Sample records for hemophilia cohort hgds-3

  1. SSV Launch Monitoring Strategies: HGDS Design and Development Through System Maturity

    NASA Technical Reports Server (NTRS)

    Shoemaker, Marc D.; Crimi, Thomas

    2010-01-01

    This poster presentation reviews the design and development of the Hazardous Gas Detection System (HGDS). It includes a overview schematic of the HGDS, pictures of the shuttle on the Mobile Launch platform, the original HGDS, the current HGDS and parts of the original and current system. There are charts showing the dynamics of the orbiter during external tank loading, and transient leaks observed on HGDS during Power Reactant Storage and Distribution (PRSD) load.

  2. SSV Launch Monitoring Strategies: HGDS Design Implementation Through System Maturity

    NASA Technical Reports Server (NTRS)

    Shoemaker, Marc D.; Crimi, Thomas

    2010-01-01

    With over 500,000 gallons of liquid hydrogen and liquid oxygen, it is of vital importance to monitor the space shuttle vehicle (SSV) from external tank (ET) load through launch. The Hazardous Gas Detection System (HGDS) was installed as the primary system responsible for monitoring fuel leaks within the orbiter and ET. The HGDS was designed to obtain the lowest possible detection limits with the best resolution while monitoring the SSV for any hydrogen, helium, oxygen, or argon as the main requirement. The HGDS is a redundant mass spectrometer used for real-time monitoring during Power Reactant Storage and Distribution (PRSD) load and ET load through launch or scrub. This system also performs SSV processing leak checks of the Tail Service Mast (TSM) umbilical quick disconnects (QD's), Ground Umbilical Carrier Plate (GUCP) QD's and supports auxiliary power unit (APU) system tests. From design to initial implementation and operations, the HGDS has evolved into a mature and reliable launch support system. This paper will discuss the operational challenges and lessons learned from facing design deficiencies, validation and maintenance efforts, life cycle issues, and evolving requirements

  3. Costs and utilization of hemophilia A and B patients with and without inhibitors.

    PubMed

    Armstrong, Edward P; Malone, Daniel C; Krishnan, Sangeeta; Wessler, Maj Jacob

    2014-11-01

    To evaluate the health system costs among patients with hemophilia A and B with and without inhibitors over 5 years. This was a retrospective, observational study utilizing medical and pharmacy electronic medical records and administrative encounters/claims data tracking US patients between 2006-2011. Patients with diagnosis codes for hemophilia A and B were identified. Patients with inhibitors were characterized by utilization of bypassing agents activated prothrombin complex concentrate or factor VIIa on two or more distinct dates. Severity was classified as mild, moderate, or severe based on laboratory tests of clotting factor. There were 160 hemophilia A patients and 54 hemophilia B patients identified. From this group, seven were designated as patients with inhibitors (five with hemophilia A and two with hemophilia B). Hemophilia A patients without inhibitors reported 65 (41.9%) as being severe, 19 (12.3%) as moderate, and 71 (45.8%) as mild. Hemophilia B patients without inhibitors reported nine (17.3%) had severe, 13 (25.0%) had moderate, and 30 (57.7%) had mild hemophilia. All patients with inhibitors had been hospitalized in the previous 5 years compared to 64 (41.3%) with hemophilia A without inhibitors and 22 (42.3%) with hemophilia B without inhibitors. The median aggregate cost per year (including factor and health resource use) was $325,780 for patients with inhibitors compared to $98,334 for hemophilia A patients without inhibitors and $23,265 for hemophilia B patients without inhibitors. The results suggest that, while the frequency of inhibitors within the hemophilia cohort was low, there was a higher frequency of hospitalizations, and the associated median aggregate costs per year were 3-fold higher than those patients without inhibitors. In contrast, hemophilia B patients experience less severe disease and account for lower aggregate yearly costs compared to either patients with hemophilia A or patients with inhibitors.

  4. Young adults with hemophilia in the U.S.: demographics, comorbidities, and health status.

    PubMed

    Curtis, Randall; Baker, Judith; Riske, Brenda; Ullman, Megan; Niu, Xiaoli; Norton, Kristi; Lou, Mimi; Nichol, Michael B

    2015-12-01

    Improvements in hemophilia care over the last several decades might lead to expectations of a near-normal quality of life for young adults with hemophilia. However, few published reports specifically examine health status indicators in this population. To remedy this knowledge gap, we examined the impact of hemophilia on physical and social functioning and quality of life among a national US cohort of 141 young men with hemophilia aged 18-34 years of age who received care at 10 geographically diverse, federally funded hemophilia treatment centers in 11 states between 2005 and 2013 and enrolled in the Hemophilia Utilization Group Studies. Indicators studied included educational achievement, employment status, insurance, health-related quality of life, and prevalence of the following comorbidities: pain, range of motion limitation, overweight/obesity, and viral status. The cohort was analyzed to compare those aged 18-24 to those aged 25-34 years. When compared to the general US adult population, this nationally representative cohort of young US adults with hemophilia experienced significant health and social burdens: more liver disease, joint damage, joint pain, and unemployment as well as lower high-school graduation rates. Nearly half were overweight or obese. Conversely, this cohort had higher levels of health insurance and equivalent mental health scores. While attention has typically focused on newborns, children, adolescents, and increasingly, on older persons with hemophilia, our findings suggest that a specific focus on young adults is warranted to determine the most effective interventions to improve health and functioning for this apparently vulnerable age group. © 2015 Wiley Periodicals, Inc.

  5. Mortality caused by intracranial bleeding in non-severe hemophilia A patients.

    PubMed

    Loomans, J I; Eckhardt, C L; Reitter-Pfoertner, S E; Holmström, M; van Gorkom, B Laros; Leebeek, F W G; Santoro, C; Haya, S; Meijer, K; Nijziel, M R; van der Bom, J G; Fijnvandraat, K

    2017-06-01

    Essentials Data on bleeding-related causes of death in non-severe hemophilia A (HA) patients are scarce. Such data may provide new insights into areas of care that can be improved. Non-severe HA patients have an increased risk of dying from intracranial bleeding. This demonstrates the need for specialized care for non-severe HA patients. Background Non-severe hemophilia (factor VIII concentration [FVIII:C] of 2-40 IU dL -1 ) is characterized by a milder bleeding phenotype than severe hemophilia A. However, some patients with non-severe hemophilia A suffer from severe bleeding complications that may result in death. Data on bleeding-related causes of death, such as fatal intracranial bleeding, in non-severe patients are scarce. Such data may provide new insights into areas of care that can be improved. Aims To describe mortality rates, risk factors and comorbidities associated with fatal intracranial bleeding in non-severe hemophilia A patients. Methods We analyzed data from the INSIGHT study, an international cohort study of all non-severe hemophilia A patients treated with FVIII concentrates during the observation period between 1980 and 2010 in 34 participating centers across Europe and Australia. Clinical data and vital status were collected from 2709 patients. We report the standardized mortality rate for patients who suffered from fatal intracranial bleeding, using a general European male population as a control population. Results Twelve per cent of the 148 deceased patients in our cohort of 2709 patients died from intracranial bleeding. The mortality rate between 1996 and 2010 for all ages was 3.5-fold higher than that in the general population (95% confidence interval [CI] 2.0-5.8). Patients who died from intracranial bleeding mostly presented with mild hemophilia without clear comorbidities. Conclusion Non-severe hemophilia A patients have an increased risk of dying from intracranial bleeding in comparison with the general population. This demonstrates the

  6. Hemophilia Diagnosis

    MedlinePlus

    ... of hemophilia and the severity. Families With a History of Hemophilia Any family history of bleeding, such ... inheritance pattern for hemophilia . Families With No Previous History of Hemophilia About one-third of babies who ...

  7. Clinical, instrumental, serological and histological findings suggest that hemophilia B may be less severe than hemophilia A.

    PubMed

    Melchiorre, Daniela; Linari, Silvia; Manetti, Mirko; Romano, Eloisa; Sofi, Francesco; Matucci-Cerinic, Marco; Carulli, Christian; Innocenti, Massimo; Ibba-Manneschi, Lidia; Castaman, Giancarlo

    2016-02-01

    Recent evidence suggests that patients with severe hemophilia B may have a less severe disease compared to severe hemophilia A. To investigate clinical, radiological, laboratory and histological differences in the arthropathy of severe hemophilia A and hemophilia B, 70 patients with hemophilia A and 35 with hemophilia B with at least one joint bleeding were consecutively enrolled. Joint bleedings (<10, 10-50, >50), regimen of treatment (prophylaxis/on demand), World Federation of Hemophilia, Pettersson and ultrasound scores, serum soluble RANK ligand and osteoprotegerin were assessed in all patients. RANK, RANK ligand and osteoprotegerin expression was evaluated in synovial tissue from 18 hemophilia A and 4 hemophilia B patients. The percentage of patients with either 10-50 or more than 50 hemarthrosis was greater in hemophilia A than in hemophilia B (P<0.001 and P=0.03, respectively), while that with less than 10 hemarthrosis was higher in hemophilia B (P<0.0001). World Federation of Hemophilia (36.6 vs. 20.2; P<0.0001) and ultrasound (10.9 vs. 4.3; P<0.0001) score mean values were significantly higher in hemophilia A patients. Serum osteoprotegerin and soluble RANK ligand were decreased in hemophilia A versus hemophilia B (P<0.0001 and P=0.006, respectively). Osteoprotegerin expression was markedly reduced in synovial tissue from hemophilia A patients. In conclusion, the reduced number of hemarthrosis, the lower World Federation of Hemophilia and ultrasound scores, and higher osteoprotegerin expression in serum and synovial tissue in hemophilia B suggest that hemophilia B is a less severe disease than hemophilia A. Osteoprotegerin reduction seems to play a pivotal role in the progression of arthropathy in hemophilia A. Copyright© Ferrata Storti Foundation.

  8. Prevalence and Risk Factors for Hypertension in Hemophilia

    PubMed Central

    von Drygalski, Annette; Kolaitis, Nicholas A; Bettencourt, Ricki; Bergstrom, Jaclyn; Kruse-Jarres, R; Quon, Doris VK; Wassel, Christina; Li, Ming C; Waalen, Jill; Elias, Darlene J; Mosnier, Laurent O; Allison, Matthew

    2013-01-01

    Hypertension is a major risk factor for intracranial hemorrhage. We therefore investigated the prevalence, treatment and control of hypertension in adult patients with hemophilia (PWH). PWH ≥18 years (n=458) from 3 geographically different cohorts in the United States were evaluated retrospectively for hypertension and risk factors. Results were compared to the nationally representative sample provided by the contemporary National Health and Nutrition Examination Survey (NHANES). PWH had a significantly higher prevalence of hypertension compared to NHANES. Overall, the prevalence of hypertension was 49.1% in PWH compared to 31.7 % in NHANES. At ages 18–44, 45–64, 65–74, and ≥ 75 the prevalence of hypertension for PWH was 31.8%, 72.6%, 89.7%, and 100.0% compared to 12.5%, 41.2%, 64.1%, and 71.7% in NHANES, respectively. Of treated hypertensive PWH, only 27.1% were controlled, compared to 47.7% in NHANES (all p-values <0.05). Age, body mass index, diabetes and renal function were independently associated with hypertension. Among patients with moderate or severe hemophilia there was a trend (~ 1.5-fold) for higher odds of having hypertension compared to patients with mild hemophilia. Based on these results, new care models for adult PWH and further studies for the etiology of hypertension in hemophilia are recommended. PMID:23630949

  9. A cross-sectional analysis of cardiovascular disease in the hemophilia population

    PubMed Central

    Sood, Suman L.; Cheng, Dunlei; Ragni, Margaret; Kessler, Craig M.; Quon, Doris; Shapiro, Amy D.; Key, Nigel S.; Manco-Johnson, Marilyn J.; Cuker, Adam; Kempton, Christine; Wang, Tzu-Fei; Eyster, M. Elaine; Kuriakose, Philip; von Drygalski, Annette; Gill, Joan Cox; Wheeler, Allison; Kouides, Peter; Escobar, Miguel A.; Leissinger, Cindy; Galdzicka, Sarah; Corson, Marshall; Watson, Crystal

    2018-01-01

    Men with hemophilia were initially thought to be protected from cardiovascular disease (CVD), but it is now clear that atherothrombotic events occur. The primary objective of the CVD in Hemophilia study was to determine the prevalence of CVD and CVD risk factors in US older men with moderate and severe hemophilia and to compare findings with those reported in age-comparable men in the Atherosclerosis Risk in Communities (ARIC) cohort. We hypothesized if lower factor levels are protective from CVD, we would see a difference in CVD rates between more severely affected and unaffected men. Beginning in October 2012, 200 patients with moderate or severe hemophilia A or B (factor VIII or IX level ≤ 5%), aged 54 to 73 years, were enrolled at 19 US hemophilia treatment centers. Data were collected from patient interview and medical records. A fasting blood sample and electrocardiogram (ECG) were obtained and assayed and read centrally. CVD was defined as any angina, any myocardial infarction by ECG or physician diagnosis, any self-reported nonhemorrhagic stroke or transient ischemic attack verified by physicians, or any history of coronary bypass graft surgery or coronary artery angioplasty. CVD risk factors were common in the population. Compared with men of similar age in the ARIC cohort, patients with hemophilia had significantly less CVD (15% vs 25.8%; P < .001). However, on an individual patient level, CVD events occur and efforts to prevent cardiovascular events are warranted. Few men were receiving secondary prophylaxis with low-dose aspirin, despite published opinion that it can be used safely in this patient population. PMID:29895623

  10. Frequently Asked Questions: Hemophilia

    MedlinePlus

    ... and Women with Hemophilia Inheritance of Hemophilia Definitions & Terminology Bleeding Symptoms Carrier Diagnosis When to Test for ... and Women with Hemophilia Inheritance of Hemophilia Definitions & Terminology Bleeding Symptoms Carrier Diagnosis When to Test for ...

  11. Hemophilia - resources

    MedlinePlus

    The following organizations provide further information on hemophilia : Centers for Disease Control and Prevention -- www.cdc.gov/ncbddd/hemophilia/index.html National Heart, Lung, and Blood Institute -- www.nhlbi.nih. ...

  12. AAV5-Factor VIII Gene Transfer in Severe Hemophilia A.

    PubMed

    Rangarajan, Savita; Walsh, Liron; Lester, Will; Perry, David; Madan, Bella; Laffan, Michael; Yu, Hua; Vettermann, Christian; Pierce, Glenn F; Wong, Wing Y; Pasi, K John

    2017-12-28

    Patients with hemophilia A rely on exogenous factor VIII to prevent bleeding in joints, soft tissue, and the central nervous system. Although successful gene transfer has been reported in patients with hemophilia B, the large size of the factor VIII coding region has precluded improved outcomes with gene therapy in patients with hemophilia A. We infused a single intravenous dose of a codon-optimized adeno-associated virus serotype 5 (AAV5) vector encoding a B-domain-deleted human factor VIII (AAV5-hFVIII-SQ) in nine men with severe hemophilia A. Participants were enrolled sequentially into one of three dose cohorts (low dose [one participant], intermediate dose [one participant], and high dose [seven participants]) and were followed through 52 weeks. Factor VIII activity levels remained at 3 IU or less per deciliter in the recipients of the low or intermediate dose. In the high-dose cohort, the factor VIII activity level was more than 5 IU per deciliter between weeks 2 and 9 after gene transfer in all seven participants, and the level in six participants increased to a normal value (>50 IU per deciliter) that was maintained at 1 year after receipt of the dose. In the high-dose cohort, the median annualized bleeding rate among participants who had previously received prophylactic therapy decreased from 16 events before the study to 1 event after gene transfer, and factor VIII use for participant-reported bleeding ceased in all the participants in this cohort by week 22. The primary adverse event was an elevation in the serum alanine aminotransferase level to 1.5 times the upper limit of the normal range or less. Progression of preexisting chronic arthropathy in one participant was the only serious adverse event. No neutralizing antibodies to factor VIII were detected. The infusion of AAV5-hFVIII-SQ was associated with the sustained normalization of factor VIII activity level over a period of 1 year in six of seven participants who received a high dose, with

  13. Animal Models of Hemophilia

    PubMed Central

    Sabatino, Denise E.; Nichols, Timothy C.; Merricks, Elizabeth; Bellinger, Dwight A.; Herzog, Roland W.; Monahan, Paul E.

    2013-01-01

    The X-linked bleeding disorder hemophilia is caused by mutations in coagulation factor VIII (hemophilia A) or factor IX (hemophilia B). Unless prophylactic treatment is provided, patients with severe disease (less than 1% clotting activity) typically experience frequent spontaneous bleeds. Current treatment is largely based on intravenous infusion of recombinant or plasma-derived coagulation factor concentrate. More effective factor products are being developed. Moreover, gene therapies for sustained correction of hemophilia are showing much promise in pre-clinical studies and in clinical trials. These advances in molecular medicine heavily depend on availability of well-characterized small and large animal models of hemophilia, primarily hemophilia mice and dogs. Experiments in these animals represent important early and intermediate steps of translational research aimed at development of better and safer treatments for hemophilia, such a protein and gene therapies or immune tolerance protocols. While murine models are excellent for studies of large groups of animals using genetically defined strains, canine models are important for testing scale-up and for longer-term follow-up as well as for studies that require larger blood volumes. PMID:22137432

  14. Both hemophilia health care providers and hemophilia a carriers report that carriers have excessive bleeding.

    PubMed

    Paroskie, Allison; Oso, Olatunde; Almassi, Benjamin; DeBaun, Michael R; Sidonio, Robert F

    2014-05-01

    Hemophilia A, the result of reduced factor VIII activity, is an X-linked recessive bleeding disorder. Previous reports of hemophilia A carriers suggest an increased bleeding tendency. Our objective was to determine the attitudes and understanding of the hemophilia A carrier bleeding phenotype, and opinions regarding timing of carrier testing from the perspective of both medical providers and affected patients. Data from this survey were used as preliminary data for an ongoing prospective study. An electronic survey was distributed to physicians and nurses employed at Hemophilia Treatment Centers, and hemophilia A carriers who were members of Hemophilia Federation of America. The questions focused on the clinical understanding of bleeding symptoms and management of hemophilia A carriers, and the timing and intensity of carrier testing. Our survey indicates that 51% (36/51) of providers compared with 78% (36/46) of carriers believe that hemophilia A carriers with normal factor VIII activity have an increased bleeding tendency (P<0.001); 72% (33/36) of hemophilia A carriers report a high frequency of bleeding symptoms. Regarding carrier testing, 72% (50/69) of medical providers recommend testing after 14 years of age, conversely 65% (29/45) of hemophilia A carriers prefer testing to be done before this age (P<0.001). Hemophilia A carriers self-report a higher frequency of bleeding than previously acknowledged, and have a preference for earlier testing to confirm carrier status.

  15. [Hemophilia camps.

    PubMed

    Juárez-Sierra, Julieta; Del Pilar Torres-Arreola, Laura; Marín-Palomares, Teresa; Dueñas-González, María Teresa; Monteros-Rincón, Martha Patricia; Osorio-Guzmán, Maricela

    2013-01-01

    We reported the experience of hemophilia camps which was accomplished with patients from hospitals of the Instituto Mexicano del Seguro Social. The aim was to prepare the families and patients regarding the disease treatment, in order to promote the self sufficiency and to know the impact of the program on the course of the disease. Surveys were applied about treatment items and personal opinions were collected. The results of the national hemophilia camp were: group of 56 patients, average 14 years, 2 % women, 51 % severe hemophilia and 43 % had hemophilic brothers. Benefits: patients increased their knowledge about earlier bleeding identification and the self-infusion method; they became aware on their responsibility in self care, timely treatment and duties at home. Hemophilia camps with patients are an option for attitude change before disease complications. Social network creation and the increase in self-sufficiency are other benefits.

  16. Gene therapy for hemophilia

    PubMed Central

    Rogers, Geoffrey L.; Herzog, Roland W.

    2015-01-01

    Hemophilia is an X-linked inherited bleeding disorder consisting of two classifications, hemophilia A and hemophilia B, depending on the underlying mutation. Although the disease is currently treatable with intravenous delivery of replacement recombinant clotting factor, this approach represents a significant cost both monetarily and in terms of quality of life. Gene therapy is an attractive alternative approach to the treatment of hemophilia that would ideally provide life-long correction of clotting activity with a single injection. In this review, we will discuss the multitude of approaches that have been explored for the treatment of both hemophilia A and B, including both in vivo and ex vivo approaches with viral and nonviral delivery vectors. PMID:25553466

  17. Both Hemophilia Health Care Providers and Hemophilia A Carriers Report that Carriers have Excessive Bleeding

    PubMed Central

    Paroskie, Allison; Oso, Olatunde; DeBaun, Michael R.; Sidonio, Robert F

    2014-01-01

    Introduction Hemophilia A, the result of reduced factor VIII (FVIII) activity, is an X-linked recessive bleeding disorder. Previous reports of Hemophilia A carriers suggest an increased bleeding tendency. Our objective was to determine the attitudes and understanding of the Hemophilia A carrier bleeding phenotype, and opinions regarding timing of carrier testing from the perspective of both medical providers and affected patients. Data from this survey was used as preliminary data for an ongoing prospective study. Material and Methods An electronic survey was distributed to physicians and nurses employed at Hemophilia Treatment Centers (HTC), and Hemophilia A carriers who were members of Hemophilia Federation of America. Questions focused on the clinical understanding of bleeding symptoms and management of Hemophilia A carriers, and the timing and intensity of carrier testing. Results Our survey indicates that 51% (36/51) of providers compared to 78% (36/46) of carriers believe that Hemophilia A carriers with normal FVIII activity have an increased bleeding tendency (p<0.001); 72% (33/36) of Hemophilia A carriers report a high frequency of bleeding symptoms. Regarding carrier testing, 72% (50/69) of medical providers recommend testing after 14 years of age, conversely 65% (29/45) of Hemophilia A carriers prefer testing to be done prior to this age (p<0.001). Discussion Hemophilia A carriers self-report a higher frequency of bleeding than previously acknowledged, and have a preference for earlier testing to confirm carrier status. PMID:24309601

  18. Inhibitor development and mortality in non-severe hemophilia A.

    PubMed

    Eckhardt, C L; Loomans, J I; van Velzen, A S; Peters, M; Mauser-Bunschoten, E P; Schwaab, R; Mazzucconi, M G; Tagliaferri, A; Siegmund, B; Reitter-Pfoertner, S E; van der Bom, J G; Fijnvandraat, K

    2015-07-01

    The life expectancy of non-severe hemophilia A (HA) patients equals the life expectancy of the non-hemophilic population. However, data on the effect of inhibitor development on mortality and on hemophilia-related causes of death are scarce. The development of neutralizing factor VIII antibodies in non-severe HA patients may dramatically change their clinical outcome due to severe bleeding complications. We assessed the association between the occurrence of inhibitors and mortality in patients with non-severe HA. In this retrospective cohort study, clinical data and vital status were collected for 2709 non-severe HA patients (107 with inhibitors) who were treated between 1980 and 2011 in 34 European and Australian centers. Mortality rates for patients with and without inhibitors were compared. During 64,200 patient-years of follow-up, 148 patients died (mortality rate, 2.30 per 1000 person-years; 95% confidence interval (CI), 1.96-2.70) at a median age of 64 years (interquartile range [IQR], 49-76). In 62 patients (42%) the cause of death was hemophilia related. Sixteen inhibitor patients died at a median age of 71 years (IQR, 60-81). In ten patients the inhibitor was present at time of death; seven of them died of severe bleeding complications. The all-cause mortality rate in inhibitor patients was > 5 times increased compared with that for those without inhibitors (age-adjusted mortality rate ratio, 5.6). Inhibitor development in non-severe hemophilia is associated with increased mortality. High rates of hemophilia-related mortality in this study indicate that non-severe hemophilia is not mild at all and stress the importance of close follow-up for these patients. © 2015 International Society on Thrombosis and Haemostasis.

  19. Knowledge, attitudes, and behaviors of youths in the US hemophilia population: results of a national survey.

    PubMed

    Nazzaro, Ann-Marie; Owens, Sally; Hoots, W Keith; Larson, Kelly L

    2006-09-01

    The National Hemophilia Foundation and the Centers for Disease Control and Prevention conducted a national survey focusing on knowledge about, attitudes toward, and behaviors associated with key prevention activities among youths with hemophilia and used the data gathered to design a health promotion campaign. A national, random sample of 459 patients was drawn from 20 hemophilia treatment centers and 8 hemophilia associations; 110 (24%) of the respondents were young people. A telephone questionnaire was used to measure knowledge, behaviors, and barriers to prevention. Thirty-six percent of the youth respondents believed that joint disease cannot be prevented; 60% managed hemophilia by avoiding physical activity. Only 31% of the respondents treated bleeding episodes within 1 hour. Although hepatitis was a clear threat to this hemophilic cohort, 78% did now know transmission routes for hepatitis C, and 67% did not know transmission routes for hepatitis B. Young people with chronic disorders need help understanding that they can prevent complications. We identified key messages for a hemophilia prevention campaign, including exercising to ensure healthy joints and treating bleeding episodes early and adequately.

