explantation following prosthesis-based breast reconstruction. Given rising rates of antibiotic resistance, focusing instead on technical considerations and the

Postauthorization safety surveillance of ADVATE [antihaemophilic factor (recombinant), plasma/albumin-free method] demonstrates efficacy, safety and low-risk for immunogenicity in routine clinical practice.

PubMed

Oldenburg, J; Goudemand, J; Valentino, L; Richards, M; Luu, H; Kriukov, A; Gajek, H; Spotts, G; Ewenstein, B

2010-11-01

  Postauthorization safety surveillance of factor VIII (FVIII) concentrates is essential for assessing rare adverse event incidence. We determined safety and efficacy of ADVATE [antihaemophilic factor (recombinant), plasma/albumin-free method, (rAHF-PFM)] during routine clinical practice. Subjects with differing haemophilia A severities and medical histories were monitored during 12 months of prophylactic and/or on-demand therapy. Among 408 evaluable subjects, 386 (95%) received excellent/good efficacy ratings for all on-demand assessments; the corresponding number for subjects with previous FVIII inhibitors was 36/41 (88%). Among 276 evaluable subjects receiving prophylaxis continuously in the study, 255 (92%) had excellent/good ratings for all prophylactic assessments; the corresponding number for subjects with previous FVIII inhibitors was 41/46 (89%). Efficacy of surgical prophylaxis was excellent/good in 16/16 evaluable procedures. Among previously treated patients (PTPs) with >50 exposure days (EDs) and FVIII≤2%, three (0.75%) developed low-titre inhibitors. Two of these subjects had a positive inhibitor history; thus, the incidence of de novo inhibitor formation in PTPs with FVIII≤2% and no inhibitor history was 1/348 (0.29%; 95% CI, 0.01-1.59%). A PTP with moderate haemophilia developed a low-titre inhibitor. High-titre inhibitors were reported in a PTP with mild disease (following surgery), a previously untreated patient (PUP) with moderate disease (following surgery) and a PUP with severe disease. The favourable benefit/risk profile of rAHF-PFM previously documented in prospective clinical trials has been extended to include a broader range of haemophilia patients, many of whom would have been ineligible for registration studies. © 2010 Blackwell Publishing Ltd.

Polarised press reporting about HIV prevention: Social representations of pre-exposure prophylaxis in the UK press.

PubMed

Jaspal, Rusi; Nerlich, Brigitte

2017-09-01

Pre-exposure prophylaxis is a novel biomedical HIV prevention option for individuals at high risk of HIV acquisition. Although pre-exposure prophylaxis has yielded encouraging results in various clinical trials, opponents argue that pre-exposure prophylaxis poses a number of risks to human health and to sexually transmitted infection prevention efforts. Using qualitative thematic analysis and social representation theory, this article explores coverage of pre-exposure prophylaxis in the UK print media between 2008 and 2015 in order to chart the emerging social representations of this novel HIV prevention strategy. The analysis revealed two competing social representations of pre-exposure prophylaxis: (1) as a positive development in the 'battle' against HIV (the hope representation) and (2) as a medical, social and psychological setback in this battle, particularly for gay/bisexual men (the risk representation). These social representations map onto the themes of pre-exposure prophylaxis as a superlatively positive development; pre-exposure prophylaxis as a weapon in the battle against HIV/AIDS; and risk, uncertainty and fear in relation to pre-exposure prophylaxis. The hope representation focuses on taking (individual and collective) responsibility, while the risk representation focuses on attributing (individual and collective) blame. The implications for policy and practice are discussed.

Nutraceuticals in the prophylaxis of pediatric migraine: Evidence-based review and recommendations.

PubMed

Orr, Serena L; Venkateswaran, Sunita

2014-07-01

The literature on complementary and alternative medicine (CAM) is expanding. One of the most common conditions for which CAM is studied in the pediatric population is migraine. Nutraceuticals are a form of CAM that is being used for pediatric migraine prophylaxis. A literature search was carried out in order to identify both observational studies and randomized controlled trials on the use of nutraceuticals for the prophylaxis of pediatric migraine. Adult studies on included nutraceuticals were also reviewed. Thirty studies were reviewed on six different nutraceuticals: butterbur, riboflavin, ginkgolide B, magnesium, coenzyme Q10 and polyunsaturated fatty acids. Overall, the quality of the evidence for the use of nutraceuticals in pediatric migraine prophylaxis is poor. Further research needs to be done in order to study the efficacy of nutraceuticals for the prophylaxis of pediatric migraine. © International Headache Society 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.