  20. [Study of gene mutation in 62 hemophilia A children].

    PubMed

    Hu, Q; Liu, A G; Zhang, L Q; Zhang, A; Wang, Y Q; Wang, S M; Lu, Y J; Wang, X

    2017-11-02

    Objective: To analyze the mutation type of FⅧ gene in children with hemophilia A and to explore the relationship among hemophilia gene mutation spectrum, gene mutation and clinical phenotype. Method: Sixty-two children with hemophilia A from Department of Pediatric Hematology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology between January 2015 and March 2017 were enrolled. All patients were male, aged from 4 months to 7 years and F Ⅷ activity ranged 0.2%-11.0%. Fifty cases had severe, 10 cases had moderate and 2 cases had mild hemophilia A. DNA was isolated from peripheral blood in hemophilia A children and the target gene fragment was amplified by PCR, in combination with the second generation sequencing, 22 and 1 introns were detected. Negative cases were detected by the second generation sequencing and results were compared with those of the international FⅧ gene mutation database. Result: There were 20 cases (32%) of intron 22 inversion, 2 cases (3%) of intron 1 inversion, 18 cases (29%) of missense mutation, 5 cases (8%) of nonsense mutation, 7 cases (11%) of deletion mutation, 1 case(2%)of splice site mutation, 2 cases (3%) of large fragment deletion and 1 case of insertion mutation (2%). No mutation was detected in 2 cases (3%), and 4 cases (7%) failed to amplify. The correlation between phenotype and genotype showed that the most common gene mutation in severe hemophilia A was intron 22 inversion (20 cases), accounting for 40% of severe patients, followed by 11 cases of missense mutation (22%). The most common mutation in moderate hemophilia A was missense mutation (6 cases), accounting for 60% of moderate patients. Conclusion: The most frequent mutation type in hemophilia A was intron 22 inversion, followed by missense mutation, again for missing mutation. The relationship between phenotype and genotype: the most frequent gene mutation in severe hemophilia A is intron 22 inversion, followed by missense

  1. Understanding Hemophilia. Implications for the Physical Educator.

    ERIC Educational Resources Information Center

    Coelho, Jeffrey D.

    1998-01-01

    Describes hemophilia and ways to provide appropriate physical education experiences to children with hemophilia. The article focuses on what hemophilia is, how to treat hemophilia, benefits of physical activity, how to teach children with hemophilia, choosing and modifying sports and activities, and safety and emergency situations. (SM)

  2. Patient and parent preferences for characteristics of prophylactic treatment in hemophilia

    PubMed Central

    Furlan, Roberto; Krishnan, Sangeeta; Vietri, Jeffrey

    2015-01-01

    Introduction New longer-acting factor products will potentially allow for less frequent infusion in prophylactic treatment of hemophilia. However, the role of administration frequency relative to other treatment attributes in determining preferences for prophylactic hemophilia treatment regimens is not well understood. Aim To identify the relative importance of frequency of administration, efficacy, and other treatment characteristics among candidates for prophylactic treatment for hemophilia A and B. Method An Internet survey was conducted among hemophilia patients and the parents of pediatric hemophilia patients in Australia, Canada, and the US. A monadic conjoint task was included in the survey, which varied frequency of administration (three, two, or one time per week for hemophilia A; twice weekly, weekly, or biweekly for hemophilia B), efficacy (no bleeding or breakthrough bleeding once every 4 months, 6 months, or 12 months), diluent volume (3 mL vs 2.5 mL for hemophilia A; 5 mL vs 3 mL for hemophilia B), vials per infusion (2 vs 1), reconstitution device (assembly required vs not), and manufacturer (established in hemophilia vs not). Respondents were asked their likelihood to switch from their current regimen to the presented treatment. Respondents were told to assume that other aspects of treatment, such as risk of inhibitor development, cost, and method of distribution, would remain the same. Results A total of 89 patients and/or parents of children with hemophilia A participated; another 32 were included in the exercise for hemophilia B. Relative importance was 47%, 24%, and 18% for frequency of administration, efficacy, and manufacturer, respectively, in hemophilia A; analogous values were 48%, 26%, and 21% in hemophilia B. The remaining attributes had little impact on preferences. Conclusion Patients who are candidates for prophylaxis and their caregivers indicate a preference for reduced frequency of administration and high efficacy, but preferences

  3. Knowledge, Attitudes, and Behaviors of Youths in the US Hemophilia Population: Results of a National Survey

    PubMed Central

    Nazzaro, Ann-Marie; Owens, Sally; Hoots, W. Keith; Larson, Kelly L.

    2006-01-01

    Objectives. The National Hemophilia Foundation and the Centers for Disease Control and Prevention conducted a national survey focusing on knowledge about, attitudes toward, and behaviors associated with key prevention activities among youths with hemophilia and used the data gathered to design a health promotion campaign. Methods. A national, random sample of 459 patients was drawn from 20 hemophilia treatment centers and 8 hemophilia associations; 110 (24%) of the respondents were young people. A telephone questionnaire was used to measure knowledge, behaviors, and barriers to prevention. Results. Thirty-six percent of the youth respondents believed that joint disease cannot be prevented; 60% managed hemophilia by avoiding physical activity. Only 31% of the respondents treated bleeding episodes within 1 hour. Although hepatitis was a clear threat to this hemophilic cohort, 78% did now know transmission routes for hepatitis C, and 67% did not know transmission routes for hepatitis B. Conclusions. Young people with chronic disorders need help understanding that they can prevent complications. We identified key messages for a hemophilia prevention campaign, including exercising to ensure healthy joints and treating bleeding episodes early and adequately. PMID:16873741

  4. Hemophilia (For Teens)

    MedlinePlus

    ... organs, treatment is necessary. Patients with more serious cases of hemophilia often get regular shots of the factor that they're missing — known ... or at home. People with moderate or mild cases of hemophilia usually don't need these shots unless they have a serious injury or require ...

  5. Impact of mild to severe hemophilia on education and work by US men, women, and caregivers of children with hemophilia B: The Bridging Hemophilia B Experiences, Results and Opportunities into Solutions (B-HERO-S) study.

    PubMed

    Cutter, Susan; Molter, Don; Dunn, Spencer; Hunter, Susan; Peltier, Skye; Haugstad, Kimberly; Frick, Neil; Holot, Natalia; Cooper, David L

    2017-04-01

    The psychosocial impact of hemophilia on work was recently investigated in the Hemophilia Experiences, Results and Opportunities (HERO) study. The findings revealed that hemophilia had an impact for adults with moderate/severe hemophilia and caregivers of children with hemophilia. HERO did not specifically evaluate impact on education in adults/children with mild/moderate hemophilia or the impact on employment of spouses/partners of caregivers of affected children. The Bridging Hemophilia B Experiences, Results and Opportunities into Solutions (B-HERO-S) study evaluated the impact of hemophilia on the lives of adult men/women with mild-severe hemophilia B and caregivers of boys/girls with hemophilia B and their spouses/partners. Many adults with hemophilia B (94%) reported that hemophilia had a negative effect on their ability to complete a formal education, often attributed to the inability to attend or concentrate in school as a result of hemophilia-related bleeding or pain. Most adults with hemophilia B (95%) and caregivers/partners (89%/84%) indicated that hemophilia had a negative impact on employment. Most adults with hemophilia were employed (81%), with construction/manufacturing (35%) as the most frequently reported industry; many worked in jobs requiring manual labor (39%). Of those unemployed, 62% never worked, and those who stopped working reported that they left the workforce due to financial issues (59%), including insurance coverage/co-pays, or hemophilia-related issues (55%). Nearly one-third of caregivers voluntarily left the workforce to care for children with hemophilia. These results suggest a need to focus more effort on career counseling for adults with hemophilia B and caregivers of affected children, especially around mild/moderate hemophilia, as this population may not be as well informed regarding potential impact in school and the workplace. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  6. 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.

  7. Association between physical activity and risk of bleeding in children with hemophilia.

    PubMed

    Broderick, Carolyn R; Herbert, Robert D; Latimer, Jane; Barnes, Chris; Curtin, Julie A; Mathieu, Erin; Monagle, Paul; Brown, Simon A

    2012-10-10

    Vigorous physical activity is thought to increase risk of bleeds in children with hemophilia, but the magnitude of the risk is unknown. To quantify the transient increase in risk of bleeds associated with physical activity in children with hemophilia. A case-crossover study nested within a prospective cohort study was conducted at 3 pediatric hemophilia centers in Australia between July 2008 and October 2010. A total of 104 children and adolescent boys aged 4 through 18 years with moderate or severe hemophilia A or B were monitored for bleeds for up to 1 year. Following each bleed, the child or parent was interviewed to ascertain exposures to physical activity preceding the bleed. Physical activity was categorized according to expected frequency and severity of collisions. The risk of bleeds associated with physical activity was estimated by contrasting exposure to physical activity in the 8 hours before the bleed with exposures in two 8-hour control windows, controlling for levels of clotting factor in the blood. Association of physical activity and factor level with risk of bleeding. The participants were observed for 4839 person-weeks during which time 436 bleeds occurred. Of these, 336 bleeds occurred more than 2 weeks after the preceding bleed and were used in the primary analysis of risk. Compared with inactivity and category 1 activities (eg, swimming), category 2 activities (eg, basketball) were associated with a transient increase in the risk of bleeding (30.6% of bleed windows vs 24.8% of first control windows; odds ratio, 2.7; 95% CI, 1.7-4.8, P < .001). Category 3 activities (eg, wrestling) were associated with a greater transient increase in risk (7.0% of bleed windows vs 3.4% of first control windows; odds ratio, 3.7; 95% CI, 2.3-7.3, P < .001). To illustrate absolute risk increase, for a child who bleeds 5 times annually and is exposed on average to category 2 activities twice weekly and to category 3 activities once weekly, exposure to these

  8. The impact of extended half-life versus conventional factor product on hemophilia caregiver burden.

    PubMed

    Schwartz, Carolyn E; Powell, Victoria E; Su, Jun; Zhang, Jie; Eldar-Lissai, Adi

    2018-05-01

    Extended half-life factor products have reduced annualized bleeding rates in hemophilia patients. The impact of extended half-life versus conventional factor products on hemophilia caregiver burden has not been investigated. This study aimed to evaluate caregiver burden in extended half-life versus conventional factor products for hemophilia A and B. This cross-sectional web-based study of caregivers of people with hemophilia A or B was recruited from a panel research company and by word of mouth. Participants completed the Hemophilia Caregiver Impact measure, the PedsQL Family Impact Module (PedsQL), and the Work Productivity and Activity Impairment Questionnaire (WPAI). We also collected demographic, insurance coverage, and medical information related to the hemophilia patient(s). Burden differences were assessed using linear regression and matched cohort analyses. The sample (n = 448) included 49 people who were caring for people on extended half-life factor products. Worse caregiver burden was associated with more infusions per week and more bleeds in the past 6 months. Regression analyses suggested that caring for someone who is on a extended half-life factor product is associated with lower emotional impact (β = - 0.11, p < 0.05, Adjusted R 2  = 0.06), and shows a trend association with lower practical impact (β = - 0.09, p < 0.10, Adjusted R 2  = 0.05). The matched cohort analysis also revealed that people on extended half-life factor product had lower Emotional Impact and Practical Impact scores (t = - 2.95 and - 2.94, respectively, p < 0.05 in both cases). No differences were detected on the PedsQL or the WPAI. The reduced required frequency of factor product infusions of extended half-life factor products appears to reduce the emotional distress and practical burden of caregiving. Future work should evaluate the longitudinal impact.

  9. EQOFIX: a combined economic and quality-of-life study of hemophilia B treatments in France.

    PubMed

    Polack, Benoît; Calvez, Thierry; Chambost, Hervé; Rothschild, Chantal; Goudemand, Jenny; Claeyssens, Ségolène; Borel-Derlon, Annie; Bardoulat, Isabelle; Maurel, Frédérique; Woronoff-Lemsi, Marie-Christine

    2015-07-01

    EQOFIX is a medicoeconomic study that analyzed the health-related quality of life (HRQoL) and costs of care of the moderate and severe forms of hemophilia B, treated on demand or by prophylaxis with either plasma-derived Factor IX (pdFIX) or recombinant FIX (rFIX). The primary objectives were evaluations of the impact of hemophilia B on HRQoL and of the costs associated with its management. The secondary objectives were evaluations of the clinical efficacy and costs of care of pdFIX and rFIX. In this observational study we included and followed for 1 year severe and moderate hemophilia B patients without inhibitor. HRQoL was evaluated through generic and disease-specific questionnaires. Information on the health resources consumed was collected every 3 months. The EQOFIX cohort was composed of 155 patients, including 51 children and 104 adults, with 114 having severe disease and 41 having moderate disease. The regimens were prophylactic for 61 and on demand for 94. Altogether, 78 were treated with rFIX and 77 with pdFIX. There was no difference in the QoL between the pdFIX and rFIX treatments. The extra cost of prophylaxis was €22,605 per bleeding event prevented. The consumption of FIX was 1.4-fold higher for the patients treated with rFIX than for the patients treated with pdFIX. Our findings in a cohort composed of 25% of the French population of moderate and severe hemophilia B patients show, with similar clinical and HRQoL results, that treatment with rFIX is more expensive than treatment with pdFIX. © 2015 The Authors. Transfusion published by Wiley Periodicals, Inc. on behalf of AABB.

  10. Hemophilia Data and Statistics

    MedlinePlus

    ... View public health webinars on blood disorders Data & Statistics Language: English (US) Español (Spanish) Recommend on Facebook ... genetic testing is done to diagnose hemophilia before birth. For the one-third ... rates and hospitalization rates for bleeding complications from hemophilia ...

  11. Gene Therapy for Hemophilia.

    PubMed

    Nienhuis, Arthur W; Nathwani, Amit C; Davidoff, Andrew M

    2017-05-03

    The X-linked bleeding disorder hemophilia causes frequent and exaggerated bleeding that can be life-threatening if untreated. Conventional therapy requires frequent intravenous infusions of the missing coagulation protein (factor VIII [FVIII] for hemophilia A and factor IX [FIX] for hemophilia B). However, a lasting cure through gene therapy has long been sought. After a series of successes in small and large animal models, this goal has finally been achieved in humans by in vivo gene transfer to the liver using adeno-associated viral (AAV) vectors. In fact, multiple recent clinical trials have shown therapeutic, and in some cases curative, expression. At the same time, cellular immune responses against the virus have emerged as an obstacle in humans, potentially resulting in loss of expression. Transient immune suppression protocols have been developed to blunt these responses. Here, we provide an overview of the clinical development of AAV gene transfer for hemophilia, as well as an outlook on future directions. Copyright © 2017. Published by Elsevier Inc.

  12. Effects of FVIII immunity on hepatocyte and hematopoietic stem cell–directed gene therapy of murine hemophilia A

    PubMed Central

    Lytle, Allison M; Brown, Harrison C; Paik, Na Yoon; Knight, Kristopher A; Wright, J Fraser; Spencer, H Trent; Doering, Christopher B

    2016-01-01

    Immune responses to coagulation factors VIII (FVIII) and IX (FIX) represent primary obstacles to hemophilia treatment. Previously, we showed that hematopoietic stem cell (HSC) retroviral gene therapy induces immune nonresponsiveness to FVIII in both naive and preimmunized murine hemophilia A settings. Liver-directed adeno-associated viral (AAV)-FIX vector gene transfer achieved similar results in preclinical hemophilia B models. However, as clinical immune responses to FVIII and FIX differ, we investigated the ability of liver-directed AAV-FVIII gene therapy to affect FVIII immunity in hemophilia A mice. Both FVIII naive and preimmunized mice were administered recombinant AAV8 encoding a liver-directed bioengineered FVIII expression cassette. Naive animals receiving high or mid-doses subsequently achieved near normal FVIII activity levels. However, challenge with adjuvant-free recombinant FVIII induced loss of FVIII activity and anti-FVIII antibodies in mid-dose, but not high-dose AAV or HSC lentiviral (LV) vector gene therapy cohorts. Furthermore, unlike what was shown previously for FIX gene transfer, AAV-FVIII administration to hemophilia A inhibitor mice conferred no effect on anti-FVIII antibody or inhibitory titers. These data suggest that functional differences exist in the immune modulation achieved to FVIII or FIX in hemophilia mice by gene therapy approaches incorporating liver-directed AAV vectors or HSC-directed LV. PMID:26909355

  13. Advances in Gene Therapy for Hemophilia.

    PubMed

    Nathwani, Amit C; Davidoff, Andrew M; Tuddenham, Edward G D

    2017-11-01

    Gene therapy provides hope for a cure for patients with hemophilia by establishing continuous endogenous expression of factor VIII or factor IX following transfer of a functional gene copy to replace the hemophilic patient's own defective gene. Hemophilia may be considered a "low-hanging fruit" for gene therapy because a small increment in blood factor levels (≥2% of normal) significantly improves the bleeding tendency from severe to moderate, eliminating most spontaneous bleeds. After decades of research, the first trial to provide clear evidence of efficiency after gene transfer in patients with hemophilia B using adeno-associated virus vectors was reported by the authors' group in 2011. This has been followed by unprecedented activity in this area, with the commencement of seven new early-phase trials involving >55 patients with hemophilia A or hemophilia B. These studies have, in large part, generated promising clinical data that lay a strong foundation for gene therapy to move forward rapidly to market authorization. This review discusses the data from the authors' studies and emerging results from other gene therapy trials in both hemophilia A and B.

  14. Phase I, randomized, double-blind, placebo-controlled, single-dose escalation study of the recombinant factor VIIa variant BAY 86-6150 in hemophilia.

    PubMed

    Mahlangu, J N; Coetzee, M J; Laffan, M; Windyga, J; Yee, T T; Schroeder, J; Haaning, J; Siegel, J E; Lemm, G

    2012-05-01

    BAY 86-6150 is a new human recombinant factor VIIa variant developed for high procoagulant activity and longer action in people with hemophilia with inhibitors. To investigate the safety, tolerability, pharmacodynamics, pharmacokinetics and immunogenicity of BAY 86-6150 in non-bleeding hemophilia subjects. The study included non-bleeding men (18-65 years of age) with moderate or severe hemophilia A or B with or without inhibitors. Sixteen subjects were randomized 3 : 1 to four cohorts of escalating doses of BAY 86-6150 (6.5, 20, 50 or 90 μg kg(-1) [n = 3 per cohort]) or placebo (n = 1 per cohort); an independent data-monitoring committee reviewed previous cohort data before the next dose escalation. Blood sampling was performed predose and postdose; subjects were monitored for 50 days postdose. At the tested doses, BAY 86-6150 was not associated with clinically significant adverse events or dose-limiting toxicities. BAY 86-6150 pharmacokinetics exhibited a linear dose response, with a half-life of 5-7 h. Subjects demonstrated consistent, dose-dependent thrombin generation ex vivo in platelet-poor plasma (PPP) (mean peak effect, 26-237 nm thrombin from 6.5 to 90 μg kg(-1)). Peak thrombin levels over time paralleled BAY 86-6150, with thrombin kinetics appearing to be slightly shorter; thus, circulating BAY 86-6150 retained activity. There were corresponding decreases in activated partial thromboplastin and prothrombin times. No subject developed de novo anti-BAY 86-6150 neutralizing antibodies during the 50-day follow-up. In this first-in-human, multicenter, randomized, double-blind, placebo-controlled, single-dose escalation study, BAY 86-6150 was tolerated at the highest dose (90 μg kg(-1)), with no safety concerns. Safety and efficacy will be further evaluated in phase II/III studies. © 2012 International Society on Thrombosis and Haemostasis.

  15. Hemophilia

    MedlinePlus

    ... have hemophilia, you have little or no clotting factor. Clotting factor is a protein needed for normal blood clotting. ... The main treatment is injecting the missing clotting factor into the bloodstream. You may need it on ...

  16. Bayesian approach to the assessment of the population-specific risk of inhibitors in hemophilia A patients: a case study

    PubMed Central

    Cheng, Ji; Iorio, Alfonso; Marcucci, Maura; Romanov, Vadim; Pullenayegum, Eleanor M; Marshall, John K; Thabane, Lehana

    2016-01-01

    Background Developing inhibitors is a rare event during the treatment of hemophilia A. The multifacets and uncertainty surrounding the development of inhibitors further complicate the process of estimating inhibitor rate from the limited data. Bayesian statistical modeling provides a useful tool in generating, enhancing, and exploring the evidence through incorporating all the available information. Methods We built our Bayesian analysis using three study cases to estimate the inhibitor rates of patients with hemophilia A in three different scenarios: Case 1, a single cohort of previously treated patients (PTPs) or previously untreated patients; Case 2, a meta-analysis of PTP cohorts; and Case 3, a previously unexplored patient population – patients with baseline low-titer inhibitor or history of inhibitor development. The data used in this study were extracted from three published ADVATE (antihemophilic factor [recombinant] is a product of Baxter for treating hemophilia A) post-authorization surveillance studies. Noninformative and informative priors were applied to Bayesian standard (Case 1) or random-effects (Case 2 and Case 3) logistic models. Bayesian probabilities of satisfying three meaningful thresholds of the risk of developing a clinical significant inhibitor (10/100, 5/100 [high rates], and 1/86 [the Food and Drug Administration mandated cutoff rate in PTPs]) were calculated. The effect of discounting prior information or scaling up the study data was evaluated. Results Results based on noninformative priors were similar to the classical approach. Using priors from PTPs lowered the point estimate and narrowed the 95% credible intervals (Case 1: from 1.3 [0.5, 2.7] to 0.8 [0.5, 1.1]; Case 2: from 1.9 [0.6, 6.0] to 0.8 [0.5, 1.1]; Case 3: 2.3 [0.5, 6.8] to 0.7 [0.5, 1.1]). All probabilities of satisfying a threshold of 1/86 were above 0.65. Increasing the number of patients by two and ten times substantially narrowed the credible intervals for the single

  17. Bayesian approach to the assessment of the population-specific risk of inhibitors in hemophilia A patients: a case study.

    PubMed

    Cheng, Ji; Iorio, Alfonso; Marcucci, Maura; Romanov, Vadim; Pullenayegum, Eleanor M; Marshall, John K; Thabane, Lehana

    2016-01-01

    Developing inhibitors is a rare event during the treatment of hemophilia A. The multifacets and uncertainty surrounding the development of inhibitors further complicate the process of estimating inhibitor rate from the limited data. Bayesian statistical modeling provides a useful tool in generating, enhancing, and exploring the evidence through incorporating all the available information. We built our Bayesian analysis using three study cases to estimate the inhibitor rates of patients with hemophilia A in three different scenarios: Case 1, a single cohort of previously treated patients (PTPs) or previously untreated patients; Case 2, a meta-analysis of PTP cohorts; and Case 3, a previously unexplored patient population - patients with baseline low-titer inhibitor or history of inhibitor development. The data used in this study were extracted from three published ADVATE (antihemophilic factor [recombinant] is a product of Baxter for treating hemophilia A) post-authorization surveillance studies. Noninformative and informative priors were applied to Bayesian standard (Case 1) or random-effects (Case 2 and Case 3) logistic models. Bayesian probabilities of satisfying three meaningful thresholds of the risk of developing a clinical significant inhibitor (10/100, 5/100 [high rates], and 1/86 [the Food and Drug Administration mandated cutoff rate in PTPs]) were calculated. The effect of discounting prior information or scaling up the study data was evaluated. Results based on noninformative priors were similar to the classical approach. Using priors from PTPs lowered the point estimate and narrowed the 95% credible intervals (Case 1: from 1.3 [0.5, 2.7] to 0.8 [0.5, 1.1]; Case 2: from 1.9 [0.6, 6.0] to 0.8 [0.5, 1.1]; Case 3: 2.3 [0.5, 6.8] to 0.7 [0.5, 1.1]). All probabilities of satisfying a threshold of 1/86 were above 0.65. Increasing the number of patients by two and ten times substantially narrowed the credible intervals for the single cohort study (1.4 [0.7, 2.3

  18. Evolving Complexity in Hemophilia Management.

    PubMed

    Croteau, Stacy E

    2018-06-01

    Rapid expansion of therapeutic options have increased the complexity of hemophilia care. Previously, on-demand therapy aimed to reduce morbidity and early mortality; however, now aggressive prophylaxis, particularly in children, encourages an active lifestyle. Accurate diagnosis, recognition of early threats to musculoskeletal health, and optimization of therapy are critical for both males and females affected by hemophilia. The diversity of emerging hemophilia therapies, from modified factor protein concentrates, to gene therapy, to nonfactor hemostatic strategies, provide an exciting opportunity to target unmet needs in the bleeding disorder community. Copyright © 2018 Elsevier Inc. All rights reserved.

  19. How to Deal with Hemophilia

    MedlinePlus

    ... organs, treatment is necessary. Patients with more serious cases of hemophilia often get regular shots of the factor that they're missing to prevent bleeding episodes. Kids with moderate or mild cases of hemophilia usually don't need these shots unless they have a more serious injury or ...

  20. F8 haplotype and inhibitor risk: results from the Hemophilia Inhibitor Genetics Study (HIGS) Combined Cohort

    PubMed Central

    Schwarz, John; Astermark, Jan; Menius, Erika D.; Carrington, Mary; Donfield, Sharyne M.; Gomperts, Edward D.; Nelson, George W.; Oldenburg, Johannes; Pavlova, Anna; Shapiro, Amy D.; Winkler, Cheryl A.; Berntorp, Erik

    2012-01-01

    Background Ancestral background, specifically African descent, confers higher risk for development of inhibitory antibodies to factor VIII (FVIII) in hemophilia A. It has been suggested that differences in the distribution of factor VIII gene (F8) haplotypes, and mismatch between endogenous F8 haplotypes and those comprising products used for treatment could contribute to risk. Design and Methods Data from the HIGS Combined Cohort were used to determine the association between F8 haplotype 3 (H3) vs. haplotypes 1 and 2 (H1+H2) and inhibitor risk among individuals of genetically-determined African descent. Other variables known to affect inhibitor risk including type of F8 mutation and HLA were included in the analysis. A second research question regarding risk related to mismatch in endogenous F8 haplotype and recombinant FVIII products used for treatment was addressed. Results H3 was associated with higher inhibitor risk among those genetically-identified (N=49) as of African ancestry, but the association did not remain significant after adjustment for F8 mutation type and the HLA variables. Among subjects of all racial ancestries enrolled in HIGS who reported early use of recombinant products (N=223), mismatch in endogenous haplotype and the FVIII proteins constituting the products used did not confer greater risk for inhibitor development. Conclusion H3 was not an independent predictor of inhibitor risk. Further, our findings did not support a higher risk of inhibitors in the presence of a haplotype mismatch between the FVIII molecule infused and that of the individual. PMID:22958194

  1. Cardiovascular disease risk factors: prevalence and management in adult hemophilia patients.

    PubMed

    Lim, Ming Y; Pruthi, Rajiv K

    2011-07-01

    With increasing longevity, the prevalence of cardiovascular disease (CVD) risk factors in hemophilia patients is expected to increase; however, evidence-based guidelines on management are lacking. The aim of the study was to determine the prevalence and management of CVD risk factors in hemophilia patients. A retrospective study of 58 adult hemophilia patients (≥35 years) attending Mayo Comprehensive Hemophilia Center between 1 January 2006 and 15 October 2009 were reviewed. The prevalence of CVD risk factors was hypertension 65.5%, diabetes 10.3%, smoking 12.5% and obesity 19.6%. A total of 31% did not have a lipid profile on record. Management of risk factors included antihypertensive medications in 84.2% and lipid-lowering agents in 12.1%. During their medical evaluation, four of seven active smokers received smoking cessation counseling and four of 11 obese patients received lifestyle modification advice. Eight patients (13.8%) experienced a CVD event: myocardial infarction (MI) (n=3), coronary artery disease (n=2), both MI and ischemic stroke (n=1) and hemorrhagic strokes (n=2). Only five of eight patients were on low-dose aspirin, of which aspirin was discontinued in one patient after he was diagnosed with hemophilia following a bleeding work-up. Another patient on dual antiplatelet therapy post stent placement developed epistaxis resulting in clopidogrel cessation. Hemophilia patients are at risk for CVD, similar to the general age-matched male population. Screening for CVD risk factors, with preventive dietary and pharmacologic interventions, play a key role in the prevention and long-term management of CVD. Collaborative efforts between primary care providers, cardiologists and hemophilia center specialists remain essential in managing these complex patients.

  2. Animal Models of Hemophilia and Related Bleeding Disorders

    PubMed Central

    Lozier, Jay N.; Nichols, Timothy C.

    2013-01-01

    Animal models of hemophilia and related diseases are important for development of novel treatments and to understand the pathophysiology of bleeding disorders in humans. Testing in animals with the equivalent human disorder provides informed estimates of doses and measures of efficacy, which aids in design of human trials. Many models of hemophilia A, hemophilia B, and von Willebrand disease have been developed from animals with spontaneous mutations (hemophilia A dogs, rats, sheep; hemophilia B dogs; and von Willebrand disease pigs and dogs), or by targeted gene disruption in mice to create hemophilia A, B, or VWD models. Animal models have been used to generate new insights into the pathophysiology of each bleeding disorder and also to perform pre-clinical assessments of standard protein replacement therapies as well as novel gene transfer technology. Both the differences between species and differences in underlying causative mutations must be considered in choosing the best animal for a specific scientific study PMID:23956467

  3. Treatment outcomes, quality of life, and impact of hemophilia on young adults (aged 18-30 years) with hemophilia.

    PubMed

    Witkop, Michelle; Guelcher, Christine; Forsyth, Angela; Hawk, Sarah; Curtis, Randall; Kelley, Laureen; Frick, Neil; Rice, Michelle; Rosu, Gabriela; Cooper, David L

    2015-12-01

    The Hemophilia Experiences, Results and Opportunities (HERO) initiative assessed psychosocial issues reported by people with moderate to severe hemophilia and was led by a multidisciplinary international advisory board. This analysis reports data from young adult respondents (aged 18-30 years), including both US and overall global (including US respondents) results, and investigates treatment outcomes, quality of life, and impacts of hemophilia on relationships. More young adults in HERO received prophylaxis than on-demand treatment, although a majority reported not using factor products exactly as prescribed, and 50% of global respondents and 26% of US respondents reported issues with access to factor replacement therapy in the previous 5 years. Many young adults with hemophilia reported comorbidities, including bone/skeletal arthritis, chronic pain, and viral infections, and nearly half of young adults reported anxiety/depression. Most reported pain interference with daily activities in the past 4 weeks, although a majority reported participating in lower-risk activities and approximately half in intermediate-risk activities. Most young adults were very or quite satisfied with the support of partners/spouses, family, and friends, although roughly one-third reported that hemophilia affected their ability to develop close relationships with a partner. A majority of young adults reported that hemophilia has had a negative impact on employment, and 62% of global respondents and 78% of US respondents were employed at least part-time. Together these data highlight the psychosocial issues experienced by young adults with hemophilia and suggest that increased focus on these issues may improve comprehensive care during the transition to adulthood. © 2015 Wiley Periodicals, Inc.

  4. High school completion rates among men with hemophilia.

    PubMed

    Drake, John H; Soucie, J Michael; Cutter, Susan C; Forsberg, Ann D; Baker, Judith R; Riske, Brenda

    2010-04-01

    The benefits of a high school diploma are well documented. Studies indicate that people with hemophilia have lower than average academic achievement, particularly if they have >12 bleeding episodes annually. This study compares the high school graduation rate of men with hemophilia to that of the U.S. population of men. Data were obtained from the Universal Data Collection Program, a surveillance project conducted by approximately 130 hemophilia treatment centers in the nation. Data from 7842 men aged >or=18 years were evaluated to determine high school graduation status and were analyzed by race/ethnicity and severity of hemophilia. These data were collected between 1998 and 2008, and analysis was conducted in 2009. Men with hemophilia A had higher or similar high school graduation rates across all racial/ethnic groups and all levels of hemophilia severity, compared with U.S. men of the same age. Graduation rates for black and Hispanic men with hemophilia B were higher or similar to rates of U.S. men, but rates for whites were lower, especially among those with moderate and mild disease. However, when graduation rates were controlled for areas where Amish populations reside, differences in graduation rates for whites disappeared. In this study, participants obtained hemophilia care at comprehensive hemophilia treatment centers. This multidisciplinary, family-centered care emphasizes prevention of complications, encourages medically supervised disease management, and facilitates psychosocial development. The care aims to maximize the affected child's participation in school. This care approach may partially explain the higher-than-expected high school graduation rates among the study population, which is affected by a rare, chronic, and potentially debilitating disorder. Copyright 2010. Published by Elsevier Inc.

  5. Advances in hemophilia care: report of two symposia at the Hemophilia 2010 World Congress.

    PubMed

    Dolan, Gerry; Cruz, Jussara Almeida; Steinhagen-Thiessen, Elisabeth; Kessler, Craig; Haaning, Jesper; Lemm, Georg; Altisent, Carmen; Guerrero, Caesar; Hermans, Cedric; Riske, Brenda; Bolton-Maggs, Paula

    2012-04-01

    The World Federation of Hemophilia (WFH) 2010 World Congress held in Buenos Aires, Argentina, in July 2010, attracted more than 4,300 participants from 106 countries. This report summarizes two symposia held during the congress. The first, titled "Emerging Co-Morbidities in the Aging Hemophilia Population: Healthcare Challenges and Treatment Opportunities," chaired by Gerry Dolan, MD, and Jussara Almeida Cruz, MD, examined the co-morbidities experienced by the aging hemophilic patient population, such as cardiovascular disease, cancer, arthritis, osteoporosis, hypertension, and obesity. In addition, Bayer's products in preclinical and clinical development were reviewed, including a novel factor VIIa variant and a long-acting factor VIII molecule, i.e., one that has undergone site-specific PEGylation (attachment of polyethylene glycol [PEG] polymer chains to another molecule). The other symposium, titled "Practical Steps to Making Better Care for Hemophilia Patients a Reality," chaired by Carmen Altisent, MD, and Cesar Guerrero, RN, reviewed the steps that hemophilia caregivers can take to improve the care of their patients. Issues such as the treatment of hemarthroses, the role of the research nurse, and the management of pediatric patients transitioning to adulthood were discussed.

  6. Recombinant factor VIIa (eptacog alfa): a review of its use in congenital hemophilia with inhibitors, acquired hemophilia, and other congenital bleeding disorders.

    PubMed

    Croom, Katherine F; McCormack, Paul L

    2008-01-01

    Recombinant factor VIIa (NovoSeven; also known as recombinant activated factor VII or eptacog alfa) is structurally similar to human plasma-derived coagulation factor VIIa, but is manufactured using DNA biotechnology. Recombinant factor VIIa interacts with thrombin-activated platelets to produce a thrombin burst leading to accelerated fibrin clot formation localized to the site of vascular injury. It is approved in many countries for use as an intravenous hemostatic agent in patients with congenital hemophilia with inhibitors, and also for acquired hemophilia, factor VII deficiency, and Glanzmann thrombasthenia in some countries. Studies have shown it to be effective and generally well tolerated when used intravenously to treat bleeding episodes or provide hemostatic cover during surgery in patients with congenital hemophilia with inhibitors, acquired hemophilia, factor VII deficiency or Glanzmann thrombasthenia. Based on available data, its efficacy in terms of patient-assessed response may be similar to that of activated prothrombin complex concentrate (aPCC), but treatment with a single 270 microg/kg dose of recombinant factor VIIa might reduce the need for rescue therapy compared with aPCC. Recombinant factor VIIa is not immunogenic in patients with hemophilia, does not produce an anamnestic response in hemophilia patients with inhibitors, and has very low thrombogenicity. It is recommended in guidelines as the treatment of choice for bleeds in patients with hemophilia B with high-responding inhibitors and for patients with factor VII deficiency, and is also a first-line therapeutic option for high-responder hemophilia A patients with inhibitors and those with acquired hemophilia. Cost data from pharmacoeconomic analyses support its use in hemophilia patients with inhibitors. Thus, recombinant factor VIIa is a valuable treatment option for patients with these rare, but potentially serious, bleeding disorders.

  7. Manual therapy in the treatment of patients with hemophilia B and inhibitor.

    PubMed

    Cuesta-Barriuso, Rubén; Trelles-Martínez, Roberto O

    2018-01-22

    The main clinical manifestations of hemophilia are muscle and joint bleeding. Recurrent bleeding leads to a degenerative process known as hemophilic arthropathy. The development of inhibitors (antibodies against FVIII/FIX concentrates) is the main complication in the treatment of hemophilia. The objective was to assess the safety and efficacy of manual therapy treatment in a patient with hemophilia and inhibitor. A 26-year-old patient with hemophilia B and inhibitor received physiotherapy treatment based on manual therapy for 3 months, with a frequency of 2 sessions per week. The joint status was evaluated using the Hemophilia Joint Health Score; pain was assessed with the Visual Analog Scale; and the range of movement was evaluated using a universal goniometer. The patient developed no joint bleeding in the knees or ankles as a result of the physiotherapy treatment. Following treatment, improvements were noted in the range of movement of knees and ankles, the perception of pain in both knees, and ankle functionality. Until now, manual therapy using joint traction was contraindicated in patients with hemophilia and inhibitor, as it was feared to cause possible joint bleeding. This is the first case study to address the safety and efficacy of manual therapy in a patient with hemophilia and an inhibitor. The results of this study may help to establish which manual therapy treatments are indicated in patients with hemophilic arthropathy and inhibitors. Thus, a physiotherapy program based on manual therapy may be safe in patients with hemophilia and inhibitor and such therapy may improve joint condition, pain, and joint range of motion in patients with hemophilia and inhibitor. Randomized clinical trials are needed to confirm the results of this case study.

  8. Hemophilia Care in the Pediatric Age

    PubMed Central

    Bertamino, Marta; Riccardi, Francesca; Banov, Laura; Svahn, Johanna; Molinari, Angelo Claudio

    2017-01-01

    Hemophilia is the most common of the severe bleeding disorders and if not properly managed since early infancy can lead to chronic disease and lifelong disabilities. However, it enjoys the most efficacious and safe treatment among the most prevalent monogenic disorders. Hemophilia should be considered in the neonatal period in the case of unusual bleeding or in the case of positive family history. Later, hemophilia should be suspected mainly in males because of abnormal bruising/bleeding or unusual bleeding following invasive procedures—for example, tonsillectomy or circumcision. Prophylactic treatment that is started early with clotting-factor concentrates has been shown to prevent hemophilic arthropathy and is, therefore, the gold standard of care for hemophilia A and B in most countries with adequate resources. Central venous access catheters and arterovenous fistulas play an important role in the management of hemophilia children requiring repeated and/or urgent administration of coagulation factor concentrates. During childhood and adolescence, personalized treatment strategies that suit the patient and his lifestyle are essential to ensure optimal outcomes. Physical activity is important and can contribute to better coordination, endurance, flexibility and strength. The present article focuses also on questions frequently posed to pediatric hematologists like vaccinations, day-care/school access and dental care. PMID:28534860

  9. Treatment of hemophilia in the near future.

    PubMed

    Peyvandi, Flora; Garagiola, Isabella

    2015-11-01

    Advancements and debacles have characterized hemophilia treatment over the past 50 years. The 1970s saw the availability of plasma-derived concentrates making prophylaxis and home therapy possible. This optimistic perception changed extremely in the early 1980s, when most people with hemophilia were infected with HIV and hepatitis viruses. Then, also in the 1980s, the rapid progress in molecular biology led to the development of recombinant therapeutic products. This important advancement was a huge technological leap fresh off from the earlier 1980s disaster. Now in the 21st century, the newer bioengineering drugs open a new hopeful phase for the management of hemophilia. The current efforts are concentrated on producing novel coagulation factors with prolonged bioavailability, increased potency, and resistance to inactivation and potentially reduced immunogenicity; this phase of evolution is improving very quickly. 2014 is the year of marketing approval by the Food and Drug Administration of the first bioengineered FVIII and FIX long-acting drugs, using Fc-fusion strategy. This represents the first significant advance in the hemophilia therapy that dramatically transforms patient management by substantially reducing the frequency of injections, improving compliance, and simplifying prophylaxis and, in turn, refining the quality of life of hemophilia patients, offering them a nearly normal life expectancy, particularly to newborns with hemophilia B. Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

  10. The Experience of Children with Hemophilia and HIV Infection.

    ERIC Educational Resources Information Center

    Hall, Christopher S.

    1994-01-01

    Children with hemophilia and Human Immunodeficiency Virus (HIV) infection are not a transmission risk to other children, and they can help enact best practices for school attendance by other such children. The article examines the National Hemophilia Foundation's work to promote appropriate inclusion of students with hemophilia and HIV in all…

  11. Treatment of hemophilia: A qualitative study of mothers' perspectives.

    PubMed

    von der Lippe, Charlotte; Frich, Jan C; Harris, Anna; Solbraekke, Kari Nyheim

    2017-01-01

    In Norway, boys with hemophilia usually begin treatment after their first bleeding episode. Boys with severe hemophilia usually start prophylactic treatment around 18-24 months. Health professionals administer factor concentrate initially, but when boys are around 4 years old most parents start treating their children at home. There is a lack of research on how parents, and especially how carrier mothers, experience the medical treatment for their sons' hemophilia. Our aim was to investigate how carrier mothers experience this treatment in the hospital setting and at home. In this qualitative study, we interviewed 16 mothers of boys or men with hemophilia A or B. Data were collected via semistructured interviews and analyzed using an inductive thematic analytical approach. Mothers experienced both practical and emotional challenges in relation to their sons' treatment, and repeated venipuncture was especially difficult emotionally. Parents preferred home treatment to hospital treatment because it was less time-consuming, less disruptive to family life, and provided a greater sense of control. Encountering healthcare professionals who were unfamiliar with hemophilia was a second major stress factor, especially when parents felt that health professionals lacked competence and were unwilling to seek advice. While home treatment for hemophilia enables freedom, flexibility, and autonomy for the boys as well as for the family, mothers may experience treatment of hemophilia as a burden. Health professionals should provide tailored practical and emotional support to parents by probing into their experiences with treating their sons' hemophilia. © 2016 Wiley Periodicals, Inc.

  12. Myelofibrosis and acquired hemophilia A: a case report.

    PubMed

    Wrobel, Marie; Comio, Emilie; Gay, Valerie; Baroudi, Noureddine; Meyer, Pascal; Chuniaud-Louche, Christine; Hacini, Maya; Pica, Gian Matteo

    2016-05-07

    Myelofibrosis and acquired hemophilia A is a rare association. To the best of our knowledge only one case of myelofibrosis and acquired hemophilia A has been previously described. A 66-year-old Caucasian man diagnosed with myelofibrosis evolving in acute myeloid leukemia was referred to us for postoperative bleeding. Hemostatic studies showed prolonged activated partial thromboplastin time, decreased factor VIII coagulation, and a high factor VIII inhibitor titer; these findings led to a diagnosis of acquired hemophilia A for which he was treated with methylprednisolone and recombinant activated factor VII on admission. Due to a lack of response he was subsequently treated with rituximab combined with activated prothrombin complex concentrates. Furthermore, he received azacytidine to treat the underlying hematological malignancies. Immunosuppressive rituximab therapy resolved acquired hemophilia A with marked efficacy. Rapid and accurate diagnosis, effective hemostatic therapy, and timely treatment for underlying disease are important in the management of acquired hemophilia A secondary to hematological malignancy.

  13. 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

  14. Hemophilia A

    MedlinePlus

    ... PA: Elsevier; 2016:chap 476. Srivastava A, Brewer AK, Mauser-Bunschoten EP, et al. Treatment Guidelines Working Group on Behalf of The World Federation Of Hemophilia. Haemophilia. 2013;19:e1-47. PMID: 22776238 www.ncbi.nlm.nih.gov/pubmed/ ...

  15. Labor and delivery in a patient with hemophilia B.

    PubMed

    Przkora, R; Euliano, T Y; Roussos-Ross, K; Zumberg, M; Robicsek, S A

    2011-07-01

    Hemophilia B is a rare X-linked disorder that may cause dramatic bleeding. Women account for only 3.2% of those clinically affected. The X-linked inheritance frequently delays the diagnosis in women and may expose the patient to an increased risk of adverse events. There is limited experience with these patients during labor and delivery. A 28-year-old primiparous woman with hemophilia B (bleeding phenotype) delivered a male infant by an unplanned cesarean delivery under general anesthesia following treatment with factor IX and normalization of her coagulation parameters, guided by thromboelastography. Postpartum vaginal bleeding required transfusion of two units of packed red blood cells. Factor IX supplementation continued for one week. Once diagnosed with hemophilia B, a multidisciplinary approach and advanced antenatal planning can increase the likelihood of a safe delivery. Neuraxial approaches and cesarean delivery are recommended only after normalization of the coagulation profile. The male fetus of a hemophilia A or B patient requires special attention. Operative vaginal delivery and invasive fetal monitoring should be avoided. Thromboelastography is an excellent technique to assess parturients with bleeding disorders or peripartum hemorrhage and may be underused. Copyright © 2011 Elsevier Ltd. All rights reserved.

  16. [Microcirculatory investigations in hemophilia patients].

    PubMed

    Davydkin, I L; Kosiakova, Iu A

    2012-01-01

    to evaluate microcirculation (MC) and its influencing factors in hemophilia patients. In 44 hemophilia patients with recurrent hemarthrosis, laser Doppler flowmetry was used to evaluate resting MC above the index fingers, knee and ankle joints during an occlusion test, with allowance made for muscle and adipose tissue mass. The increased perfusion value above the afflicted joints was found to correspond to the phase of an exacerbation of posthemorrhagic inflammation and to be a risk factor of recurrent hemarrthrosis. Analysis of the occlusion test above the knee joints and index fingers revealed a diminished MC reserve and a tendency to precapillary spasm. MC changes were more pronounced in a shortage of muscle and adipose tissue mass. Hemophilia patients must regularly do physical exercises to make skeletal muscles develop well in order to prevent an exacerbation of the joint inflammatory process.

  17. Gene therapy in an era of emerging treatment options for hemophilia B.

    PubMed

    Monahan, P E

    2015-06-01

    Factor IX deficiency (hemophilia B) is less common than factor VIII deficiency (hemophilia A), and innovations in therapy for hemophilia B have generally lagged behind those for hemophilia A. Recently, the first sustained correction of the hemophilia bleeding phenotype by clotting factor gene therapy has been described using recombinant adeno-associated virus (AAV) to deliver factor IX. Despite this success, many individuals with hemophilia B, including children, men with active hepatitis, and individuals who have pre-existing natural immunity to AAV, are not eligible for the current iteration of hemophilia B gene therapy. In addition, recent advances in recombinant factor IX protein engineering have led some hemophilia treaters to reconsider the urgency of genetic cure. Current clinical and preclinical approaches to advancing AAV-based and alternative approaches to factor IX gene therapy are considered in the context of current demographics and treatment of the hemophilia B population. © 2015 International Society on Thrombosis and Haemostasis.

  18. The Hemophilia Games: An Experiment in Health Education Planning.

    ERIC Educational Resources Information Center

    National Heart and Lung Inst. (DHEW/PHS), Bethesda, MD.

    The Hemophilia Health Education Planning Project was designed to (1) create a set of tools useful in hemophilia planning and education, and (2) create a planning model for other diseases with similar factors. The project used the game-simulations technique which was felt to be particularly applicable to hemophilia health problems, since as a…

  19. Hemophilia in Sports: A Case Report and Prophylactic Protocol

    PubMed Central

    Maffet, Mark; Roton, Jimmy

    2017-01-01

    Objective: To describe a successful prophylactic protocol for managing an athlete with hemophilia playing at a high level of contact sports. Background: Published data show that team physicians are not comfortable either treating athletes with bleeding disorders or allowing them to participate in contact sports. Much of the literature historically has recommended against allowing athletes with bleeding disorders to play sports at all and certainly against playing contact sports. Hemophilia treatment can now include prophylactic injections of recombinant factor VIII to prevent bleeding episodes. Modern treatments hold the promise of allowing athletes with hemophilia to participate in contact sports. Differential Diagnosis: Mild, moderate, or severe hemophilia; von Willebrand disease; other factor deficiencies. Treatment: A treatment protocol was developed that included prophylactic factor VIII injections on a regular basis and when the athlete was injured. Uniqueness: This is the first published case report of an athlete with known hemophilia being successfully treated and participating in National Collegiate Athletic Association collegiate basketball for 2 full seasons. Conclusions: Sports medicine teams can successfully manage an athlete with hemophilia playing a contact sport. PMID:27863189

  20. Platelets and hemophilia: A review of the literature.

    PubMed

    Riedl, Julia; Ay, Cihan; Pabinger, Ingrid

    2017-07-01

    Hemophilia A and B are inherited bleeding disorders due to deficiencies of the clotting factors VIII and IX, respectively. The severity of the disease correlates with remaining factor levels, although individual differences in bleeding tendency are seen despite similar factor levels. While thrombin generation is severely impaired in persons with hemophilia, primary hemostasis, i.e. platelet function, has been generally considered to be normal. However, some studies reported prolonged bleeding times in hemophilia, suggesting that also primary hemostasis is affected. In several other studies different aspects of platelet function in hemophilia have been investigated in more detail and various alterations were discovered, such as increased platelet P-selectin expression, a lower number of procoagulant, so-called 'coated' platelets, lower aggregation upon co-incubation with tissue factor, or reduced platelet contractile forces during clot formation in comparison to healthy individuals. An influence of platelet function on clinical phenotype was suggested, which might contribute in part to variations in bleeding tendency in hemophilic patients with similar factor levels. However, the available evidence is currently limited and no clear correlations between platelet function parameters and clinical phenotypes have been demonstrated. The impact of alterations of platelet function in hemophilia remains to be better defined. Another interesting role of platelets in hemophilia has been reported recently by establishing a novel gene-therapeutic strategy using platelets as a delivery system for FVIII, showing promising results in animal models. This review gives an overview on the currently published literature on platelet function and the potential roles of platelets in hemophilia. Copyright © 2017 Elsevier Ltd. All rights reserved.