Cost-effectiveness of active-passive prophylaxis and antiviral prophylaxis during pregnancy to prevent perinatal hepatitis B virus infection.

PubMed

Fan, Lin; Owusu-Edusei, Kwame; Schillie, Sarah F; Murphy, Trudy V

2016-05-01

In an era of antiviral treatment, reexamination of the cost-effectiveness of strategies to prevent perinatal hepatitis B virus (HBV) transmission in the United States is needed. We used a decision tree and Markov model to estimate the cost-effectiveness of the current U.S. strategy and two alternatives: (1) Universal hepatitis B vaccination (HepB) strategy: No pregnant women are screened for hepatitis B surface antigen (HBsAg). All infants receive HepB before hospital discharge; no infants receive hepatitis B immunoglobulin (HBIG). (2) Current strategy: All pregnant women are screened for HBsAg. Infants of HBsAg-positive women receive HepB and HBIG ≤12 hours of birth. All other infants receive HepB before hospital discharge. (3) Antiviral prophylaxis strategy: All pregnant women are screened for HBsAg. HBsAg-positive women have HBV-DNA load measured. Antiviral prophylaxis is offered for 4 months starting in the third trimester to women with DNA load ≥10(6) copies/mL. HepB and HBIG are administered at birth to infants of HBsAg-positive women, and HepB is administered before hospital discharge to infants of HBsAg-negative women. Effects were measured in quality-adjusted life years (QALYs) and incremental cost-effectiveness ratios (ICER). Compared to the universal HepB strategy, the current strategy prevented 1,006 chronic HBV infections and saved 13,600 QALYs (ICER: $6,957/QALY saved). Antiviral prophylaxis dominated the current strategy, preventing an additional 489 chronic infections, and saving 800 QALYs and $2.8 million. The results remained robust over a wide range of assumptions. The current U.S. strategy for preventing perinatal HBV remains cost-effective compared to the universal HepB strategy. An antiviral prophylaxis strategy was cost saving compared to the current strategy and should be considered to continue to decrease the burden of perinatal hepatitis B in the United States. Published 2015. This article is a U.S. Government work and is in the public

Variation in DVT prophylaxis for adolescent trauma patients: a survey of the Society of Trauma Nurses.

PubMed

O'Brien, Sarah H; Haley, Kathy; Kelleher, Kelly J; Wang, Wei; McKenna, Christine; Gaines, Barbara A

2008-01-01

We performed a survey of the Society of Trauma Nurses to explore current practice patterns for deep venous thrombosis prophylaxis in adolescent trauma patients and analyzed responses from 133 institutions. The majority of adult prophylaxis protocols include older adolescents. Only 41% of adult programs identified patient age as "very" important in prophylaxis decision making. Pelvic fracture, spinal cord injury, and expected immobilization were rated most important. Pharmacologic prophylaxis in 11- to 15-year-olds was infrequent, with 60% of centers using never or rarely. Use was much higher but variable among older adolescents. No consensus on deep venous thrombosis prophylaxis in adolescent trauma emerged from our survey.

The Johns Hopkins Venous Thromboembolism Collaborative: Multidisciplinary team approach to achieve perfect prophylaxis.

PubMed

Streiff, Michael B; Lau, Brandyn D; Hobson, Deborah B; Kraus, Peggy S; Shermock, Kenneth M; Shaffer, Dauryne L; Popoola, Victor O; Aboagye, Jonathan K; Farrow, Norma A; Horn, Paula J; Shihab, Hasan M; Pronovost, Peter J; Haut, Elliott R