  1. The management of hemophilia in elderly patients

    PubMed Central

    Franchini, Massimo; Tagliaferri, Annarita; Mannucci, Pier Mannuccio

    2007-01-01

    After the increasing rate of deaths observed during the 1980s due to human immunodeficiency virus (HIV) infection, the health-related quality of life and life expectancy of persons with hemophilia have improved, mainly due to the progresses of replacement therapy and antiviral drugs and to the improvement of the global comprehensive care provided by specialized centers. As a consequence, an increasing number of hemophiliacs have reached an older age and nowadays physicians in hemophilia centers find that they must handle age-related clinical problems never previously observed in this population. The management of elderly persons with congenital hemophilia is discussed in the first part of this review. The second part describes the general aspects of acquired hemophilia due to anti-factor VIII autoantibodies, focusing on the clinical management of elderly patients, one of the groups most frequently affected by this acquired bleeding disorder. PMID:18044186

  2. Emerging drugs for hemophilia B.

    PubMed

    Mannucci, Pier Mannuccio; Franchini, Massimo

    2014-09-01

    Hemophilia B is a rare congenital bleeding disorder characterized by a deficiency of coagulation factor IX (FIX). Hemophilia B patients experience mild-to-severe bleeding complications according to the degree of FIX defect. Prophylaxis, with regular infusion of FIX concentrates, is nowadays, the mainstay of hemophilia care. However, because the relatively short half-life of such products necessitates frequent infusions and thus makes patients' adherence difficult, a number of strategies have been implemented to improve the pharmacokinetics of FIX clotting factors. This review summarizes the main results of Phase I/II and III studies on new FIX molecules engineered to have a longer half-life. Several technologies are being applied to extend FIX half-life, including Fc fusion, recombinant (r) albumin fusion and the addition of PEG polymers. By prolonging the FIX half-life up to 5 times, long-acting FIX products are expected to substantially improve the management of hemophilia B patients, allowing less frequent infusions and improving patients' adherence to prophylactic regimens and individualized treatments. Some of them are at an advanced stage of development, such as the rFIX-Fc which has been launched in March 2014. Along with the ongoing Phase III trials, long-term post-marketing surveillance studies are needed to assess their safety and effectiveness and their impact on patients' quality of life.

  3. 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.

  4. Multiple Comorbid Conditions among Middle-Aged and Elderly Hemophilia Patients: Prevalence Estimates and Implications for Future Care

    PubMed Central

    Khleif, Aroub A.; Rodriguez, Nidra; Brown, Deborah; Escobar, Miguel A.

    2011-01-01

    Introduction. Advances in hemophilia care and treatment have led to increases in the life expectancy among hemophiliacs. As a result, persons with hemophilia are reaching an older age and experiencing various age-related health conditions never seen before in this population. Aim. To determine the prevalence of comorbidities among middle-aged and elderly hemophilia A and hemophilia B patients. Methods. Retrospective chart review among all hemophilia patients, who attended the Gulf States Hemophilia and Thrombophilia Center. Results. All patients had at least one comorbid condition other than hemophilia, and the majority had between 3 and 6 comorbidities. The most common conditions identified were chronic hepatitis C, hypertension, HIV, chronic arthropathy, and overweight/obesity. Conclusions. Since persons with comorbidities are more likely to have poorer health outcomes and require greater care in managing their health needs, caring for aging hemophiliacs is likely to pose various social and economic challenges for both patients and providers. PMID:21912745

  5. Human parvovirus B19 and parvovirus 4 among Iranian patients with hemophilia.

    PubMed

    Javanmard, Davod; Ziaee, Masood; Ghaffari, Hadi; Namaei, Mohammad Hasan; Tavakoli, Ahmad; Mollaei, Hamidreza; Moghoofei, Mohsen; Mortazavi, Helya Sadat; Monavari, Seyed Hamidreza

    2017-12-01

    Human parvovirus B19 (B19V) is one of the smallest DNA viruses and shows great resistance to most disinfectants. Therefore, it is one of the common contaminant pathogens present in blood and plasma products. Parvovirus 4 (PARV4) is a newly identified parvovirus, which is also prevalent in parenteral transmission. In this study, we aimed to evaluate the prevalence of B19V and PARV4 DNA among patients with hemophilia in Birjand County in eastern Iran. This was a cross-sectional epidemiological study comprising nearly all people with hemophilia in this region. Whole blood samples were taken after patient registration and sent for plasma isolation. After nucleic acid extraction, B19V was detected with real-time polymerase chain reaction, PARV4 DNA was then detected using sensitive semi-nested PCR. In total, there were 86 patients with hemophilia, with mean age 28.5±1.5 years. Of these, 90.7% were men and 9.3% women; 84.9% had hemophilia A and 7.0% had hemophilia B. We found 11 patients (12.8%) were positive for B19V DNA and 8 were positive (9.3%) for PARV4 DNA. The prevalence of B19V was higher in middle-aged groups rather than younger people, whereas PARV4 infection was more common in younger patients ( P <0.05). There was a high prevalence of B19V and PARV4 infection in this high-risk group of patients with hemophilia. Due to the clinical significance of the B19 virus, imposing more precautionary measures for serum and blood products is recommended.

  6. Clinical and Laboratory Approaches to Hemophilia A

    PubMed Central

    Mansouritorghabeh, Hassan

    2015-01-01

    Hemophilia A is a worldwide disorder of coagulation system. It is a male disorder, yet females with hemophilia are rarely seen in communities with high rate of consanguineous marriages. The abnormalities in factor VIII gene transfer as an X-linked pattern in the family, affects as many as one-third of patients who had no family history of abnormality and thus the occurrence of a sporadic mutation could be documented. Hemorrhagic symptoms usually correlate with the plasma level of factor VIII and comprise a wide range of hemorrhagic pictures, including from fatal spontaneous bleeding in the brain to ecchymosis of the skin. The coagulation study needs to differentiate between the two types of hemophilia A and B as well as the categorization of the disease severity. In the developing countries, due to limitations in diagnostic hemostasis facilities and a scant number of experts in the field, it is estimated that noticeable numbers of undiagnosed patients with hemophilia A exist. Occasionally, we encounter undiagnosed cases by general physicians while having hemorrhagic symptoms. The purpose of this review is to recap clinical and diagnostic parameters, pitfalls, and interpretation of coagulation assay in hemophilia A. A literature review was done in PubMed and Scopus medical search engines using the keywords “Hemophilia” and “Haemophilia”. A time limitation for the publication beyond 1995 and publication in the English language were considered. A total of 94 original articles and chapters of books was selected for the current review. Additionally, a comprehensive and up-to-date information on the clinical and laboratory features for the diagnosis of hemophilia is also presented. PMID:25999618

  7. An examination of the symptoms of anxiety and parental attitude in children with hemophilia.

    PubMed

    Abali, Osman; Zülfikar, Osman Bülent; Karakoç Demirkaya, Sevcan; Ayaydin, Hamza; Kircelli, Fuat; Duman, Mehtap

    2014-01-01

    Hemophilia is an inherited disease with serious repercussions. Psychiatric symptoms are frequently seen in children and adolescents with hemophilia. The aim of this study was to assess symptoms of anxiety in children with hemophilia and parental attitude towards children with hemophilia. 42 boys were assessed according to child and adolescent psychiatry. Anxiety symptoms and parental attitude were obtained by the State-Trait Anxiety Scale, the Self-Report for Childhood Anxiety Related Disorders (SCARED) and the Parent Attitude Research Instrument (PARI). The mean age was 11.6 ± 2.5 (range; 7-16). State anxiety scores (44.02 ± 6.9) were higher than trait anxiety scores (32.7 + 7.5). The most interesting results were high scores related to overprotective mothering (47.9 ± 9.7) and the application of strict discipline (39.4 ± 9.1). The total SCARED scores obtained were (23.25 ± 11.3). Assuring a high quality of life is important for children and adolescents with chronic illness. Quality of life is negatively affected by psychiatric symptoms (e.g. anxiety symptoms, depression, intra-familial stress symptoms) in children with hemophilia. This study suggests that high anxiety scores and problems related to parental attitude can be seen in children and adolescents with hemophilia. These problems caused by parental attitude and anxiety symptoms should be considered in the treatment of hemophilia.

  8. Treatment of hemophilia B: focus on recombinant factor IX

    PubMed Central

    Franchini, Massimo; Frattini, Francesco; Crestani, Silvia; Sissa, Cinzia; Bonfanti, Carlo

    2013-01-01

    Hemophilia B is a recessive X-linked bleeding disorder characterized by deficiency of the coagulation factor IX (FIX). In hemophilia B patients the severity of the bleeding phenotype is related to the degree of the FIX defect. Hemophilia B treatment has improved greatly in the last 20 years with the introduction first of plasma-derived and then of recombinant FIX concentrates. Replacement therapy may be administered through on-demand or prophylaxis regimens, but the latter treatment modality has been shown to be superior in prevention of hemophilic arthropathy and in improvement of patients’ quality of life. The purpose of this narrative review is to summarize the current knowledge on treatment strategies for hemophilia B, focusing on recombinant FIX products either clinically used or in development. There is only one rFIX product that is licensed to treat hemophilia B patients; from the analysis of the literature data presented in this review, the authors conclude that this rFIX product has demonstrated an excellent safety profile and excellent clinical efficacy for halting and preventing bleeds in hemophilia B patients. While prophylaxis has emerged as the best therapeutic strategy for such patients because of its ability to prevent hemophilic arthropathy and to improve patients’ quality of life, the pharmacokinetically tailored dosing of rFIX is another key point when planning hemophilia B treatment, as it allows optimization of the factor concentrate usage. Further clinical studies are needed to better assess the safety and efficacy (ie, the incidence of adverse reactions and inhibitor development) of newer rFIX products. PMID:23430394

  9. Emicizumab Prophylaxis in Hemophilia A with Inhibitors.

    PubMed

    Oldenburg, Johannes; Mahlangu, Johnny N; Kim, Benjamin; Schmitt, Christophe; Callaghan, Michael U; Young, Guy; Santagostino, Elena; Kruse-Jarres, Rebecca; Negrier, Claude; Kessler, Craig; Valente, Nancy; Asikanius, Elina; Levy, Gallia G; Windyga, Jerzy; Shima, Midori

    2017-08-31

    Emicizumab (ACE910) bridges activated factor IX and factor X to restore the function of activated factor VIII, which is deficient in persons with hemophilia A. This phase 3, multicenter trial assessed once-weekly subcutaneous emicizumab prophylaxis in persons with hemophilia A with factor VIII inhibitors. We enrolled participants who were 12 years of age or older. Those who had previously received episodic treatment with bypassing agents were randomly assigned in a 2:1 ratio to emicizumab prophylaxis (group A) or no prophylaxis (group B). The primary end point was the difference in bleeding rates between group A and group B. Participants who had previously received prophylactic treatment with bypassing agents received emicizumab prophylaxis in group C. A total of 109 male participants with hemophilia A with inhibitors were enrolled. The annualized bleeding rate was 2.9 events (95% confidence interval [CI], 1.7 to 5.0) among participants who were randomly assigned to emicizumab prophylaxis (group A, 35 participants) versus 23.3 events (95% CI, 12.3 to 43.9) among those assigned to no prophylaxis (group B, 18 participants), representing a significant difference of 87% in favor of emicizumab prophylaxis (P<0.001). A total of 22 participants in group A (63%) had zero bleeding events, as compared with 1 participant (6%) in group B. Among 24 participants in group C who had participated in a noninterventional study, emicizumab prophylaxis resulted in a bleeding rate that was significantly lower by 79% than the rate with previous bypassing-agent prophylaxis (P<0.001). Overall, 198 adverse events were reported in 103 participants receiving emicizumab prophylaxis; the most frequent events were injection-site reactions (in 15% of participants). Thrombotic microangiopathy and thrombosis were reported in 2 participants each (in the primary analysis) who had received multiple infusions of activated prothrombin complex concentrate for breakthrough bleeding. No antidrug antibodies

  10. Role of bone marrow transplantation for correcting hemophilia A in mice

    PubMed Central

    Follenzi, Antonia; Raut, Sanj; Merlin, Simone; Sarkar, Rita

    2012-01-01

    To better understand cellular basis of hemophilia, cell types capable of producing FVIII need to be identified. We determined whether bone marrow (BM)–derived cells would produce cells capable of synthesizing and releasing FVIII by transplanting healthy mouse BM into hemophilia A mice. To track donor-derived cells, we used genetic reporters. Use of multiple coagulation assays demonstrated whether FVIII produced by discrete cell populations would correct hemophilia A. We found that animals receiving healthy BM cells survived bleeding challenge with correction of hemophilia, although donor BM-derived hepatocytes or endothelial cells were extremely rare, and these cells did not account for therapeutic benefits. By contrast, donor BM-derived mononuclear and mesenchymal stromal cells were more abundant and expressed FVIII mRNA as well as FVIII protein. Moreover, injection of healthy mouse Kupffer cells (liver macrophage/mononuclear cells), which predominantly originate from BM, or of healthy BM-derived mesenchymal stromal cells, protected hemophilia A mice from bleeding challenge with appearance of FVIII in blood. Therefore, BM transplantation corrected hemophilia A through donor-derived mononuclear cells and mesenchymal stromal cells. These insights into FVIII synthesis and production in alternative cell types will advance studies of pathophysiological mechanisms and therapeutic development in hemophilia A. PMID:22368271

  11. Renal Abnormalities Among Egyptian Children With Hemophilia A Using Renal Scintigraphy: Relation to Risk Factors and Disease Severity.

    PubMed

    Hamed, Ahmed Alsaeed; Shalaby, Mennatallah Hatem; El-Kinawy, Nihal Saad; Elamawy, Alaa Adel; Abd El-Ghany, Shereen Mohamed

    2017-07-01

    Many risk factors may contribute to renal disease in patients with hemophilia A. We aimed to evaluate functional and structural renal abnormalities among a group of Egyptian children with severe and moderate hemophilia A using technetium-99m diethylene triamine pentaacetic acid ( 99m Tc-DTPA) and technetium-99 m dimercaptusuccinic acid ( 99m Tc-DMSA) scan. We also aimed to determine the relation between these abnormalities and different risk factors and disease severity. Forty male patients, 16 with severe and 24 with moderate hemophilia A, were enrolled in this study. Their mean age was 10.2 ± 4.3 years (range, 5-17 years). Full history taking, clinical examination, laboratory, and radionuclide investigations including serum creatinine, blood urea nitrogen (BUN), urine analysis, creatinine clearance, 24-hour urinary protein, 99m Tc-DTPA scan, and 99m Tc-DMSA scan were performed to all enrolled patients. Serum creatinine and BUN were normal in all patients, and corrected creatinine clearance was diminished in 2 patients. However, 99m Tc-DTPA results yielded 19 (47.5%) patients with diminished glomerular filtration rate (GFR). Moreover, it showed that 14 (35%) had obstructive uropathy, 15 (37.5%) had obstructive nephropathy, while 11 (27.5%) patients showed normal scan. One patient had atrophy of 1 kidney on 99m Tc-DMSA scan. Among our cohort, 5 (12.5%) patients were hypertensive. Microscopic hematuria was detected in 14 (35%) patients while 72.5% had proteinuria. We found an association between hematuria and hypertension with diminished GFR. Despite normal kidney functions (serum creatinine and BUN), we found a high rate of diminished GFR and obstructive uropathy and nephropathy as detected by 99m Tc-DTPA scan among children with hemophilia A.

  12. Hemophilia and von Willebrand's disease: 2. Management. Association of Hemophilia Clinic Directors of Canada.

    PubMed Central

    1995-01-01

    OBJECTIVE: To present current strategies for the treatment of hemophilia and von Willebrand's disease. OPTIONS: Prophylactic and corrective therapy with hemostatic and adjunctive agents: DDAVP (1-desamino-8-D-arginine vasopressin [desmopressin acetate]), recombinant coagulation products (human Factor VIII and human Factor VIIa) or virally inactivated plasma-derived products (high- or ultra-high-purity human Factor VIII or human Factor VIII concentrate containing von Willebrand factor activity, porcine Factor VIII, high-purity human Factor IX, human prothrombin-complex concentrate, human activated prothrombin-complex concentrate), adjunctive antifibrinolytic agents, topical thrombin and fibrin sealant. The induction of immune tolerance in patients in whom inhibitors develop should also be considered. OUTCOMES: Morbidity and quality of life associated with bleeding and treatment. EVIDENCE: Relevant clinical studies and reports published from 1974 to 1994 were examined. A search was conducted of our reprint files, MEDLINE, citations in the articles reviewed and references provided by colleagues. In the MEDLINE search the following terms were used singly or in combination: "hemophilia," "von Willebrand's disease," "Factor VIII," "Factor IX," "von Willebrand factor," "diagnosis," "management," "home care," "comprehensive care," "inhibitor," "AIDS," "hepatitis," "life expectancy," "complications," "practice guidelines," "consensus statement" and "controlled trial." The in-depth review included only articles written in English from North America and Europe that were relevant to human disease and pertinent to a predetermined outline. The availability of treatment products in Canada was also considered. VALUES: Minimizing morbidity and maximizing functional status and quality of life were given a high value. BENEFITS, HARMS AND COSTS: Proper prophylactic or early treatment with appropriate hemostatic agents minimizes morbidity and functional disability and improves quality

  13. 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

  14. Hemophilia and Sports: Guidelines for Participation. Case Report.

    ERIC Educational Resources Information Center

    McLain, Larry G.; Heldrich, Fred T.

    1990-01-01

    Presents a case report of a 15-year-old boy with severe hemophilia who played soccer 1 school year but was denied continued participation following another screening examination. Before deciding about participation, physicians must assess the type and severity of hemophilia and risk factors for injury. Appropriate sports for hemophiliacs are…

  15. HIV-infected adolescents with hemophilia: adaptation and coping. The Hemophilia Behavioral Intervention Evaluation Project.

    PubMed

    Brown, L K; Schultz, J R; Gragg, R A

    1995-09-01

    It is estimated that 70% of individuals with factor VIII deficiency hemophilia who received blood products before 1985 are infected with human immunodeficiency virus (HIV). The goal of the current study was to assess how adolescents with hemophilia cope with reminders of their HIV status, because adaptation is likely to have implications for these individuals' quality of life and adherence to safer sex recommendations. Participants included 297 HIV-positive adolescents with hemophilia who were recruited from 11 sites across the United States. Adolescents reported on the use and effectiveness of strategies for coping with reminders of their HIV status. A significant degree of distress was reported in response to such reminders, with anger being the most commonly reported emotion. Although a wide variety of coping strategies had been tried, participants reported using resignation (80.9%), self-calming (78.8%), and distraction (76.4%) most frequently in their attempts to cope with reminders of HIV. Self-blame (3.6%), engaging in risky behaviors (22.2%), thinking about sex (25.4%), and drug/alcohol use (29.1%) were used least. These adolescents tended to rate more active cognitive and behavioral coping strategies (eg, cognitive restructuring, seeking social support, physical activity) as most effective, whereas passive strategies (eg, wishful thinking, blaming others) were reported to be least helpful. Those individuals who reported being distressed by reminders of HIV endorsed most of the coping strategies significantly more often than the nondistressed group, although ineffective strategies were commonly chosen. Sexually active adolescents were more likely than their abstinent peers to cope by thinking about sex, engaging in risky behaviors, or using alcohol and drugs. In this population of adolescents who have known their serostatus for several years, distress about everyday reminders of HIV appears to be associated with ineffective coping strategies.

  16. Hemophilia (For Parents)

    MedlinePlus

    ... use caution when treating children with hemophilia. For example, when giving immunization shots that are normally given in the muscle, doctors ... when children are becoming more independent — can be one of the most ... and their parents. For example, a preschooler may not tell mom and dad ...

  17. Causes of Death Among 379 Patients With Hemophilia: A Developing Country's Report.

    PubMed

    Mansouritorghabeh, Hassan; Rahimi, Hossein; Mohades, Seyed Tahereh; Behboudi, Maryam

    2018-05-01

    There are steps to achieve an optimum life for patients with hemophilia in developing countries, and awareness of the pattern of death in patients with hemophilia is a prerequisite for any health-care program. Owing to the lack of any data on the pattern of death in patients with hemophilia from developing countries, the current study was done to address common causes of death, and the spectrum of causes of death among individuals with hemophilia A and B. To address the pattern of death in northeast of Iran, we retrospectively collected demographic data regarding deceased patients with hemophilia A and B. Overall, among 379 people with hemophilia A and B, there were 46 deaths. Thirty-two deaths happened in the severe forms of the diseases. The obtained results show the patterns of death in the patients studied are not as parallel as some reports from the developed countries. Traumatic and spontaneous bleeding events were the main causes of death. The trend of death shows a decrease in the current decade post better therapeutic facilities. Evaluation of causes of death in hemophilia can be a useful indicator for managing the efficacy of health care in the current patients.

  18. Hemophilia and von Willebrand's disease: 1. Diagnosis, comprehensive care and assessment. Association of Hemophilia Clinic Directors of Canada.

    PubMed Central

    1995-01-01

    OBJECTIVE: To present current strategies for the assessment and comprehensive care of patients with hemophilia and von Willebrand's disease. OPTIONS: Hospital care, home care, single-provider care and multidisciplinary care. OUTCOMES: Morbidity and quality of life associated with bleeding and treatment. EVIDENCE: Relevant clinical studies and reports published from 1974 to 1994 were examined. A search was conducted of own reprint files, MEDLINE, citations in the articles reviewed and references provided by colleagues. In the MEDLINE search the following terms were used singly or in combination: "hemophilia," "von Willebrand's disease," "Factor VIII," "Factor IX," "von Willebrand factor," "diagnosis," "management," "home care," "comprehensive care," "inhibitor," "AIDS," "hepatitis," "life expectancy," "complications," "practice guidelines," "consensus statement" and "controlled trial." The in-depth review included only articles written in English from North America and Europe that were relevant to human disease and to a predetermined outline. The availability of treatment products in Canada was also considered. VALUES: Minimizing morbidity and maximizing functional status and quality of life were given a high value. BENEFITS, HARMS AND COSTS: The optimal use of treatment procedures and home care offers patients the advantages of minimized disability, improved survival and financial benefit. It is also cost effective. Potential harm, including the risk of hepatitis B, hepatitis C and HIV infection, has now been minimized through viral inactivation of plasma-derived coagulation-factor concentrates and through the use of recombinant clotting factor concentrates and other non-plasma-derived hemostatic agents. RECOMMENDATIONS: Patients with hemophilia and severe von Willebrand's disease should be followed in comprehensive care centres that offer expertise in the diagnosis, assessment and management of bleeding and complications and that can meet the educational and

  19. Brief Report: The Impact of Ledipasvir/Sofosbuvir on HIV-Positive and HIV-Negative Japanese Hemophilia Patients With 1, 4, and Mixed-Genotype HCV.

    PubMed

    Nagao, Azusa; Hanabusa, Hideji

    2017-04-01

    Approximately 80% of patients with hemophilia who received nonheated coagulation factor concentrates in the early 1980s were infected with hepatitis C virus (HCV), and approximately 40% of them were infected with HIV. We evaluated the efficacy and safety of administering ledipasvir (LDV)/sofosbuvir (SOF) to Japanese patients with hemophilia. Forty-three patients with hemophilia with genotype 1 or 4 HCV were treated with LDV/SOF for 12 weeks. The efficacy, safety, and results of the laboratory tests were evaluated. Twenty patients were coinfected with HIV and HCV. The sustained virological response (SVR) at 12 weeks after therapy was 90% in HIV-positive patients and 100% in HIV-negative patients. The efficacy of LDV/SOF was not significantly different between HIV-positive and HIV-negative patients (P = 0.12). However, the rate of SVR at 12 weeks after therapy in the patients with cirrhosis was significantly lower than that in patients without cirrhosis (P = 0.005). Overall, 20 patients (46%) had adverse events, and while the severity of most was mild to moderate, 3 were serious, including 1 death in the HIV-positive group. All patients completed treatment with no alterations in the antiretroviral regimen. No significant abnormalities in the renal function were detected in patients taking an antiretroviral regimen of tenofovir disoproxil fumarate. In this cohort study, LDV/SOF was effective and safe, but the SVR in patients with cirrhosis was lower than that in the noncirrhosis group. Thus, patients with hemophilia with genotype 1/4 HCV should be treated as early as possible before the onset of cirrhosis.

  20. Understanding cardiovascular risk in hemophilia: A step towards prevention and management.

    PubMed

    Sousos, Nikolaos; Gavriilaki, Eleni; Vakalopoulou, Sofia; Garipidou, Vasileia

    2016-04-01

    Advances in hemophilia care have led to increased life expectancy and new challenges in the management of the aging hemophilia population, including cardiovascular risk. Despite the deep knowledge into cardiovascular disease in terms of pathophysiology, risk prediction, prevention, early detection and management gained over the last decades, studies in hemophiliacs are scarce and mainly descriptive. As a growing amount of evidence points towards a similar or increased prevalence of traditional cardiovascular risk factors in hemophilia compared to the general population, the role of non-traditional, disease-related and treatment-related cardiovascular risk factors remains under investigation. Better understanding of cardiovascular risk in hemophilia is mandatory for proper cardiovascular risk prevention and management. Therefore, this review aims to summarize current knowledge on cardiovascular risk in hemophilia patients focusing on a) cardiovascular risk factors (traditional, non-traditional, disease-related and treatment-related), b) cardiovascular morbidity and mortality and c) cardiovascular prevention and management. Copyright © 2016 Elsevier Ltd. All rights reserved.

  1. The German Registry of immune tolerance treatment in hemophilia--1999 update.

    PubMed

    Lenk, H

    2000-10-01

    As of 1999, the German registry of immune tolerance treatment in hemophilia has received reports on 146 patients who have undergone this therapy from 25 hemophilia centers. In 16 of the reported patients treatment is ongoing. Therapy has been completed in 126 patients of all groups with hemophilia A; most of them are children. In 78.6% of hemophilia A patients full success was achieved, 8.7% finished with partial success, and in 12.7% ITT failed. Statistical analysis demonstrates that interruptions of therapy have a negative influence on success. The inhibitor titer has the highest predictive value for success or failure of therapy. A high maximum titer as well as a high titer at start of treatment were related to a low success rate. Other variables such as exposure days and time interval between inhibitor detection and start of ITT were not statistically significant. Four patients with hemophilia B have also completed therapy, only one of them with success.

  2. Shortened Lifespan and Lethal Hemorrhage in a Hemophilia A Mouse Model.

    PubMed

    Staber, Janice M; Pollpeter, Molly J

    2016-01-01

    Hemophilia A animal models have helped advance our understanding of factor VIII deficiency. Previously, factor VIII deficient mouse models were reported to have a normal life span without spontaneous bleeds. However, the bleeding frequency and survival in these animals has not been thoroughly evaluated. To investigate the survival and lethal bleeding frequency in two strains of E-16 hemophilia A mice. We prospectively studied factor VIII deficient hemizygous affected males (n = 83) and homozygous affected females (n = 55) for survival and bleeding frequency. Animals were evaluated for presence and location of bleeds as potential cause of death. Hemophilia A mice had a median survival of 254 days, which is significantly shortened compared to wild type controls (p < 0.0001). In addition, the hemophilia A mice experienced hemorrhage in several tissues. This previously-underappreciated shortened survival in the hemophilia A murine model provides new outcomes for investigation of therapeutics and also reflects the shortened lifespan of patients if left untreated.

  3. Pain Experience in Hemophilia Patients: A Hermeneutic Phenomenological Study

    PubMed Central

    Rambod, Masoume; Sharif, Farkhondeh; Molazem, Zahra; Khair, Kate

    2016-01-01

    ABSTRACT Background: Pain, as a crucial subsequence of joint hemorrhages in hemophilia patients, is chronic, debilitating, and distracting. This study aimed to describe and interpret pain experiences of hemophilia patients in their lives. Methods: This qualitative study with hermeneutic phenomenological approach was conducted on fourteen hemophilia patients who had been referred to a hemophilia center affiliated to Shiraz University of Medical Sciences, Shiraz, Iran. The study question was “what is the meaning of pain in hemophilia patients’ lives? The data were collected through semi-structured interviews and field notes through purposeful sampling. Then, thematic analysis with van Manen’s six-step methodological framework was used. MAX.QDA qualitative software package, 2010, was used to analyze the data. Results: The three main themes that emerged in this study were “alteration in physical health”, “engagement in psychological problems”, and “impairment in social relationships”. Alteration in physical health consisted of three subthemes, namely “impairment of physical function”, “change in body physics”, and “disturbance in sleep quality”. In addition, two subthemes including “nostalgia of pain in adults with hemophilia” and “psychological distress” emerged from engagement in psychological problems. Finally, “loss of social activity” and “change in relationships” were related to impairment in social relationships. Conclusion: The present study highlighted alteration in physical health, engagement in psychological problems, and impairment in social relationship as a result of pain in hemophilia patients. Thus, healthcare providers and family members have to pay special attention to these problems. Besides, providing complementary therapy interventions is suggested for reducing these issues. PMID:27713894

  4. Prevalent Inhibitors in Hemophilia B Subjects Enrolled in the Universal Data Collection Database

    PubMed Central

    Puetz, John; Soucie, J. Michael; Kempton, Christine L.; Monahan, Paul E.

    2015-01-01

    Summary Background Several risk factors for inhibitors have recently been described for hemophilia A. It has been assumed that similar risk factors are also relevant for hemophilia B, but there is limited data to confirm this notion. Objectives To determine the prevalence of and risk factors associated with inhibitors in hemophilia B Methods The database of the Universal Data Collection (UDC) project of the Centers for Disease Control for the years 1998 – 2011 was queried to determine the prevalence of inhibitors in hemophilia B subjects. In addition, disease severity, race/ethnicity, age, factor exposure, and prophylaxis usage were evaluated to determine their impact on inhibitor prevalence. Results Of the 3800 male subjects with hemophilia B enrolled in the UDC database, 75 (2%) were determined to have an inhibitor at some point during the study period. Severe disease (OR 13.1, 95% CI 6.2-27.7), black race (OR 2.2, 95% CI 1.2-4.1), and age less than 11 (OR 2.5, 95% CI 1.5-4.0) were found to be significantly associated with having an inhibitor. There was insufficient data to determine if type of factor used and prophylaxis were associated with inhibitors. Conclusions Inhibitors in hemophilia B are much less prevalent than hemophilia A, especially in patients with mild disease. Similar factors associated with inhibitors in hemophilia A also seem to be present for hemophilia B. The information collected by this large surveillance project did not permit evaluation of potential risk factors related to treatment approaches and exposures, and additional studies will be required. PMID:23855900

  5. Comparing thrombin generation in patients with hemophilia A and patients on vitamin K antagonists.

    PubMed

    de Koning, M L Y; Fischer, K; de Laat, B; Huisman, A; Ninivaggi, M; Schutgens, R E G

    2017-05-01

    Essentials It is unknown if hemophilia patients with atrial fibrillation need anticoagulation. Endogenous thrombin potentials (ETP) in hemophilia patients and patients on coumarins were compared. Severe hemophilia patients had comparable ETP to therapeutic international normalized ratio (INR). In non-severe hemophilia, 33% had higher ETP than therapeutic INR and may need anticoagulation. Click to hear Dr Negrier's perspective on global assays for assessing coagulation SUMMARY: Background It is unknown whether patients with hemophilia A with atrial fibrillation require treatment with vitamin K antagonists (VKAs) to the same extent as the normal population. Objective To compare hemostatic potential in hemophilia patients and patients on VKAs using thrombin generation (TG). Methods In this cross-sectional study, TG, initiated with 1pM tissue factor, was measured in 133 patients with severe (FVIII < 1%, n = 15) and non-severe (FVIII 1-50%, n = 118) hemophilia A, 97 patients on a VKA with an international normalized ratio (INR) ≥ 1.5 and healthy controls. Endogenous thrombin potential (ETP) (nm*min) was compared according to FVIII level (< 1%, 1-19% and 20-50%) with healthy controls and patients with sub-therapeutic INR (1.5-1.9) and therapeutic INR (≥ 2.0). Medians and interquartile ranges (IQRs) were calculated. Results Compared with healthy controls (898 [IQR 803-1004]), both hemophilia patients and patients on VKAs had lower median ETPs at 304 (196-449) and 176 (100-250), respectively. ETP was quite similar in severe hemophilia patients (185 [116-307]) and patients with a therapeutic INR (156 [90-225]). Compared with patients with therapeutic INR, ETP in patients with FVIII 1-19% and patients with FVIII 20-50% was higher at 296 (203-430) and 397 (219-632), respectively. All patients with therapeutic INR had an ETP < 400. Considering this threshold, 93% of severe hemophilia patients, 70% of patients with FVIII 1-19% and 52% of patients with FVIII 20-50% had an

  6. Novel approach to genetic analysis and results in 3000 hemophilia patients enrolled in the My Life, Our Future initiative

    PubMed Central

    Johnsen, Jill M.; Fletcher, Shelley N.; Huston, Haley; Roberge, Sarah; Martin, Beth K.; Kircher, Martin; Josephson, Neil C.; Shendure, Jay; Ruuska, Sarah; Koerper, Marion A.; Morales, Jaime; Pierce, Glenn F.; Aschman, Diane J.

    2017-01-01

    Hemophilia A and B are rare, X-linked bleeding disorders. My Life, Our Future (MLOF) is a collaborative project established to genotype and study hemophilia. Patients were enrolled at US hemophilia treatment centers (HTCs). Genotyping was performed centrally using next-generation sequencing (NGS) with an approach that detected common F8 gene inversions simultaneously with F8 and F9 gene sequencing followed by confirmation using standard genotyping methods. Sixty-nine HTCs enrolled the first 3000 patients in under 3 years. Clinically reportable DNA variants were detected in 98.1% (2357/2401) of hemophilia A and 99.3% (595/599) of hemophilia B patients. Of the 924 unique variants found, 285 were novel. Predicted gene-disrupting variants were common in severe disease; missense variants predominated in mild–moderate disease. Novel DNA variants accounted for ∼30% of variants found and were detected continuously throughout the project, indicating that additional variation likely remains undiscovered. The NGS approach detected >1 reportable variants in 36 patients (10 females), a finding with potential clinical implications. NGS also detected incidental variants unlikely to cause disease, including 11 variants previously reported in hemophilia. Although these genes are thought to be conserved, our findings support caution in interpretation of new variants. In summary, MLOF has contributed significantly toward variant annotation in the F8 and F9 genes. In the near future, investigators will be able to access MLOF data and repository samples for research to advance our understanding of hemophilia. PMID:29296726

  7. The Impact of HIV Infection on the Hemophilia Community.

    ERIC Educational Resources Information Center

    Whitney, Christopher K.

    1989-01-01

    The hemophilia community has been deeply affected by the catastrophe of AIDS (Acquired Immune Deficiency Syndrome). The use of blood products that had first restored the potential for normal survival now bring the threat of AIDS infection and fear and discrimination from others. Strong leadership has come from the National Hemophilia Foundation.…

  8. Practice of Iranian Adolescents with Hemophilia in Prevention of Complications of Hemophilia

    PubMed Central

    Valizadeh, Leila; Hosseini, Fahimeh Alsadat; Zamanzadeh, Vahid; Heidarnezhad, Fatemeh; Jasemi, Madineh; Lankarani, Kamran Bagheri

    2015-01-01

    Background: Prerequisite for management of a chronic disease involves knowledge about its complications and their prevention. Hemophilia in adolescents influences all the aspects of their lives and thier performance. Objectives: The present study aimed to determine the performance of Iranian hemophilic adolescents in prevention of disease complications. Patients and Methods: In this descriptive-analytical study, 108 adolescents with hemophilia were selected through convenience sampling. Their performance in preventing the complications of hemophilia was evaluated by sending a semi-structured questionnaire to their addresses throughout Iran. Then, the data was analysed using the Statistical Package for Social Sciences (SPSS) software (v. 13) and descriptive and interferential statistics were used. Results: Overall, 32.1% of the participants controlled bleeding during the 1st hour. Inaccessibility of coagulation products was mainly responsible for inhibiting timely and proper bleeding control. In order to relieve bleeding associated pain, only 39.0% of the adolescents used analgesics. On the other hand, 19.8% of the subjects used nonpharmacological methods to relieve pain. The majority of the adolescents did not participate in sport activities (65.4%) others allocated less than 5 hours a week to physical activities (70.5%). In addition, the participants did not have favorable dietary patterns, exercise habits, and dental care. The results showed a significant relationship between the adolescents’ preventive practice with coagulation disorders and utilization of pharmacological pain relief methods. Also, significant relationships were found between severity of the disease; participating in physical activities, number of hours of physical activities; and disease complications. Conclusions: Iranian adolescents did not exhibit favorable practices towards complication prevention. PMID:26600702

  9. 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.

  10. Evaluation of joint findings with gait analysis in children with hemophilia.

    PubMed

    Cayir, Atilla; Yavuzer, Gunes; Sayli, Revide Tülin; Gurcay, Eda; Culha, Vildan; Bozkurt, Murat

    2014-01-01

    Hemophilic arthropathy due to recurrent joint bleeding leads to physical, psychological and socioeconomic problems in children with hemophilia and reduces their quality of life. The purpose of this study was to evaluate joint damage through various parameters and to determine functional deterioration in the musculoskeletal system during walking using kinetic and kinematic gait analysis. Physical examination and kinetic and kinematic gait analysis findings of 19 hemophilic patients aged 7-20 years were compared with those of age, sex and leg length matched controls. Stride time was longer in the hemophilia group (p=0.001) compared to the age matched healthy control group, while hip, knee and ankle joint rotation angles were more limited (p=0.001, p=0.035 and p=0.001, respectively). In the hemophilia group, the extensor moment of the knee joint in the stance phase was less than that in the control group (p=0.001). Stride time was longer in the severe hemophilia group compared to the mild-moderate hemophilia and control groups (p=0.011 and p=0.001, respectively). Rotation angle of the ankle was wider in the control group compared to the other two groups (p=0.001 for both). Rotation angle of the ankle joint was narrower in the severe hemophilia group compared to the others (p=0.001 for each). Extensor moment of the knee joint was greater in the control group compared to the other two groups (p=0.003 and p=0.001, respectively). Walking velocity was higher in the control group compared to the severe hemophilia group. Kinetic and kinematic gait analysis has the sensitivity to detect minimal changes in biomechanical parameters. Gait analysis can be used as a reliable method to detect early joint damage.

  11. Biodistribution of Liver-Derived Mesenchymal Stem Cells After Peripheral Injection in a Hemophilia A Patient.

    PubMed

    Sokal, Etienne M; Lombard, Catherine Anne; Roelants, Véronique; Najimi, Mustapha; Varma, Sharat; Sargiacomo, Camillo; Ravau, Joachim; Mazza, Giuseppe; Jamar, François; Versavau, Julia; Jacobs, Vanessa; Jacquemin, Marc; Eeckhoudt, Stéphane; Lambert, Catherine; Stéphenne, Xavier; Smets, Françoise; Hermans, Cédric

    2017-08-01

    With the exception of liver transplantation, there is no cure for hemophilia, which is currently managed by preemptive replacement therapy. Liver-derived stem cells are in clinical development for inborn and acquired liver diseases and could represent a curative treatment for hemophilia A. The liver is a major factor VIII (FVIII) synthesis site, and mesenchymal stem cells have been shown to control joint bleeding in animal models of hemophilia. Adult-derived human liver stem cells (ADHLSCs) have mesenchymal characteristics and have been shown able to engraft in and repopulate both animal and human livers. Thus, the objectives were to evaluate the potency of ADHLSCs to control bleeding in a hemophilia A patient and assess the biodistribution of the cells after intravenous injection. A patient suffering from hemophilia A was injected with repeated doses of ADHLSCs via a peripheral vein (35 million In-oxine-labeled cells, followed by 125 million cells the next day, and 3 infusions of 250 million cells every 2 weeks thereafter; total infusion period, 50 days). After cell therapy, we found a temporary (15 weeks) decrease in the patient's FVIII requirements and severe bleeding complications, despite a lack of increase in circulating FVIII. The cells were safely administered to the patient via a peripheral vein. Biodistribution analysis revealed an initial temporary entrapment of the cells in the lungs, followed by homing to the liver and to a joint afflicted with hemarthrosis. These results suggest the potential use of ADHLSCs in the treatment of hemophilia A.

  12. The Utilization of Rehabilitation in Patients with Hemophilia A in Taiwan: A Nationwide Population-Based Study

    PubMed Central

    Yang, Yao-Hsu; Chang, Chia-Hao; Chen, Chih-Cheng; Chen, Pau-Chung

    2016-01-01

    Introduction Rehabilitation plays an important role in the physical health of patients with hemophilia. However, comprehensive information regarding the utilization of rehabilitation for such patients remains scarce. Aim This population-based study aimed to examine the characteristics, trends, and most important factors affecting rehabilitation usage in patients with hemophilia A using a nationwide database in Taiwan. Methods Data from 777 patients with hemophilia A who were registered in the National Health Insurance Research Database between 1998 and 2008 were analyzed using SAS 9.0. Results Musculoskeletal or nervous system-related surgical procedures and clotting factor VIII concentrate costs were identified as factors affecting rehabilitation usage; musculoskeletal or nervous system-related surgical procedures (odds ratio = 3.788; P < 0.001) were the most important predictor of whether a patient with hemophilia A would use rehabilitation services. Joint disorders, arthropathies, bone and cartilage disorders, intracranial hemorrhage, and brain trauma were common diagnoses during rehabilitation use. The costs of physical therapy (physiotherapy) comprised the majority (71.2%) of rehabilitation therapy categories. Increasingly, rehabilitation therapy was performed at physician clinics. The total rehabilitation costs were <0.1% of the total annual medical costs. Conclusion Musculoskeletal or nervous system-related surgical procedures and increased use of clotting factor VIII concentrate affect the rehabilitation utilization of patients with hemophilia A the most. The findings in this study could help clinicians comprehensively understand the rehabilitation utilization of patients with hemophilia A. PMID:27690229

  13. Omental implantation of BOECs in hemophilia dogs results in circulating FVIII antigen and a complex immune response.

    PubMed

    Ozelo, Margareth C; Vidal, Barbara; Brown, Christine; Notley, Colleen; Hegadorn, Carol; Webster, Sandra; Harpell, Lori; Ahlin, James; Winterborn, Andrew; Handforth, Janine; Arruda, Valder R; Hough, Christine; Lillicrap, David

    2014-06-26

    Ex vivo gene therapy strategies avoid systemic delivery of viruses thereby mitigating the risk of vector-associated immunogenicity. Previously, we delivered autologous factor VIII (FVIII)-expressing blood outgrowth endothelial cells (BOECs) to hemophilia A mice and showed that these cells remained sequestered within the implanted matrix and provided therapeutic levels of FVIII. Prior to translating this strategy into the canine (c) model of hemophilia A, we increased cFVIII transgene expression by at least 100-fold with the use of the elongation factor 1 alpha (EF1α) promoter and a strong endothelial enhancer element. BOECs isolated from hemophilia A dogs transduced with this lentiviral vector express levels of cFVIII ranging between 1.0 and 1.5 U/mL per 10(6) cells over 24 hours. Autologous BOECs have been implanted into the omentum of 2 normal and 3 hemophilia A dogs. These implanted cells formed new vessels in the omentum. All 3 hemophilia A dogs treated with FVIII-expressing autologous BOECs developed anti-FVIII immunoglobulin G2 antibodies, but in only 2 of the dogs were these antibodies inhibitory. FVIII antigen levels >40% in the absence of FVIII coagulant function were detected in the circulation for up to a year after a single gene therapy treatment, indicating prolonged cellular viability and synthesis of FVIII. © 2014 by The American Society of Hematology.

  14. Protein Replacement Therapy and Gene Transfer in Canine Models of Hemophilia A, Hemophilia B, von Willebrand Disease, and Factor VII Deficiency

    PubMed Central

    Nichols, Timothy C.; Dillow, Aaron M.; Franck, Helen W.G.; Merricks, Elizabeth P.; Raymer, Robin A.; Bellinger, Dwight A.; Arruda, Valder R.; High, Katherine A.

    2011-01-01

    Dogs with hemophilia A, hemophilia B, von Willebrand disease (VWD), and factor VII deficiency faithfully recapitulate the severe bleeding phenotype that occurs in humans with these disorders. The first rational approach to diagnosing these bleeding disorders became possible with the development of reliable assays in the 1940s through research that used these dogs. For the next 60 years, treatment consisted of replacement of the associated missing or dysfunctional protein, first with plasma-derived products and subsequently with recombinant products. Research has consistently shown that replacement products that are safe and efficacious in these dogs prove to be safe and efficacious in humans. But these highly effective products require repeated administration and are limited in supply and expensive; in addition, plasma-derived products have transmitted bloodborne pathogens. Recombinant proteins have all but eliminated inadvertent transmission of bloodborne pathogens, but the other limitations persist. Thus, gene therapy is an attractive alternative strategy in these monogenic disorders and has been actively pursued since the early 1990s. To date, several modalities of gene transfer in canine hemophilia have proven to be safe, produced easily detectable levels of transgene products in plasma that have persisted for years in association with reduced bleeding, and correctly predicted the vector dose required in a human hemophilia B liver-based trial. Very recently, however, researchers have identified an immune response to adeno-associated viral gene transfer vector capsid proteins in a human liver-based trial that was not present in preclinical testing in rodents, dogs, or nonhuman primates. This article provides a review of the strengths and limitations of canine hemophilia, VWD, and factor VII deficiency models and of their historical and current role in the development of improved therapy for humans with these inherited bleeding disorders. PMID:19293459

  15. Therapeutic approaches for treating hemophilia A using embryonic stem cells.

    PubMed

    Kasuda, Shogo; Tatsumi, Kohei; Sakurai, Yoshihiko; Shima, Midori; Hatake, Katsuhiko

    2016-06-01

    Hemophilia A is an X-linked rescessive bleeding disorder that results from F8 gene aberrations. Previously, we established embryonic stem (ES) cells (tet-226aa/N6-Ainv18) that secrete human factor VIII (hFVIII) by introducing the human F8 gene in mouse Ainv18 ES cells. Here, we explored the potential of cell transplantation therapy for hemophilia A using the ES cells. Transplant tet-226aa/N6-Ainv18 ES cells were injected into the spleens of severe combined immunodeficiency (SCID) mice, carbon tetrachloride (CCl4)-pretreated wild-type mice, and CCl4-pretreated hemophilia A mice. F8 expression was induced by doxycycline in drinking water, and hFVIII-antigen production was assessed in all cell transplantation experiments. Injecting the ES cells into SCID mice resulted in an enhanced expression of the hFVIII antigen; however, teratoma generation was confirmed in the spleen. Transplantation of ES cells into wild-type mice after CCl4-induced liver injury facilitated survival and engraftment of transplanted cells without teratoma formation, resulting in hFVIII production in the plasma. Although CCl4 was lethal to most hemophilia A mice, therapeutic levels of FVIII activity, as well as the hFVIII antigen, were detected in surviving hemophilia A mice after cell transplantation. Immunolocalization results for hFVIII suggested that transplanted ES cells might be engrafted at the periportal area in the liver. Although the development of a safer induction method for liver regeneration is required, our results suggested the potential for developing an effective ES-cell transplantation therapeutic model for treating hemophilia A in the future. Copyright © 2016 King Faisal Specialist Hospital & Research Centre. Published by Elsevier Ltd. All rights reserved.

  16. Gene Therapy for Hemophilia and Duchenne Muscular Dystrophy in China.

    PubMed

    Liu, Xionghao; Liu, Mujun; Wu, Lingqian; Liang, Desheng

    2018-02-01

    Gene therapy is a new technology that provides potential for curing monogenic diseases caused by mutations in a single gene. Hemophilia and Duchenne muscular dystrophy (DMD) are ideal target diseases of gene therapy. Important advances have been made in clinical trials, including studies of adeno-associated virus vectors in hemophilia and antisense in DMD. However, issues regarding the high doses of viral vectors required and limited delivery efficiency of antisense oligonucleotides have not yet been fully addressed. As an alternative strategy to classic gene addition, genome editing based on programmable nucleases has also shown promise to correct mutations in situ. This review describes the recent progress made by Chinese researchers in gene therapy for hemophilia and DMD.

  17. Inhibitor Formation in Congenital Hemophilia A: an Immunological Perspective.

    PubMed

    Delignat, Sandrine; Rayes, Julie; Russick, Jules; Kaveri, Srinivas V; Lacroix-Desmazes, Sebastien

    2018-06-04

    The immunogenicity of therapeutic factor VIII (FVIII) in patients with hemophilia A has been puzzling scientific and clinical communities for more than 3 decades. Indeed, the development of inhibitory antibodies to FVIII remains a major clinical challenge and is associated with enormous societal costs. Thus, the reasons for which a presumably innocuous, short-lived, intravenously administered glycoprotein triggers such a deleterious, long-lasting neutralizing immune response is an enigma. This review does not pretend to bring an answer to this challenging question. It will however summarize the latest findings regarding the molecular interactions at play in the recognition of FVIII by the immune cells, the validity of the proposed risk factors for FVIII alloimmunization, and the different solutions that allow induction of FVIII-specific tolerance in preclinical models of hemophilia A. Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

  18. 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

  19. Emerging therapies for hemophilia: controversies and unanswered questions

    PubMed Central

    Arruda, Valder R.; Doshi, Bhavya S.; Samelson-Jones, Benjamin J.