2016-12-01

Venous thromboembolism (VTE) is an important cause of preventable harm in hospitalized patients. The critical steps in delivery of optimal VTE prevention care include (1) assessment of VTE and bleeding risk for each patient, (2) prescription of risk-appropriate VTE prophylaxis, (3) administration of risk-appropriate VTE prophylaxis in a patient-centered manner, and (4) continuously monitoring outcomes to identify new opportunities for learning and performance improvement. To ensure that every hospitalized patient receives VTE prophylaxis consistent with their individual risk level and personal care preferences, we organized a multidisciplinary task force, the Johns Hopkins VTE Collaborative. To achieve the goal of perfect prophylaxis for every patient, we developed evidence-based, specialty-specific computerized clinical decision support VTE prophylaxis order sets that assist providers in ordering risk-appropriate VTE prevention. We developed novel strategies to improve provider VTE prevention ordering practices including face-to-face performance reviews, pay for performance, and provider VTE scorecards. When we discovered that prescription of risk-appropriate VTE prophylaxis does not ensure its administration, our multidisciplinary research team conducted in-depth surveys of patients, nurses, and physicians to design a multidisciplinary patient-centered educational intervention to eliminate missed doses of pharmacologic VTE prophylaxis that has been funded by the Patient Centered Outcomes Research Institute. We expect that the studies currently underway will bring us closer to the goal of perfect VTE prevention care for every patient. Our learning journey to eliminate harm from VTE can be applied to other types of harm. Journal of Hospital Medicine 2016;11:S8-S14. © 2016 Society of Hospital Medicine. © 2016 Society of Hospital Medicine.

Deep-vein thrombosis prophylaxis in foot and ankle surgery: what is the current state of practice?

PubMed

Shah, Kalpesh; Thevendran, Gowreeson; Younger, Alastair; Pinney, Stephen J

2015-04-01

When contemplating thromboprophylaxis for patients undergoing elective foot and ankle surgery the potential for complications secondary to venous thromboembolism (VTE) must be balanced against the cost, risk, and effectiveness of prophylactic treatment. The incidence of pulmonary embolism (PE) following foot and ankle surgery is considerably lower than after hip or knee surgery. The purpose of this study was to assess current trends in practice regarding VTE prophylaxis among expert orthopaedic foot and ankle surgeons. An e-mail-based survey of active AOFAS (American Orthopaedic Foot and Ankle Society) committee members was conducted (n = 100). Surgeons were questioned as to their use, type, and duration of thromboprophylaxis following elective ankle fusion surgery. Scenarios included the following: (1) A 50-year-old woman with no risk factors; (2) a 50-year-old woman with a history of PE; and (3) a 35-year-old woman actively using birth control pills (BCPs). The response rate for the survey was 80% (80/100). Replies regarding the use of thromboprophylaxis were as follows: (1) in the absence of risk factors, 57% of respondents (45/80) answered, "No prophylaxis required"; (2) for the scenario in which the patient had experienced a previous PE, 97.5% of respondents (78/80) answered, "Yes" to prophylaxis use; (3) for the scenario in which the patient was on BCP, 61.3% of respondents (49/80) stated that they would give some type of thromboprophylaxis. The most commonly recommended methods of prophylaxis were aspirin, 49% (24/49), and low-molecular-weight heparin, 47% (23/49). The recommended length of time for thromboprophylaxis varied widely, from 1 day to more than 6 weeks. . There remains wide variation in the practice of deep-vein thrombosis thromboprophylaxis within the foot and ankle community. Because risks for foot and ankle patients differ from those in the well-studied areas of hip and knee, specific guidelines are needed for foot and ankle surgery. Level V

Evaluation of the impact of dental prophylaxis on the oral microbiota of dogs.

PubMed

Flancman, Rebecca; Singh, Ameet; Weese, J Scott

2018-01-01

Periodontal disease is one of the most commonly diagnosed oral diseases in dogs and can result from undisturbed dental plaque. Dental prophylaxis is a routinely practiced veterinary procedure, but its effects on both the plaque and oral microbiota is not fully understood. The objectives of this study were to evaluate the impact of dental prophylaxis on the composition of the supragingival plaque and composite oral microbiota in clinically healthy dogs and to determine if composite sampling could be used in lieu of sampling the plaque microbiota directly. Thirty dogs received a dental prophylaxis. Supragingival plaque and composite oral samples were collected just prior to, and one week after dental prophylaxis. A subsample of 10 dogs was followed, and additional samples were collected two and five weeks post-prophylaxis. The V4 region of the 16S rRNA gene was used for Illumina MiSeq next-generation sequencing. Results demonstrate that decreases in Treponema as well as increases in Moraxella and Neisseria distinguished the plaque pre- and one week post-prophylaxis timepoints (all P<0.05). Within the oral microbiota, the initially dominant Psychrobacter (20% relative abundance) disappeared one week later (P<0.0001), and Pseudomonas became the dominant taxon one week after treatment (80% relative abundance, P<0.0001). A rapid transition back towards the pre-dental prophylaxis microbiota by five weeks post-treatment was seen for both niches, suggesting the canine oral microbiota is resilient. Direct comparison of the two environments yielded striking differences, with complete separation of groups. Firmicutes (40%) and Spirochaetes (22%) predominated in the plaque while Proteobacteria (58%) was predominant in the oral microbiota. Greater richness was also seen in the plaque microbiota. This study reveals that prophylaxis had a profound impact on both the plaque and oral microbiota, and the longitudinal results help elucidate the pathophysiology of periodontal disease