    2018-01-01

    Several new therapies for hemophilia have emerged in recent years. These strategies range from extended half-life factor replacement products and non-factor options with improved pharmacokinetic profiles to gene therapy aiming for phenotypic cure. While these products have the potential to change hemophilia care dramatically, several challenges and questions remain regarding broader applicability, long-term safety, and which option to pursue for each patient. Here, we review these emerging therapies with a focus on controversies and unanswered questions in each category. PMID:29770199

  20. Challenges and successes in the treatment of hemophilia: the story of a patient with severe hemophilia A and high-titer inhibitors

    PubMed Central

    Saba, Hussain I; Tran, Duc Quang

    2012-01-01

    In the past, patients with severe hemophilia have suffered a substantially reduced quality of life with frequent bleeding episodes, disabling arthropathy, and shorter life expectancy. In addition, methods of treatment and management have been costly and time-consuming, and have placed a considerable burden on patients’ physical and psychological well-being. With the advent of the on-demand therapy and prophylactic treatment paradigm, patients have been able to receive care with less interruption of daily activities. Treatments may be more challenging for hemophiliacs with inhibitors to replacement factor; however, recent advances in the use of bypassing agents and immune tolerance therapy have enabled them to aggressively manage their disease while maintaining their independence. This review focuses on the challenges of treating such a severe hemophiliac through examination of the lifetime experience of a young adult male with a severe form of congenital hemophilia A. At this stage of his life, the patient has minimal disabilities and is inhibitor-free through optimal care and strong family support. His aspiration to pursue a productive life has led him to a career in medicine. After receiving his medical degree, he pursued a specialty in the treatment of hemophilia. By assisting other hemophilia patients, he exemplifies both the rewards of persevering through episodes of bleeding and other complications and the fact that disabilities can be minimized when managed meticulously and in a timely fashion to enable a productive and dignified life. PMID:22715320

  1. THROMBIN GENERATION AND BLEEDING IN HEMOPHILIA A

    PubMed Central

    Brummel-Ziedins, Kathleen E.; Whelihan, Matthew F.; Gissel, Matthew; Mann, Kenneth G.; Rivard, Georges E.

    2012-01-01

    Introduction Hemophilia A displays phenotypic heterogeneity with respect to clinical severity. Aim To determine if tissue factor (TF)-initiated thrombin generation profiles in whole blood in the presence of corn trypsin inhibitor (CTI) are predictive of bleeding risk in hemophilia A. Methods We studied factor(F) VIII deficient individuals (11 mild, 4 moderate and 12 severe) with a well-characterized five-year bleeding history that included hemarthrosis, soft tissue hematoma and annual FVIII concentrate usage. This clinical information was used to generate a bleeding score. The bleeding scores (range 0–32) were separated into three groups (bleeding score groupings: 0, 0 and ≤9.6, >9.6), with the higher bleeding tendency having a higher score. Whole blood collected by phlebotomy and contact pathway suppressed by 100μg/mL CTI was stimulated to react by the addition of 5pM TF. Reactions were quenched at 20min by inhibitors. Thrombin generation, determined by ELISA for thrombin – antithrombin was evaluated in terms of clot time (CT), maximum level (MaxL) and maximum rate (MaxR) and compared to the bleeding score. Results Data are shown as the mean±SD. MaxL was significantly different (p<0.001) between the groups: 504±114nM, 315±117nM, and 194±91nM; with higher thrombin concentrations in the groups with lower bleeding scores. MaxR was higher in the groups with a lower bleeding score; 97±51nM/min, 86±60nM/min and 39±16nM/min (p=0.09). No significant difference was detected in CT among the groups, 5.6±1.3min, 4.7±0.7min, 5.6±1.3min. Conclusions Our empirical study in CTI-inhibited whole blood shows that the MaxL of thrombin generation appears to correlate with the bleeding phenotype of hemophilia A. PMID:19563500

  2. Experience of Preimplantation Genetic Diagnosis for Hemophilia at the University Hospital Virgen Del Rocío in Spain: Technical and Clinical Overview

    PubMed Central

    Fernández, Raquel M.; Peciña, Ana; Sánchez, Beatriz; Lozano-Arana, Maria Dolores; García-Lozano, Juan Carlos; Pérez-Garrido, Rosario; Núñez, Ramiro; Antiñolo, Guillermo

    2015-01-01

    Hemophilia A and B are the most common hereditary hemorrhagic disorders, with an X-linked mode of inheritance. Reproductive options for the families affected with hemophilia, aiming at the prevention of the birth of children with severe coagulation disorders, include preimplantation genetic diagnosis (PGD). Here we present the results of our PGD Program applied to hemophilia, at the Department of Genetics, Reproduction and Fetal Medicine of the University Hospital Virgen del Rocío in Seville. A total of 34 couples have been included in our program since 2005 (30 for hemophilia A and 4 for hemophilia B). Overall, 60 cycles were performed, providing a total of 508 embryos. The overall percentage of transfers per cycle was 81.7% and the live birth rate per cycle ranged from 10.3 to 24.1% depending on the methodological approach applied. Although PGD for hemophilia can be focused on gender selection of female embryos, our results demonstrate that methodological approaches that allow the diagnosis of the hemophilia status of every embryo have notorious advantages. Our PGD Program resulted in the birth of 12 healthy babies for 10 out of the 34 couples (29.4%), constituting a relevant achievement for the Spanish Public Health System within the field of haematological disorders. PMID:26258137

  3. Motivational techniques to improve self-care in hemophilia: the need to support autonomy in children.

    PubMed

    Bérubé, Sarah; Mouillard, Florine; Amesse, Claudine; Sultan, Serge

    2016-01-11

    In pediatric hemophilia, caregivers are facing unique challenges to adherence and self-care in children and adolescents with hemophilia. Hemophilia treatment requires adequate prophylaxis and on-demand treatment, as well as a clear behavioral strategy to limit risk-taking in terms of physical exercise and diet. Medication adherence rates of hemophilia patients have been reported to decrease during late childhood and adolescence. In the developing child, moving safely from parent-care to self-care is one of the greatest challenges of integrative care within this domain. There is a clear need for initiatives designed to increase an individual's motivation for treatment and self-care activities. Among motivational approaches, the self-determination perspective offers a useful framework to explain how the transition to self-care can be facilitated. We discuss how motivation regarding hemophilia treatment may be increased through parental autonomy support and we offer examples of applied communication techniques to facilitate autonomy-supportive caregiving. Although it has not yet been tested in the context of hemophilia, these communication techniques could potentially help caregivers promote adherence and self-care in children. Confronted by unique challenges to adherence and self-care, caregivers of children with hemophilia should move from an exclusive focus on illness-management education to an integrative strategy, including motivation-enhancing communication. The self-determination perspective provides important proximal objectives (e.g. autonomy support) to maintain optimal adherence in adolescents as they move from parent-care to self-care. Future research initiatives should address the practice of these communication techniques and evaluate them in the context of hemophilia.

  4. Assessment of Musculoskeletal Function and its Correlation with Radiological Joint Score in Children with Hemophilia A.

    PubMed

    Gupta, Samriti; Garg, Kapil; Singh, Jagdish

    2015-12-01

    To evaluate the functional independence of children with hemophilia A and its correlation to radiological joint score. The present cross sectional study was conducted at SPMCHI, SMS Medical College, Jaipur, India. Children in the age group of 4-18 y affected with severe, moderate and mild hemophilia A and with a history of hemarthrosis who attended the OPD, emergency or got admitted in wards of SPMCHI, SMS Medical College were examined. Musculoskeletal function was measured in 98 patients using Functional Independence Score in Hemophilia (FISH) and index joints (joints most commonly affected with repeated bleeding) were assessed radiologically with plain X rays using Pettersson score. The mean FISH score was 28.07 ± 3.90 (range 17-32) with squatting, running and step climbing as most affected tasks. The mean Pettersson score was 3.8 ± 3.2. A significant correlation was found between mean Pettersson score and FISH (r = -0.875, P < 0.001) with knee and elbow having r = -0.810 and -0.861 respectively, but not in case of ankle with r = -0.420 (P 0.174). The FISH and radiological joint (Pettersson's) scores may be extremely useful in the clinical practice in the absence of magnetic resonance imaging (MRI), which is considered very sensitive to detect early joint damage, but at a cost that makes it relatively inaccessible. FISH seems to be a reliable tool for assessment of functional independence in patients with hemophilia A.

  5. Trenonacog alfa for prophylaxis, on-demand and perioperative management of hemophilia B.

    PubMed

    Brennan, Yvonne; Curnow, Jennifer; Favaloro, Emmanuel J

    2018-01-01

    Current treatment for hemophilia B involves replacing the missing coagulation factor IX (FIX) with either plasma-derived or recombinant (r) FIX. Trenonacog alfa is the third normal half-life rFIX that has been granted FDA approval. Area covered: In this review, the authors examine trenonacog alfa for the treatment of hemophilia B including prophylaxis, on-demand and perioperative hemostasis. They compare the PK profile to nonacog alfa and evaluate the drug's efficacy and safety from published studies. Expert opinion: Trenonacog alfa appears to be an effective and safe treatment option for patients with hemophilia B with a PK profile similar to that of nonacog alfa. Despite the advent of extended half-life rFIX and other novel therapeutic approaches, normal half-life rFIX products, including trenonacog alfa, are likely to continue to have a place in hemophilia B treatment for at least the immediate future while the new landscape takes shape, particularly in countries that cannot afford the newer treatments.

  6. Emergency department care for patients with hemophilia and von Willebrand disease.

    PubMed

    Singleton, Tammuella; Kruse-Jarres, Rebecca; Leissinger, Cindy

    2010-08-01

    Patients with bleeding disorders such as hemophilia A, hemophilia B, and von Willebrand disease (VWD) are routinely treated at home, with their care managed in specialized centers. In emergency situations, these patients often present to their local emergency department (ED), where their management can represent a challenge to the emergency physicians and staff who rarely encounter them. Delays in diagnosis and administration of replacement therapy are the factors most commonly identified as predictive of death. Patients and family members are often very well educated in the disease and its management, which can significantly reduce morbidity and mortality. Children with bleeding disorders confer different challenges to the emergency physician and staff: they may present with no obvious signs of trauma or they may present with bruises consistent with non-accidental injury. All possible causes of bruising/bleeding should be investigated, although treatment should be administered promptly. The initial presentation of a bleeding disorder in the pediatric population is often made in the ED. Treatment of hemophilia A and B requires rapid replacement of the deficient clotting factor, with the desired factor level and dosage dependent on the product used and the hemorrhagic situation encountered. In patients with VWD, the main treatments are desmopressin or intravenous infusion of plasma-derived concentrates containing factor VIII and von Willebrand factor. The aim of this review is to outline some of the issues facing emergency physicians and the options available for the treatment of patients with hemophilia A, hemophilia B, and VWD. Copyright 2010. Published by Elsevier Inc.

  7. Prevention of inhibitor development in hemophilia A in 2016. A glimpse into the future?

    PubMed

    Franchini, Massimo; Lippi, Giuseppe

    2016-12-01

    Thanks to considerable progresses made over the last 30years, hemophilia benefits from the most efficacious and safe treatment among the many monogenic inherited disorders. The most challenging complication of replacement therapy in hemophilia A is the occurrence of alloantibodies against infused factor VIII (FVIII), thus predisposing the patients to increased morbidity and disability. Extensive research in this field has definitively unraveled that development of inhibitors in hemophilia A is a complex and multifactorial process, in which inherited and environmental factors dynamically interact. This narrative review, after providing a concise overview about the main genetic and non-genetic risk factors, is aimed to focus on prediction risk models and preventive strategies for minimizing the risk of developing inhibitors in hemophilia A patients. Copyright © 2016 Elsevier Ltd. All rights reserved.

  8. Assessment of the frequency of regulatory T cells (CD4+CD25+CD127-) in children with hemophilia A: relation to factor VIII inhibitors and disease severity.

    PubMed

    El-Asrar, Mohamed Abo; Hamed, Ahmed El-Saeed; Darwish, Yasser Wagih; Ismail, Eman Abdel Rahman; Ismail, Noha Ali

    2016-01-01

    A rapidly growing evidence showed that regulatory T cells (Tregs) play a crucial role in tolerance to coagulation factors and may be involved in the pathogenesis of inhibitor formation in patients with hemophilia. We determined the percentage of Tregs (CD4CD25CD127) in 45 children with hemophilia A compared with 45 healthy controls, and assessed their relation to the clinical characteristics of patients and factor VIII (FVIII) inhibitors. Patients were studied stressing on frequency of bleeding attacks, joint pain, history of viral hepatitis, and the received therapy (FVIII precipitate/cryotherapy). FVIII activity and FVIII inhibitors were assessed with flow cytometric analysis of CD4CD25CD127 Tregs. According to residual FVIII activity levels, 30 patients (66.7%) had mild/moderate hemophilia A, whereas 15 (33.3%) patients had severe hemophilia A. The frequency of Tregs was significantly lower among all patients with hemophilia A compared with controls (2.59 ± 1.1 versus 3.73 ± 1.12%; P = 0.002). Tregs were significantly decreased among patients with FVIII inhibitors compared with the inhibitor-negative group (P < 0.001). Patients with hematuria or severe hemophilia A had lower Tregs levels than those without (P = 0.34 and P = 0.011, respectively). A significant positive correlation was found between the percentage of Tregs and FVIII among hemophilia A patients. ROC curve analysis revealed that the cut-off value of Tregs at 1.91% could differentiate patients with and without FVIII inhibitors, with a sensitivity of 100% and a specificity of 91.3%. We suggest that alteration in the frequency of Tregs in young patients with hemophilia A may contribute to inhibitor formation and disease severity.

  9. Adenovirus-Associated Virus Vector–Mediated Gene Transfer in Hemophilia B

    PubMed Central

    Nathwani, Amit C.; Tuddenham, Edward G.D.; Rangarajan, Savita; Rosales, Cecilia; McIntosh, Jenny; Linch, David C.; Chowdary, Pratima; Riddell, Anne; Pie, Arnulfo Jaquilmac; Harrington, Chris; O’Beirne, James; Smith, Keith; Pasi, John; Glader, Bertil; Rustagi, Pradip; Ng, Catherine Y.C.; Kay, Mark A.; Zhou, Junfang; Spence, Yunyu; Morton, Christopher L.; Allay, James; Coleman, John; Sleep, Susan; Cunningham, John M.; Srivastava, Deokumar; Basner-Tschakarjan, Etiena; Mingozzi, Federico; High, Katherine A.; Gray, John T.; Reiss, Ulrike M.; Nienhuis, Arthur W.; Davidoff, Andrew M.

    2012-01-01

    BACKGROUND Hemophilia B, an X-linked disorder, is ideally suited for gene therapy. We investigated the use of a new gene therapy in patients with the disorder. METHODS We infused a single dose of a serotype-8–pseudotyped, self-complementary adenovirus-associated virus (AAV) vector expressing a codon-optimized human factor IX (FIX) transgene (scAAV2/8-LP1-hFIXco) in a peripheral vein in six patients with severe hemophilia B (FIX activity, <1% of normal values). Study participants were enrolled sequentially in one of three cohorts (given a high, intermediate, or low dose of vector), with two participants in each group. Vector was administered without immunosuppressive therapy, and participants were followed for 6 to 16 months. RESULTS AAV-mediated expression of FIX at 2 to 11% of normal levels was observed in all participants. Four of the six discontinued FIX prophylaxis and remained free of spontaneous hemorrhage; in the other two, the interval between prophylactic injections was increased. Of the two participants who received the high dose of vector, one had a transient, asymptomatic elevation of serum aminotransferase levels, which was associated with the detection of AAV8-capsid–specific T cells in the peripheral blood; the other had a slight increase in liver-enzyme levels, the cause of which was less clear. Each of these two participants received a short course of glucocorticoid therapy, which rapidly normalized aminotransferase levels and maintained FIX levels in the range of 3 to 11% of normal values. CONCLUSIONS Peripheral-vein infusion of scAAV2/8-LP1-hFIXco resulted in FIX transgene expression at levels sufficient to improve the bleeding phenotype, with few side effects. Although immune-mediated clearance of AAV-transduced hepatocytes remains a concern, this process may be controlled with a short course of glucocorticoids without loss of transgene expression. (Funded by the Medical Research Council and others; ClinicalTrials.gov number, NCT00979238

  10. Traumatic Hemarthrosis of the Knee Secondary to Hemophilia A in a Collegiate Soccer Player: A Case Report

    PubMed Central

    Fiala, Kelly A.; Hoffmann, Sandra J.; Ritenour, Donna M.

    2002-01-01

    Objective: To present the case of a collegiate soccer player who suffered from a traumatic knee hemarthrosis secondary to hemophilia A. This case presents an opportunity to discuss the participation status of athletes with hemophilia. Background: Hemophilia is a hereditary blood disease characterized by impaired coagulability of the blood. Hemophilia A is the most common of the severe, inherited bleeding disorders. This type, also called classic hemophilia, is due to a deficiency of clotting factor VIII. The athlete with hemophilia A reported pain and loss of function of his knee during a soccer game despite the absence of injury. Differential Diagnosis: Anterior cruciate ligament tear, intra-articular fracture, meniscus tear, capsular tear, hemarthrosis. Treatment: After the injury, the athlete was admitted to the hospital, where his knee joint was aspirated and he was infused with factor VIII. Later, he participated in traditional knee rehabilitation and was returned to play at the discretion of the orthopaedist and the hematologist. Uniqueness: In past participation guidelines, individuals with bleeding disorders were disqualified from athletic participation; however, with advances in medical care, these individuals may be permitted to participate in accordance with the law. Conclusions: Individuals with hemophilia participate in athletics; therefore, team physicians and athletic trainers must be prepared to care for these individuals. PMID:12937588

  11. Reduced bleeding events with subcutaneous administration of recombinant human factor IX in immune-tolerant hemophilia B dogs.

    PubMed

    Russell, Karen E; Olsen, Eva H N; Raymer, Robin A; Merricks, Elizabeth P; Bellinger, Dwight A; Read, Marjorie S; Rup, Bonita J; Keith, James C; McCarthy, Kyle P; Schaub, Robert G; Nichols, Timothy C

    2003-12-15

    Intravenous administration of recombinant human factor IX (rhFIX) acutely corrects the coagulopathy in hemophilia B dogs. To date, 20 of 20 dogs developed inhibitory antibodies to the xenoprotein, making it impossible to determine if new human FIX products, formulations, or methods of chronic administration can reduce bleeding frequency. Our goal was to determine whether hemophilia B dogs rendered tolerant to rhFIX would have reduced bleeding episodes while on sustained prophylactic rhFIX administered subcutaneously. Reproducible methods were developed for inducing tolerance to rhFIX in this strain of hemophilia B dogs, resulting in a significant reduction in the development of inhibitors relative to historical controls (5 of 12 versus 20 or 20, P <.001). The 7 of 12 tolerized hemophilia B dogs exhibited shortened whole blood clotting times (WBCTs), sustained detectable FIX antigen, undetectable Bethesda inhibitors, transient or no detectable antihuman FIX antibody titers by enzyme-linked immunosorbent assay (ELISA), and normal clearance of infused rhFIX. Tolerized hemophilia B dogs had 69% reduction in bleeding frequency in year 1 compared with nontolerized hemophilia B dogs (P =.0007). If proven safe in human clinical trials, subcutaneous rhFIX may provide an alternate approach to prophylactic therapy in selected patients with hemophilia B.

  12. Cost-effectiveness analysis of carrier and prenatal genetic testing for X-linked hemophilia.

    PubMed

    Tsai, Meng-Che; Cheng, Chao-Neng; Wang, Ru-Jay; Chen, Kow-Tong; Kuo, Mei-Chin; Lin, Shio-Jean

    2015-08-01

    Hemophilia involves a lifelong burden from the perspective of the patient and the entire healthcare system. Advances in genetic testing provide valuable information to hemophilia-affected families for family planning. The aim of this study was to analyze the cost-effectiveness of carrier and prenatal genetic testing in the health-economic framework in Taiwan. A questionnaire was developed to assess the attitudes towards genetic testing for hemophilia. We modeled clinical outcomes of the proposed testing scheme by using the decision tree method. Incremental cost-effectiveness analysis was conducted, based on data from the National Health Insurance (NHI) database and a questionnaire survey. From the NHI database, 1111 hemophilic patients were identified and required an average medical expenditure of approximately New Taiwan (NT) $2.1 million per patient-year in 2009. By using the decision tree model, we estimated that 26 potential carriers need to be tested to prevent one case of hemophilia. At a screening rate of 79%, carrier and prenatal genetic testing would cost NT $85.9 million, which would be offset by an incremental saving of NT $203 million per year by preventing 96 cases of hemophilia. Assuming that the life expectancy for hemophilic patients is 70 years, genetic testing could further save NT $14.2 billion. Higher screening rates would increase the savings for healthcare resources. Carrier and prenatal genetic testing for hemophilia is a cost-effective investment in healthcare allocation. A case management system should be integrated in the current practice to facilitate patient care (e.g., collecting family pedigrees and providing genetic counseling). Copyright © 2013. Published by Elsevier B.V.

  13. Liver-Directed Lentiviral Gene Therapy in a Dog Model of Hemophilia B

    PubMed Central

    Bartholomae, Cynthia C.; Volpin, Monica; Della Valle, Patrizia; Sanvito, Francesca; Sergi Sergi, Lucia; Gallina, Pierangela; Benedicenti, Fabrizio; Bellinger, Dwight; Raymer, Robin; Merricks, Elizabeth; Bellintani, Francesca; Martin, Samia; Doglioni, Claudio; D’Angelo, Armando; VandenDriessche, Thierry; Chuah, Marinee K.; Schmidt, Manfred; Nichols, Timothy; Montini, Eugenio; Naldini, Luigi

    2017-01-01

    We investigated the safety and efficacy of liver-directed gene therapy using lentiviral vectors in a large animal model of hemophilia B, and evaluated the risk of insertional mutagenesis in tumor-prone mouse models. We show that gene therapy using lentiviral vectors targeting expression of a canine factor IX transgene to hepatocytes was well-tolerated and provided stable long-term production of coagulation factor IX in dogs with hemophilia B. By exploiting three different mouse models designed to amplify the consequences of insertional mutagenesis, we show that no genotoxicity was detected with these lentiviral vectors. Our findings suggest that lentiviral vectors may be an attractive candidate for gene therapy targeted to the liver and may be useful for the treatment of hemophilia. PMID:25739762

  14. Impact of acute bleeding on daily activities of patients with congenital hemophilia with inhibitors and their caregivers and families: observations from the Dosing Observational Study in Hemophilia (DOSE).

    PubMed

    Recht, Michael; Neufeld, Ellis J; Sharma, Vivek R; Solem, Caitlyn T; Pickard, A Simon; Gut, Robert Z; Cooper, David L

    2014-09-01

    There is limited understanding of the effects of bleeding episodes on the daily lives of patients with congenital hemophilia with inhibitors and their caregivers. This analysis of the Dosing Observational Study in Hemophilia examined the impact of acute bleeding episodes on work, school, and family activities. Patients and caregivers participated in a diary study for 90 or more days or until patients experienced four bleeding episodes. All bleed treatments, interference with daily activities, and quality-of-life assessments were captured in daily records. Patients and caregivers reported planned workdays or school days eligible to be "lost" so as to differentiate from days lost because of disability or nonworking status, weekends, and vacations. Diaries were completed for 39 patients (18 adults and 21 children). Bleeding episodes that continued for 3 or more days (16.4%) accounted for most of the major changes to family plans. For the 38 patients with bleeding episodes, 47% of 491 bleed days fell on planned workdays or school days; the remainder fell on weekends, holidays, or nonworkdays or non-school days and therefore did not count as "lost days." Patients reported a loss of productivity on a greater percentage of eligible bleed days than did caregivers (3.9% vs. 0.8%, respectively). Patients and caregivers reported 13.5%/9.3% fully missed and 3.5%/7.6% partially missed days. This study demonstrated that in hemophilia with inhibitors, bleeding episodes interfere with the daily activities of patients and their caregivers. Furthermore, documenting only lost days underestimated the impact of bleeding episodes because of the high percentage of days without planned work or school. Copyright © 2014 International Society for Pharmacoeconomics and Outcomes Research (ISPOR). Published by Elsevier Inc. All rights reserved.

  15. Noninvasive prenatal diagnosis of hemophilia by microfluidics digital PCR analysis of maternal plasma DNA.

    PubMed

    Tsui, Nancy B Y; Kadir, Rezan A; Chan, K C Allen; Chi, Claudia; Mellars, Gillian; Tuddenham, Edward G; Leung, Tak Y; Lau, Tze K; Chiu, Rossa W K; Lo, Y M Dennis

    2011-03-31

    Hemophilia is a bleeding disorder with X-linked inheritance. Current prenatal diagnostic methods for hemophilia are invasive and pose a risk to the fetus. Cell-free fetal DNA analysis in maternal plasma provides a noninvasive mean of assessing fetal sex in such pregnancies. However, the disease status of male fetuses remains unknown if mutation-specific confirmatory analysis is not performed. Here we have developed a noninvasive test to diagnose whether the fetus has inherited a causative mutation for hemophilia from its mother. The strategy is based on a relative mutation dosage approach, which we have previously established for determining the mutational status of fetuses for autosomal disease mutations. In this study, the relative mutation dosage method is used to deduce whether a fetus has inherited a hemophilia mutation on chromosome X by detecting whether the concentration of the mutant or wild-type allele is overrepresented in the plasma of heterozygous women carrying male fetuses. We correctly detected fetal genotypes for hemophilia mutations in all of the 12 studied maternal plasma samples obtained from at-risk pregnancies from as early as the 11th week of gestation. This development would make the decision to undertake prenatal testing less traumatic and safer for at-risk families.

  16. Liver-directed lentiviral gene therapy in a dog model of hemophilia B.

    PubMed

    Cantore, Alessio; Ranzani, Marco; Bartholomae, Cynthia C; Volpin, Monica; Valle, Patrizia Della; Sanvito, Francesca; Sergi, Lucia Sergi; Gallina, Pierangela; Benedicenti, Fabrizio; Bellinger, Dwight; Raymer, Robin; Merricks, Elizabeth; Bellintani, Francesca; Martin, Samia; Doglioni, Claudio; D'Angelo, Armando; VandenDriessche, Thierry; Chuah, Marinee K; Schmidt, Manfred; Nichols, Timothy; Montini, Eugenio; Naldini, Luigi

    2015-03-04

    We investigated the efficacy of liver-directed gene therapy using lentiviral vectors in a large animal model of hemophilia B and evaluated the risk of insertional mutagenesis in tumor-prone mouse models. We showed that gene therapy using lentiviral vectors targeting the expression of a canine factor IX transgene in hepatocytes was well tolerated and provided a stable long-term production of coagulation factor IX in dogs with hemophilia B. By exploiting three different mouse models designed to amplify the consequences of insertional mutagenesis, we showed that no genotoxicity was detected with these lentiviral vectors. Our findings suggest that lentiviral vectors may be an attractive candidate for gene therapy targeted to the liver and may be potentially useful for the treatment of hemophilia. Copyright © 2015, American Association for the Advancement of Science.

  17. Hemophilia: The Role of the School Nurse.

    ERIC Educational Resources Information Center

    Damiano, Mary Lou; And Others

    1980-01-01

    Care of the school student with hemophilia requires a cooperative effort by the health care team. A multidisciplinary approach is suggested for the team, whose members include a hematologist, orthopedist, oral surgeon, geneticist, physical therapist, social worker, and school nurse. (JD)

  18. Unmet needs in the transition to adulthood: 18- to 30-year-old people with hemophilia.

    PubMed

    Quon, Doris; Reding, Mark; Guelcher, Chris; Peltier, Skye; Witkop, Michelle; Cutter, Susan; Buranahirun, Cathy; Molter, Don; Frey, Mary Jane; Forsyth, Angela; Tran, Duc Bobby; Curtis, Randall; Hiura, Grant; Levesque, Justin; de la Riva, Debbie; Compton, Matthew; Iyer, Neeraj N; Holot, Natalia; Cooper, David L

    2015-12-01

    Young adults with hemophilia face unique challenges during the transition to adulthood, including issues associated with switching from pediatric to adult hematology care, building mature interpersonal relationships, and establishing an independent career with an assurance of medical insurance coverage. A greater understanding of these challenges is essential for developing effective strategies to address the specific needs of this population. These challenges may be differentiated from those of older adults with hemophilia in large part because of more extensive childhood prophylaxis and safer factor products, resulting in fewer joint problems and lower rates of HIV and HCV infections. This analysis of the changing nature and unmet needs of today's young adults entering into adult hemophilia treatment centers, as well as potential strategies for optimally addressing these needs, was developed following roundtable discussions between patients, caregivers, hematologists, and other health care professionals participating in comprehensive care. Challenges identified among young adults with hemophilia include psychosocial issues related to maturity, personal responsibility, and increased independence, as well as concerns regarding when and with whom to share information about one's hemophilia, limited awareness of educational and financial resources, and a low perceived value of regular hematology care. The initiatives proposed herein highlight important opportunities for health care professionals at pediatric and adult hemophilia treatment centers, as well as national organizations, community groups, and career counselors, to address key unmet needs of this patient population. © 2015 Wiley Periodicals, Inc.

  19. Consensus Review of the Treatment of Cardiovascular Disease in People With Hemophilia A and B

    PubMed Central

    Boral, Leonard I.; Cohen, Alice J.; Smyth, Susan S.; White, Gilbert C.

    2015-01-01

    With advances in care, increasing numbers of people with hemophilia (PWH) achieve near-normal life expectancies and present with typical age-related cardiovascular conditions. Evidence-based guidelines for medical or surgical management of cardiovascular conditions in individuals with hemophilia are limited. Published recommendations exist for the management of some common cardiovascular conditions (eg, ischemic heart disease, atrial fibrillation), but identifying optimal strategies for anticoagulant or antithrombotic therapy constitutes the primary challenge of managing nonoperative cardiovascular disease (CVD) in PWH. In general, as long as factor concentrates or other hemostatic therapies maintain adequate hemostasis, the recommended medical and surgical management of CVD in PWH parallels that in individuals without hemophilia. The presence of factor inhibitors complicates hemophilia management. Published outcomes of CVD treatment in PWH are similar to those in the general population. Specific knowledge about factor replacement, factor inhibitors, and disease-specific treatment distinguishes the cardiovascular care of PWH from similar care of individuals without this rare bleeding disorder. Furthermore, a multidisciplinary approach incorporating a hematologist with an onsite coagulation laboratory, ideally associated with a hemophilia treatment center, is integral to the management of CVD in PWH. PMID:25436468

  20. Communication about carrier testing within hemophilia A families.

    PubMed

    Sorenson, James R; Jennings-Grant, Tracey; Newman, Jamie

    2003-05-15

    Genetic diseases are family diseases. Although there is considerable research on how individuals decide to have genetic testing and their individual reactions to testing, there is limited research on the familial context of genetic testing. In the present study, we focus on three aspects of the family context of genetic testing for hemophilia A carrier status among women at risk to be carriers. We look at the extent to which there was discussion of carrier testing for hemophilia before we offered DNA-based carrier testing to these at-risk women; with which family members these tested women communicated the results of their carrier testing; and concerns these women had about communicating their carrier test results with relatives, including their children. Data suggest that members of families with hemophilia discussed carrier testing prior to study participation, that the communication of testing information within families was selective, not universal, largely following gender lines for this X-linked disorder, and that there was limited concern about communicating carrier status information to children and other relatives. These data reinforce observations that families are social systems, and within these systems information is selectively communicated. A more complete understanding of how families communicate genetic test information will enable providers to develop more effective means of assisting individuals in handling the familial communication aspects of genetic testing. Copyright 2002 Wiley-Liss, Inc.

  1. Interventions for treating acute bleeding episodes in people with acquired hemophilia A.

    PubMed

    Zeng, Yan; Zhou, Ruiqing; Duan, Xin; Long, Dan; Yang, Songtao

    2014-08-28

    Acquired hemophilia A is a rare bleeding disorder caused by autoantibodies to coagulation factor VIII (FVIII). In most cases, bleeding episodes are spontaneous and severe at presentation. The optimal hemostatic therapy is controversial. To determine the efficacy of hemostatic therapies for acute bleeds in people with acquired hemophilia A; and to compare different forms of therapy for these bleeds. We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2014, Issue 4) and MEDLINE (Ovid) (1948 to 30 April 2014). We searched the conference proceedings of the: American Society of Hematology; European Hematology Association; International Society on Thrombosis and Haemostasis (ISTH); and the European Association for Haemophilia and Allied Disorders (EAHAD) (from 2000 to 30 April 2014). In addition to this we searched clinical trials registers. All randomised controlled trials and quasi-randomised trials of hemostatic therapies for people with acquired hemophilia A, with no restrictions on gender, age or ethnicity. No trials matching the selection criteria were eligible for inclusion. No trials matching the selection criteria were eligible for inclusion. No randomised clinical trials of hemostatic therapies for acquired hemophilia A were found. Thus, we are not able to draw any conclusions or make any recommendations on the optimal hemostatic therapies for acquired hemophilia A based on the highest quality of evidence. GIven that carrying out randomized controlled trials in this field is a complex task, the authors suggest that, while planning randomised controlled trials in which patients can be enrolled, clinicians treating the disease continue to base their choices on alternative, lower quality sources of evidence, which hopefully, in the future, will also be appraised and incorporated in a Cochrane Review.

  2. Advanced therapies for the treatment of hemophilia: future perspectives.

    PubMed

    Liras, Antonio; Segovia, Cristina; Gabán, Aline S

    2012-12-13

    Monogenic diseases are ideal candidates for treatment by the emerging advanced therapies, which are capable of correcting alterations in protein expression that result from genetic mutation. In hemophilia A and B such alterations affect the activity of coagulation factors VIII and IX, respectively, and are responsible for the development of the disease. Advanced therapies may involve the replacement of a deficient gene by a healthy gene so that it generates a certain functional, structural or transport protein (gene therapy); the incorporation of a full array of healthy genes and proteins through perfusion or transplantation of healthy cells (cell therapy); or tissue transplantation and formation of healthy organs (tissue engineering). For their part, induced pluripotent stem cells have recently been shown to also play a significant role in the fields of cell therapy and tissue engineering. Hemophilia is optimally suited for advanced therapies owing to the fact that, as a monogenic condition, it does not require very high expression levels of a coagulation factor to reach moderate disease status. As a result, significant progress has been possible with respect to these kinds of strategies, especially in the fields of gene therapy (by using viral and non-viral vectors) and cell therapy (by means of several types of target cells). Thus, although still considered a rare disorder, hemophilia is now recognized as a condition amenable to gene therapy, which can be administered in the form of lentiviral and adeno-associated vectors applied to adult stem cells, autologous fibroblasts, platelets and hematopoietic stem cells; by means of non-viral vectors; or through the repair of mutations by chimeric oligonucleotides. In hemophilia, cell therapy approaches have been based mainly on transplantation of healthy cells (adult stem cells or induced pluripotent cell-derived progenitor cells) in order to restore alterations in coagulation factor expression.

  3. The Patient Experience of Hemophilia and Human Immunodeficiency Virus: A Systematic Review of Qualitative Evidence.

    PubMed

    Omura, Kayoko; Tsuchiya, Sayaka

    The objective of this review is to describe and synthesize the experiences and perspectives of illness for patients living with both hemophilia and human immunodeficiency virus (HIV). Hemophilia is an inherited bleeding disorder caused by low concentrations of specific coagulation factors. There are two major types of this condition characterized by deficiencies of factor VIII (hemophilia A) and factor IX (hemophilia B). Bleeding occurs in hemophilia owing to failure of secondary hemostasis. The bleeding tendency is related to the measured concentration of the factor and is classified as mild, moderate, or severe. Severe hemophilia A and B is classified as repeated (as often as weekly) bleeds into joints and muscles. The main treatment is to arrest spontaneous and traumatic bleeds by prophylactic injection of factor concentrates or to prevent injury by restriction of exercise. Most people with severe hemophilia are on therapy at home with intravenous infusion of the relevant missing factor. Joint bleeds are painful, and the build up of blood is irritating to the synovial lining and damages joint tissue, so that adherence to hemophilia therapy is important.Global research in 18 countries reported that compliance with therapy by patients with hemophilia was low with self-injection adherence under 75% with as few as 53-65% of adults complying with therapy. Some of the most frequently cited factors affecting patients' compliance to therapy are as follows; inability to understand potential benefits (75%); denial (67%); interference with life style (62%); and lack of time (42%).The self-injection method of administering coagulation products became popular in the 1970s. In the early 1980s, 1,432 patients with hemophilia in Japan were infected with HIV (human immunodeficiency virus) because of the use of untreated blood products contaminated with the HIV virus. In addition commercial factor concentrates, which are prepared from pools of 2 to 6000 liters of plasma obtained

  4. Hemophilia Treatments Have Come a Long Way

    MedlinePlus

    ... Nisha Jain, M.D., chief of the Clinical Review Branch in FDA’s Office of Blood Research and Review. Hemophilia A occurs when people have low levels, ... Nisha Jain, M.D., chief of the Clinical Review Branch in FDA’s Office of Blood Research and ...

  5. Bruising and Hemophilia: Accident or Child Abuse?

    ERIC Educational Resources Information Center

    Johnson, Charles F.; Coury, Daniel L.

    1988-01-01

    Two case histories illustrate the difficulty in evaluating abuse/neglect in children with bleeding problems such as hemophilia. Discussed are guidelines for diagnosis and prevention of abuse, including: screening techniques, the need for protection from environmental trauma, parental stress, evaluation of parents' disciplinary methods, and the…

  6. Effect of BAX499 aptamer on tissue factor pathway inhibitor function and thrombin generation in models of hemophilia

    PubMed Central

    Gissel, Matthew; Orfeo, Thomas; Foley, Jonathan H; Butenas, Saulius

    2012-01-01

    Summary Introduction In hemophilia, thrombin generation is significantly suppressed due to decreased factor (F)X activation. Clinical studies and experiments with transgenic mice have suggested that the severity of hemophilia is substantially reduced by tissue factor pathway inhibitor (TFPI) deficiency. Methods We evaluated the effect of TFPI antagonist aptamer BAX499 (formerly ARC19499) on TFPI function in purified systems and on thrombin generation and clot formation in plasma and blood. Results BAX499 effectively neutralized TFPI inhibition of FXa and FXa dependent inhibition of TF/FVIIa by TFPI. BAX499 did not inhibit FXa or TF/FVIIa when used up to 500 nM. In the synthetic coagulation proteome with TFPI at its mean physiologic concentration, BAX499 at 1 – 10 nM increased thrombin generation triggered with 5 pM relipidated TF in a concentration-dependent manner. In severe hemophilia A or B models using the synthetic coagulation proteome, the addition of BAX499 at 5 nM increased thrombin generation to the levels observed in normal control. Thrombin generation measured in induced hemophilia B plasma required ~100 nM BAX499 to restore thrombin levels to those seen in untreated plasma. In induced hemophilia B whole blood, BAX499 repaired the clotting time but failed to appreciably impact the propagation phase of thrombin generation. Conclusion These data suggest that inhibition of TFPI by BAX499 may have potential for hemophilia treatment but requires further study in blood-based hemophilia systems. PMID:22951415

  7. The influence of prophylactic factor VIII in severe hemophilia A

    PubMed Central

    Gissel, Matthew; Whelihan, Matthew F; Ferris, Lauren A; Mann, Kenneth G; Rivard, Georges E; Brummel-Ziedins, Kathleen E

    2013-01-01

    Introduction Hemophilia A individuals displaying a similar genetic defect have heterogeneous clinical phenotypes. Aim To evaluate the underlying effect of exogenous factor (f)VIII on tissue factor (Tf)-initiated blood coagulation in severe hemophilia utilizing both empirical and computational models. Methods We investigated twenty-five clinically severe hemophilia A patients. All individuals were on fVIII prophylaxis and had not received fVIII from 0.25 to 4 days prior to phlebotomy. Coagulation was initiated by the addition of Tf to contact-pathway inhibited whole blood ± an anti-fVIII antibody. Aliquots were quenched over 20 min and analyzed for thrombin generation and fibrin formation. Coagulation factor levels were obtained and used to computationally predict thrombin generation with fVIII set to either zero or its value at the time of the draw. Results Due to prophylactic fVIII, at the time of the blood draw, the individuals had fVIII levels that ranged from <1% to 22%. Thrombin generation (maximum level and rate) in both empirical and computational systems increased as the level of fVIII increased. FXIII activation rates also increased as the fVIII level increased. Upon suppression of fVIII, thrombin generation became comparable in both systems. Plasma composition analysis showed a negative correlation between bleeding history and computational thrombin generation in the absence of fVIII. Conclusion Residual prophylactic fVIII directly causes an increase in thrombin generation and fibrin cross-linking in individuals with clinically severe hemophilia A. The combination of each individual's coagulation factors (outside of fVIII) determine each individual's baseline thrombin potential and may affect bleeding risk. PMID:21899664

  8. [Analysis of individualized primary prophylactic treatment of 19 cases of children with severe hemophilia A].

    PubMed

    Liu, G Q; Tang, L; Wu, X Y; Zhen, Y Z; Li, G; Chen, Z P; Wang, Y; Zhang, N N; Zhang, J S; Yu, G X; Wu, R H

    2016-12-02

    Objective: To study the current situation of primary prophylaxis in severe hemophilia A children and to explore rational regimen in order to provide evidence for the development of primary prophylaxis in China. Method: A retrospective clinical data collection and analysis was conducted for 19 severe hemophilia A children who received primary prophylaxis in Beijing Children's Hospital outpatient clinic between February 2011 and September 2015 and evaluated the regimen and efficacy. Result: (1) Primary prophylaxis regimen: the median beginning age 1.8 (range 0.5-2.9) years, the median FⅧ preparation using dosage 16.7 (8.0-23.5) U/(kg·time), the median using frequency was 1.0 (1.0-3.0) time/week. Eight cases among the patients received escalation of treatment intensity because of the poor bleeding control. (2) Efficacy: the median annual bleeding rate (ABR) was 1.9 (0-6.0) times/year, the median annual joint bleeding rate (AJBR) was 0 (0-3.3) times/year, without life threatening bleeding. All of them kept in 4th scale of Beijing Children Hospital daily activity level. The median annual factor consumption was 1 844 (840-5 040) U/kg. Conclusion: Low-dose primary prophylaxis regimen which were in low-dose /low frequencies and adjusted by bleeding frequency could decrease bleeding and joint bleeding frequency significantly, maintained the normal daily activity capacity and saved the factor consumption compared to standard regimen in severe hemophilia A children.

  9. Vitamin D levels in children with severe hemophilia A: an underappreciated deficiency.

    PubMed

    Albayrak, Canan; Albayrak, Davut

    2015-04-01

    Osteoporosis in hemophilic patients is a significant problem. The causes of osteoporosis in hemophilic patients are lack of adequate exercise, multiple hemorrhage and inflammation, and low vitamin D levels. The aim of this study was to retrospectively determine the frequency of vitamin D deficiency and insufficiency in children with severe hemophilia A. Forty-seven children with severe hemophilia were included in the study. None of the patients had previously received vitamin D supplementation. No patient had clinical or radiologic findings of rickets or seropositivity of hepatitis C virus or HIV. The mean age of the patients was 11.64 ± 5.70 (range, 2-18) years. The mean vitamin D level was 16.35 ± 7.49 ng/ml (range, 3.25-33.80). Vitamin D levels were below 10 ng/ml (severe vitamin D deficiency) in 9 cases (19%), between 10 and 19.99 ng/ml (vitamin D deficiency) in 23 cases (49%), between 20 and 29.99 ng/ml (vitamin D insufficiency) in 13 cases (28%), and above 30 ng/ml (normal vitamin D level) in 2 cases (4%). The mean serum levels of 25-hydroxy vitamin D in the children with hemophilia during winter and autumn were significantly lower than that during summer (P = 0.0028 and P = 0.0091, respectively). A majority of our hemophilic patients (96%) had low vitamin D levels. The study showed that the risk of vitamin D deficiency is the most highest during winter and autumn. Normal lifelong vitamin D levels are especially important in hemophilia because of the possible synergistic effect of vitamin D levels on periarticular and general osteoporosis, which is intrinsic to hemophilic conditions. We advise routine checking of vitamin D levels twice a year and vitamin D supplementation to maintain its level between 30 and 100 ng/ml.

  10. BE EMPOWERED, a specialty pharmacy education program for hemophilia B patients, impacts adult joint bleeds and pediatric use of RICE.

    PubMed

    Blankenship, Crystal S; Tortella, Bartholomew J; Bruno, Marianna

    2014-02-01

    Traditional education about hemophilia B in hemophilia treatment centers (HTCs) and episodic contact with HTCs limit the amount of education patients and their caregivers receive. Specialty care providers have frequent, continuing contact with patients. Each contact with a specialty care provider (e.g., coordinating a refill or addressing a patient inquiry) is another opportunity to support patient self-management of the disease and to give counsel on appropriate medication administration. The role of specialty pharmacy in improving patient self-management and supporting medication management and adherence is well established and reported with rheumatoid arthritis, multiple sclerosis, and renal transplant. With hemophilia, specialty pharmacies can support educational reinforcement of HTCs as well as support patient self-management and education of medication therapy. Utilization of patient education materials and programs can facilitate such a role. BE EMPOWERED, a specialty pharmacy education program for hemophilia B patients, is a multimodule education program coupled with frequent telephonic outreach.   To provide education about hemophilia B, based upon discrete curriculum modules, facilitated by a specialty pharmacy-based nurse educator.   Patients with hemophilia B (or, for children, their caregivers) were enrolled in the BE EMPOWERED program, and data were prospectively collected regarding bleeding and hemophilia-specific quality of life (QoL) outcomes (n = 21 caregivers, n = 17 adults).  BE EMPOWERED was associated with a statistically significant impact on the use of RICE (rest, ice, compression, and elevation) by caregivers whose utilization increased from 81% to 95% (P = 0.05). Adults in the BE EMPOWERED program experienced a statistically significant drop in the annualized bleeding rate (ABR), decreasing from 4.7 to 2.5 for total bleeds and decreasing from 3.5 to 1.7 for joint bleeds (P ≤ 0.02). For children with hemophilia B

  11. Translational Data from Adeno-Associated Virus-Mediated Gene Therapy of Hemophilia B in Dogs

    PubMed Central

    Whitford, Margaret H.; Arruda, Valder R.; Stedman, Hansell H.; Kay, Mark A.; High, Katherine A.

    2015-01-01

    Abstract Preclinical testing of new therapeutic strategies in relevant animal models is an essential part of drug development. The choice of animal models of disease that are used in these studies is driven by the strength of the translational data for informing about safety, efficacy, and success or failure of human clinical trials. Hemophilia B is a monogenic, X-linked, inherited bleeding disorder that results from absent or dysfunctional coagulation factor IX (FIX). Regarding preclinical studies of adeno-associated virus (AAV)-mediated gene therapy for hemophilia B, dogs with severe hemophilia B (<1% FIX) provide well-characterized phenotypes and genotypes in which a species-specific transgene can be expressed in a mixed genetic background. Correction of the hemophilic coagulopathy by sustained expression of FIX, reduction of bleeding events, and a comprehensive assessment of the humoral and cell-mediated immune responses to the expressed transgene and recombinant AAV vector are all feasible end points in these dogs. This review compares the preclinical studies of AAV vectors used to treat dogs with hemophilia B with the results obtained in subsequent human clinical trials using muscle- and liver-based approaches. PMID:25675273

  12. Translational data from adeno-associated virus-mediated gene therapy of hemophilia B in dogs.

    PubMed

    Nichols, Timothy C; Whitford, Margaret H; Arruda, Valder R; Stedman, Hansell H; Kay, Mark A; High, Katherine A

    2015-03-01

    Preclinical testing of new therapeutic strategies in relevant animal models is an essential part of drug development. The choice of animal models of disease that are used in these studies is driven by the strength of the translational data for informing about safety, efficacy, and success or failure of human clinical trials. Hemophilia B is a monogenic, X-linked, inherited bleeding disorder that results from absent or dysfunctional coagulation factor IX (FIX). Regarding preclinical studies of adeno-associated virus (AAV)-mediated gene therapy for hemophilia B, dogs with severe hemophilia B (<1% FIX) provide well-characterized phenotypes and genotypes in which a species-specific transgene can be expressed in a mixed genetic background. Correction of the hemophilic coagulopathy by sustained expression of FIX, reduction of bleeding events, and a comprehensive assessment of the humoral and cell-mediated immune responses to the expressed transgene and recombinant AAV vector are all feasible end points in these dogs. This review compares the preclinical studies of AAV vectors used to treat dogs with hemophilia B with the results obtained in subsequent human clinical trials using muscle- and liver-based approaches.