Factor VIII, Protein C and Cardiovascular Disease Risk: The REasons for Geographic and Racial Differences in Stroke Study (REGARDS).

PubMed

Zakai, Neil A; Judd, Suzanne E; Kissela, Brett; Howard, George; Safford, Monika M; Cushman, Mary

2018-06-11

 Haemostatic balance represented by low protein C (PC) and elevated factor VIII (FVIII) has been inconsistently associated with stroke and coronary heart disease (CHD) risk.  This article assesses whether an elevated FVIII and a low PC would increase cardiovascular risk more than either individually.  REGARDS recruited 30,239 black and white U.S. participants aged ≥ 45 years between 2003 and 2007. FVIII and PC were measured in a case-cohort sample of 646 stroke, 654 CHD, and a 1,104-person random sample with follow-up for approximately 4.5 years. Hazard ratios (HRs) were estimated using Cox models adjusted for demographic and cardiovascular risk factors.  Elevated FVIII (per standard deviation [SD] increase) was associated with increased risk of both stroke (HR, 1.26; 95% confidence interval [CI], 1.08, 1.46) and CHD (HR, 1.52; 95% CI, 1.29, 1.79), while there was no association of PC per SD decrease. For PC, there was a trend towards increased cardiovascular disease risk in the lowest values (bottom 5%). For stroke, there was no interaction between FVIII and low PC ( p interaction  = 0.55). For CHD, the adjusted HR of FVIII per SD increase was significantly greater with PC in the bottom 5% (HR, 3.59; 95% CI, 1.39, 8.29) than PC in the upper 95% (HR, 1.45; 95% CI, 1.23, 1.71; p interaction  = 0.07).  Higher FVIII was associated with both CHD and stroke risk and the risk potentiated by low PC for CHD. Findings demonstrate that risks for cardiovascular diseases conferred by adverse levels of haemostasis biomarkers may be augmented by levels of other biomarkers. Schattauer GmbH Stuttgart.

Antifungal prophylaxis during neutropenia and immunodeficiency.

PubMed Central

Lortholary, O; Dupont, B

1997-01-01

Fungal infections represent a major source of morbidity and mortality in patients with almost all types of immunodeficiencies. These infections may be nosocomial (aspergillosis) or community acquired (cryptococcosis), or both (candidiasis). Endemic mycoses such as histoplasmosis, coccidioidomycosis, and penicilliosis may infect many immunocompromised hosts in some geographic areas and thereby create major public health problems. With the wide availability of oral azoles, antifungal prophylactic strategies have been extensively developed. However, only a few well-designed studies involving strict criteria have been performed, mostly in patients with hematological malignancies or AIDS. In these situations, the best dose and duration of administration of the antifungal drug often remain to be determined. In high-risk neutropenic or bone marrow transplant patients, fluconazole is effective for the prevention of superficial and/or systemic candidal infections but is not always able to prolong overall survival and potentially selects less susceptible or resistant Candida spp. Primary prophylaxis against aspergillosis remains investigative. At present, no standard general recommendation for primary antifungal prophylaxis can be proposed for AIDS patients or transplant recipients. However, for persistently immunocompromised patients who previously experienced a noncandidal systemic fungal infection, prolonged suppressive antifungal therapy is often indicated to prevent a relapse. Better strategies for controlling immune deficiencies should also help to avoid some potentially life-threatening deep mycoses. When prescribing antifungal prophylaxis, physicians should be aware of the potential emergence of resistant strains, drug-drug interactions, and the cost. Well-designed, randomized, multicenter clinical trials in high-risk immunocompromised hosts are urgently needed to better define how to prevent severe invasive mycoses. PMID:9227863