  13. Outcomes in Patients With Hemophilia and von Willebrand Disease Undergoing Invasive or Surgical Procedures.

    PubMed

    Chapin, John; Bamme, Jaqueline; Hsu, Fraustina; Christos, Paul; DeSancho, Maria

    2017-03-01

    Adults with hemophilia A (HA), hemophilia B (HB), and von Willebrand disease (VWD) frequently require surgery and invasive procedures. However, there is variability in perioperative management guidelines. We describe our periprocedural outcomes in this setting. A retrospective chart review from January 2006 to December 2012 of patients with HA, HB, and VWD undergoing surgery or invasive procedures was conducted. Type of procedures, management including the use of continuous factor infusion, and administration of antifibrinolytics were reviewed. Adverse outcomes were defined as acute bleeding (<48 hours), delayed bleeding (≥48 hours), transfusion, inhibitor development, and thrombosis. We identified 59 patients with HA and HB. In all, 24 patients had severe hemophilia and 12 had mild/moderate hemophilia. Twelve patients had inhibitors. There were also 5 female carriers of HA and 6 patients with VWD. There were 34 major surgeries (26 orthopedic, 8 nonorthopedic) and 129 minor surgeries. Continuous infusion was used in 55.9% of major surgeries versus 8.5% of minor surgeries. Antifibrinolytics were administered in 14.7% of major surgeries versus 23.2% of minor surgeries. In all, 4 patients developed acute bleeding and 10 patients developed delayed bleeding. Delayed bleeding occurred in 28.6% of genitourinary procedures and in 16.1% of dental procedures. Five patients acquired an inhibitor and 2 had thrombosis. In conclusion, patients with HA, HB, or VWD had similar rates of adverse outcomes when undergoing minor surgeries or major surgeries. This finding underscores the importance of an interdisciplinary management and procedure-specific guidelines for patients with hemophilia and VWD prior to even minor invasive procedures.

  14. Progress and challenges in the development of a cell-based therapy for hemophilia A

    PubMed Central

    Fomin, Marina E.; Togarrati, Padma Priya; Muench, Marcus O.

    2015-01-01

    Hemophilia A results from an insufficiency of factor VIII (FVIII). Although replacement therapy with plasma-derived or recombinant FVIII is a life-saving therapy for hemophilia A patients, such therapy is a life-long treatment rather than a cure for the disease. In this review we discuss the possibilities, progress and challenges that remain in the development of a cell-based cure for hemophilia A. The success of cell therapy depends on the type and availability of donor cells, the age of the host and method of transplantation, and the levels of engraftment and production of FVIII by the graft. Early therapy, possibly even prenatal transplantation, may yield the highest levels of engraftment by avoiding immunological rejection of the graft. Potential cell sources of FVIII include a specialized subset of endothelial cells known as liver sinusoidal endothelial cells (LSECs) present in the adult and fetal liver, or patient-specific endothelial cells derived from induced pluripotent stem cells (iPSCs) that have undergone gene editing to produce FVIII. Achieving sufficient engraftment of transplanted LSECs is one of the obstacles to successful cell therapy for hemophilia A. We discuss recent results from transplants performed in animals that show production of functional and clinically relevant levels of FVIII obtained from donor LSECs. Hence, the possibility of treating hemophilia A can be envisioned through persistent production of FVIII from transplanted donor cells derived from a number of potential cell sources or through creation of donor endothelial cells from patient-specific iPSCs. PMID:25297648

  15. Long-Term Safety and Efficacy of Factor IX Gene Therapy in Hemophilia B

    PubMed Central

    Nathwani, A.C.; Reiss, U.M.; Tuddenham, E.G.D.; Rosales, C.; Chowdary, P.; McIntosh, J.; Della Peruta, M.; Lheriteau, E.; Patel, N.; Raj, D.; Riddell, A.; Pie, J.; Rangarajan, S.; Bevan, D.; Recht, M.; Shen, Y.-M.; Halka, K.G.; Basner-Tschakarjan, E.; Mingozzi, F.; High, K.A.; Allay, J.; Kay, M.A.; Ng, C.Y.C.; Zhou, J.; Cancio, M.; Morton, C.L.; Gray, J.T.; Srivastava, D.; Nienhuis, A.W.; Davidoff, A.M.

    2014-01-01

    BACKGROUND In patients with severe hemophilia B, gene therapy that is mediated by a novel self-complementary adeno-associated virus serotype 8 (AAV8) vector has been shown to raise factor IX levels for periods of up to 16 months. We wanted to determine the durability of transgene expression, the vector dose–response relationship, and the level of persistent or late toxicity. METHODS We evaluated the stability of transgene expression and long-term safety in 10 patients with severe hemophilia B: 6 patients who had been enrolled in an initial phase 1 dose-escalation trial, with 2 patients each receiving a low, intermediate, or high dose, and 4 additional patients who received the high dose (2×1012 vector genomes per kilogram of body weight). The patients subsequently underwent extensive clinical and laboratory monitoring. RESULTS A single intravenous infusion of vector in all 10 patients with severe hemophilia B resulted in a dose-dependent increase in circulating factor IX to a level that was 1 to 6% of the normal value over a median period of 3.2 years, with observation ongoing. In the high-dose group, a consistent increase in the factor IX level to a mean (±SD) of 5.1±1.7% was observed in all 6 patients, which resulted in a reduction of more than 90% in both bleeding episodes and the use of prophylactic factor IX concentrate. A transient increase in the mean alanine aminotransferase level to 86 IU per liter (range, 36 to 202) occurred between week 7 and week 10 in 4 of the 6 patients in the high-dose group but resolved over a median of 5 days (range, 2 to 35) after prednisolone treatment. CONCLUSIONS In 10 patients with severe hemophilia B, the infusion of a single dose of AAV8 vector resulted in long-term therapeutic factor IX expression associated with clinical improvement. With a follow-up period of up to 3 years, no late toxic effects from the therapy were reported. (Funded by the National Heart, Lung, and Blood Institute and others; Clinical

  16. Factoring nonviral gene therapy into a cure for hemophilia A.

    PubMed

    Gabrovsky, Vanessa; Calos, Michele P

    2008-10-01

    Gene therapy for hemophilia A has fallen short of success despite several clinical trials conducted over the past decade. Challenges to its success include vector immunogenicity, insufficient transgene expression levels of Factor VIII, and inhibitor antibody formation. Gene therapy has been dominated by the use of viral vectors, as well as the immunogenic and oncogenic concerns that accompany these strategies. Because of the complexity of viral vectors, the development of nonviral DNA delivery methods may provide an efficient and safe alternative for the treatment of hemophilia A. New types of nonviral strategies, such as DNA integrating vectors, and the success of several nonviral animal studies, suggest that nonviral gene therapy has curative potential and justifies its clinical development.

  17. Anti-factor IXa/X bispecific antibody ACE910 prevents joint bleeds in a long-term primate model of acquired hemophilia A

    PubMed Central

    Yoshihashi, Kazutaka; Takeda, Minako; Kitazawa, Takehisa; Soeda, Tetsuhiro; Igawa, Tomoyuki; Sampei, Zenjiro; Kuramochi, Taichi; Sakamoto, Akihisa; Haraya, Kenta; Adachi, Kenji; Kawabe, Yoshiki; Nogami, Keiji; Shima, Midori; Hattori, Kunihiro

    2014-01-01

    ACE910 is a humanized anti-factor IXa/X bispecific antibody mimicking the function of factor VIII (FVIII). We previously demonstrated in nonhuman primates that a single IV dose of ACE910 exerted hemostatic activity against hemophilic bleeds artificially induced in muscles and subcutis, and that a subcutaneous (SC) dose of ACE910 showed a 3-week half-life and nearly 100% bioavailability, offering support for effective prophylaxis for hemophilia A by user-friendly SC dosing. However, there was no direct evidence that such SC dosing of ACE910 would prevent spontaneous bleeds occurring in daily life. In this study, we newly established a long-term primate model of acquired hemophilia A by multiple IV injections of an anti-primate FVIII neutralizing antibody engineered in mouse-monkey chimeric form to reduce its antigenicity. The monkeys in the control group exhibited various spontaneous bleeding symptoms as well as continuous prolongation of activated partial thromboplastin time; notably, all exhibited joint bleeds, which are a hallmark of hemophilia. Weekly SC doses of ACE910 (initial 3.97 mg/kg followed by 1 mg/kg) significantly prevented these bleeding symptoms; notably, no joint bleeding symptoms were observed. ACE910 is expected to prevent spontaneous bleeds and joint damage in hemophilia A patients even with weekly SC dosing, although appropriate clinical investigation is required. PMID:25274508

  18. Two-incision laparoscopic appendectomy for a severe hemophilia A child patient with coagulation factor VII deficiency

    PubMed Central

    He, Jin Peng; Feng, Jie Xiong

    2017-01-01

    Abstract Rationale: The main complication of patients with severe hemophilia is recurrent bleeding events that usually affected musculoskeletal contractures. And replacement therapy methods were continuously improved to minimize adverse impacts brought by those complications. However, only several cases reported about the appendectomy for hemophilia A. We report a case of acute appendicitis treated by two-incision laparoscopy in a boy with hemophilia A and coagulation factor VII deficiency for the first time. Patient concerns: An 8y7m-old Chinese boy presented with half a day of right sided abdominal pain, fever, nausea, and vomiting. Diagnoses: He received a computed tomography (CT) scan which revealed an enlarged appendix, thickened wall and appendiceal fecalith, and had received a conservative anti-bacterial treatment for his acute appendicitis but failed. He was diagnosed with hemophilia A and coagulation factor VII deficiency. Interventions: Two-incision laparoscopic appendectomy was made in success with a careful management of perioperative period. We monitored the clotting factor FVIII level and gave him a replacement therapy. Outcomes: The patient had an uneventful recovery. Lessons: It is important to exclude intraabdominal or retroperitoneal hemorrhage in patients suffering from hemophilia and acute abdominal pain. Pre-operative evaluation of validity of the FVIII replacement therapy is another effective strategy to assess the safety and feasibility of applying an operation procedure. The two-incision laparoscopic appendectomy is an effective treatment for this kind of patients for its minimal trauma and fast recovery characteristics. Our report shows that laparoscopic appendectomy is feasible in a child suffering from hemophilia after adequate blood clotting factor replacement treatment. PMID:29019885

  19. Atherosclerotic Heart Disease: Prevalence and Risk Factors in Hospitalized Men with Hemophilia A

    PubMed Central

    Ragni, Margaret V.; Moore, Charity G.

    2011-01-01

    Summary Background Atherosclerotic heart disease (ASHD) is a common cause of morbidity and mortality in Western society. Few studies have determined prevalence and predictors of ASHD in hemophilia (HA), a population whose survival is improving with safer blood products and effective treatments for AIDS and hepatitis C. Objectives The purpose of this study was to determine prevalence and factors associated with ASHD in hemophilia A patients in Pennsylvania. Methods The prevalence of ASHD (myocardial infarction, angina, coronary disease), cardiac catheterization, coronary angiography, co-morbidities, and in-hospital mortality were assessed on statewide ASHD discharge data, 2001–2006, from the Pennsylvania Health Care Cost Containment Council (PHC4). Results The prevalence of hemophilia ASHD admissions fluctuated between 6.5% and 10.5% for 2001 to 2006, p=0.62. Compared to HA without ASHD, HA with ASHD were older and more likely to be hypertensive, hyperlipidemic, and diabetic, all p<0.0001, with greater severity of illness, p=0.013. By contrast, HA and non-HA with ASHD had similar rates of hypertension, diabetes, and ICD-9 specified ischemic heart disease, including acute myocardial infarction (MI), p=0.39, old MI, p=0.47, and angina, p=0.63. Rates of catheterization and angiography, p=0.06 and p=0.07, were marginally lower, but primary circulatory system admitting diagnoses, p=0.29, were similar between HA and non-HA ASHD groups, as was length of stay, p=0.14, severity of illness, p=0.64, and in-hospital deaths, p=0.75. Conclusions Hemophilia patients with ASHD have similar cardiovascular risk factors, admitting diagnoses, severity of illness, and in-hospital mortality as the general population. These findings suggest cardiovascular prevention measures should be promoted in hemophilia. PMID:21371197

  20. Major and Minor Classifications for Surgery in People With Hemophilia: A Literature Review.

    PubMed

    Solimeno, Luigi Piero; Escobar, Miguel A; Krassova, Snejana; Seremetis, Stephanie

    2018-05-01

    Agents that control bleeding and the usage of bypassing agents have made surgery an option to consider in people with hemophilia. However, the lack of consistent definitions for major or minor surgery may lead to inconsistencies in patient management. This literature review has evaluated how surgical procedures in people with hemophilia were categorized as major or minor surgery and assessed the consistency across publications. After screening 926 potentially relevant articles, 547 were excluded and 379 full-text articles were reviewed. Ninety-five articles categorized major or minor surgical procedures; of these, 35 publications categorized three or more major or minor surgical procedures and were included for analysis. Seven (20%) publications provided varying criteria for defining major or minor surgery, five of which defined surgery according to the level of surgical invasiveness. Across all 35 publications, there was considerable variance in the categorization of major and minor surgical procedures and some overlap in surgical nomenclature (eg, type of synovectomy, arthroscopy, and central venous access device insertion/removals). The lack of consistent guidance when referring to major or minor surgery in people with hemophilia needs to be addressed. Clear and consistent definitions, achieved by consensus and promoted by relevant international hemophilia committees, are desirable, to provide guidance on appropriate treatment, to increase the accuracy of trial data and may confound the interpretation of surgical outcomes.

  1. Effects of recombinant human prothrombin on thrombin generation in plasma from patients with hemophilia A and B.

    PubMed

    Hansson, K M; Gustafsson, D; Skärby, T; Frison, L; Berntorp, E

    2015-07-01

    The present study was carried out to investigate the impact of FII levels, and their increase, on the hemostatic potential in plasma from hemophilia A and B patients with and without inhibitors. Recombinant human factor (F) II (rhFII) was added ex vivo to plasma from 68 patients with hemophilia A and B, with or without inhibitors. The hemostatic potential as measured by thrombin generation (calibrated automated thrombogram [CAT]) was focused on the endogenous thrombin potential (ETP) as it has been shown to correlate with the clinical phenotype of bleeding in hemophilia patients and has also been used to guide bypassing therapy in hemophilia patients with inhibitors before elective surgery. The factor eight inhibitor bypassing agent (FEIBA(®) ) was used as a reference to the clinical situation. The study shows that rhFII concentration-dependently increased ETP by a similar magnitude in hemophilia A and B, both with and without inhibitors. Compared with FEIBA, rhFII showed a shallower concentration-response curve. In both types of hemophilia 100 mg L(-1) of rhFII roughly doubled the ETP. A corresponding response was obtained by 0.5 U mL(-1) of FEIBA. These data support the theory that FII is one of the major components responsible for the efficacy of FEIBA. The data also indicate that rhFII may be useful, alone or in combination with other coagulation factors, in some of the conditions for which FEIBA is used today, although more data are needed to substantiate this. © 2015 International Society on Thrombosis and Haemostasis.

  2. 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.

  3. In vitro evidence of a tissue factor-independent mode of action of recombinant factor VIIa in hemophilia.

    PubMed

    Augustsson, Cecilia; Persson, Egon

    2014-11-13

    Successful competition of activated factor VII (FVIIa) with zymogen factor VII (FVII) for tissue factor (TF) and loading of the platelet surface with FVIIa are plausible driving forces behind the pharmacological effect of recombinant FVIIa (rFVIIa) in hemophilia patients. Thrombin generation measurements in platelet-rich hemophilia A plasma revealed competition for TF, which potentially could reduce the effective (r)FVIIa:TF complex concentration and thereby attenuate factor Xa production. However, (auto)activation of FVII apparently counteracted the negative effect of zymogen binding; a small impact was observed at endogenous concentrations of FVII and FVIIa but was virtually absent at pharmacological amounts of rFVIIa. Moreover, corrections of the propagation phase in hemophilia A required rFVIIa concentrations above the range where a physiological level of FVII was capable to downregulate thrombin generation. These data strongly suggest that rFVIIa acts independently of TF in hemophilia therapy and that FVII displacement by rFVIIa is a negligible mechanistic component. © 2014 by The American Society of Hematology.

  4. Impact of hemophilia B on quality of life in affected men, women, and caregivers-Assessment of patient-reported outcomes in the B-HERO-S study.

    PubMed

    Buckner, Tyler W; Witkop, Michelle; Guelcher, Christine; Sidonio, Robert; Kessler, Craig M; Clark, David B; Owens, Wendy; Frick, Neil; Iyer, Neeraj N; Cooper, David L

    2018-06-01

    Health-related quality of life (HRQoL) is impaired in patients with hemophilia; however, the impact in mild/moderate hemophilia B and affected women is not well characterized. To evaluate factors that affect HRQoL in adults with hemophilia B and caregivers of affected children. US adult patients and caregivers of affected children completed distinct ~1-hour online surveys including patient-reported outcome instruments. In total, 299 adult patients and 150 caregivers participated. Adults with moderate hemophilia reported poorer health status (median EQ-5D-5L index score, 0.63) than those with mild (0.73) or severe (0.74) hemophilia. Women reported greater pain severity than men on the Brief Pain Inventory v2 Short Form (median, 7.00 vs 5.00). Based on the Patient Health Questionnaire, mild or worse depression was observed in >50% of adult respondents, and depression was reported more often in those with moderate and severe hemophilia vs those with mild hemophilia. Most caregivers reported at least mild depression. Pain, functional impairment, and depression/anxiety are present at higher-than-expected levels in individuals with hemophilia B. The large proportion of individuals with mild/moderate hemophilia and women with reduced health status suggests significant unmet needs in this population. © 2018 The Authors. European Journal of Haematology Published by John Wiley & Sons Ltd.

  5. 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

  6. Targeting of Antithrombin in Hemophilia A or B with RNAi Therapy.

    PubMed

    Pasi, K John; Rangarajan, Savita; Georgiev, Pencho; Mant, Tim; Creagh, Michael D; Lissitchkov, Toshko; Bevan, David; Austin, Steve; Hay, Charles R; Hegemann, Inga; Kazmi, Rashid; Chowdary, Pratima; Gercheva-Kyuchukova, Liana; Mamonov, Vasily; Timofeeva, Margarita; Soh, Chang-Heok; Garg, Pushkal; Vaishnaw, Akshay; Akinc, Akin; Sørensen, Benny; Ragni, Margaret V

    2017-08-31

    Current hemophilia treatment involves frequent intravenous infusions of clotting factors, which is associated with variable hemostatic protection, a high treatment burden, and a risk of the development of inhibitory alloantibodies. Fitusiran, an investigational RNA interference (RNAi) therapy that targets antithrombin (encoded by SERPINC1), is in development to address these and other limitations. In this phase 1 dose-escalation study, we enrolled 4 healthy volunteers and 25 participants with moderate or severe hemophilia A or B who did not have inhibitory alloantibodies. Healthy volunteers received a single subcutaneous injection of fitusiran (at a dose of 0.03 mg per kilogram of body weight) or placebo. The participants with hemophilia received three injections of fitusiran administered either once weekly (at a dose of 0.015, 0.045, or 0.075 mg per kilogram) or once monthly (at a dose of 0.225, 0.45, 0.9, or 1.8 mg per kilogram or a fixed dose of 80 mg). The study objectives were to assess the pharmacokinetic and pharmacodynamic characteristics and safety of fitusiran. No thromboembolic events were observed during the study. The most common adverse events were mild injection-site reactions. Plasma levels of fitusiran increased in a dose-dependent manner and showed no accumulation with repeated administration. The monthly regimen induced a dose-dependent mean maximum antithrombin reduction of 70 to 89% from baseline. A reduction in the antithrombin level of more than 75% from baseline resulted in median peak thrombin values at the lower end of the range observed in healthy participants. Once-monthly subcutaneous administration of fitusiran resulted in dose-dependent lowering of the antithrombin level and increased thrombin generation in participants with hemophilia A or B who did not have inhibitory alloantibodies. (Funded by Alnylam Pharmaceuticals; ClinicalTrials.gov number, NCT02035605 .).

  7. 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.

  8. An intronic mutation c.6430-3C>G in the F8 gene causes splicing efficiency and premature termination in hemophilia A.

    PubMed

    Xia, Zunjing; Lin, Jie; Lu, Lingping; Kim, Chol; Yu, Ping; Qi, Ming

    2018-06-01

    : Hemophilia A is a bleeding disorder caused by coagulation factor VIII protein deficiency or dysfunction, which is classified into severe, moderate, and mild according to factor clotting activity. An overwhelming majority of missense and nonsense mutations occur in exons of F8 gene, whereas mutations in introns can also be pathogenic. This study aimed to investigate the effect of an intronic mutation, c.6430-3C>G (IVS22-3C>G), on pre-mRNA splicing of the F8 gene. We applied DNA and cDNA sequencing in a Chinese boy with hemophilia A to search if any pathogenic mutation in the F8 gene. Functional analysis was performed to investigate the effect of an intronic mutation at the transcriptional level. Human Splicing Finder and PyMol were also used to predict its effect. We found the mutation c.6430-3C>G (IVS22-3C>G) in the F8 gene in the affected boy, with his mother being a carrier. cDNA from the mother and pSPL3 splicing assay showed that the mutation IVS22-3C>G results in a two-nucleotide AG inclusion at the 3' end of intron 22 and leads to a truncated coagulation factor VIII protein, with partial loss of the C1 domain and complete loss of the C2 domain. The in-silico tool predicted that the mutation induces altered pre-mRNA splicing by using a cryptic acceptor site in intron 22. The IVS22-3C>G mutation was confirmed to affect pre-mRNA splicing and produce a truncated protein, which reduces the stability of binding between the F8 protein and von Willebrand factor carrier protein due to the loss of an interaction domain.

  9. Moderate-intensity exercise improves the thromboelastography coagulation index in children with severe hemophilia A.

    PubMed

    Li, Kui-Xing; Xiao, Juan; Zhao, Yong-Qiang; Shou, Wei-Ling; Chen, Meng; Li, Zhuo; Poon, Man-Chiu; Han, Hui-Jun

    2016-10-01

    This pilot study explored the effect of moderate-intensity exercise on factor VIII (FVIII) activity and global hemostatic status of the children with severe hemophilia A. Eleven children aged 6 to 15 years with severe hemophilia A participated in a moderate-intensity exercise test by using Recumbent Cross Trainer (NuStep, T5XR) for at least 10 min after reaching the target heart rate or until volitional exhaustion within a safety framework. Blood samples were collected pre and postexercise for plasma FVIII: C and thromboelastography (TEG) parameters and coagulation index. The average duration of exercise was 11.8 min (10-13 min). There was no report on bleeding events or adverse symptoms requiring termination of the exercise test. The average FVIII activity of the 11 children was 0.66 (0.5-0.8) IU/dl before and 0.93 (0.5-2.3) IU/dl after exercise. The increase of FVIII in the 11 children as a group was not statistically significant (P = 0.052). There were significant changes of TEG measurements, with shortening of R (P < 0.05), and increase in K decrease (P < 0.05), alpha angle (P < 0.05), maximum amplitude (P < 0.05), and coagulation index (P < 0.01). Among the 11 children, the relative coagulation index increase after exercise was greater than 50% in seven (63.6%), less than 20% in three (27.3%), and less than 10% in one (9.1%). TEG analysis showed that the global hemostatic function for the children with severe hemophilia A can be enhanced after moderate-intensity exercise.

  10. Risk factors for inhibitor development in severe hemophilia a.

    PubMed

    Garagiola, Isabella; Palla, Roberta; Peyvandi, Flora

    2018-05-25

    Although significant advances in hemophilia treatment have improved patient outcomes and quality of life, one of the greatest complications in severe hemophilia A is the development of anti-Factor VIII (FVIII) antibodies that inhibit FVIII activity in almost 30% of previously untreated patients (PUPs). Inhibitors make very difficult the management of patients and increase their morbidity and mortality reducing drastically their quality of life. Numerous studies have investigated the mechanisms leading to the development of FVIII inhibitors. However, the etiology of their onset is complex and not yet fully understood. Inhibitors develop from a multicausal immune response involving both genetic (unmodifiable) and environmental (modifiable) factors. F8 gene mutations are the most important genetic risk factor, with null mutations being associated with the highest risk of inhibitor development. Immune response genes (e.g. the human leukocyte antigen complex) and proteins (e.g. cytokines) were studied without any strong confirmation of their role in modulating of inhibitor development. Type of FVIII product is the most important modifiable risk factor. The plasma-derived products containing von Willebrand factor were recently suggested to determine a lower incidence of inhibitor development than recombinant products in PUPs, in the first 50 exposure days (EDs). Other environmental factors including, age at first treatment, treatment intensity and the danger signal effect (surgery, severe bleeds, vaccinations and infections) has also been postulated as an explanation for environment-related inhibitor risk. This review reports the current knowledge on genetic and environmental risk factors on inhibitor development in patients with severe hemophilia A. Copyright © 2018 Elsevier Ltd. All rights reserved.

  11. 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

  12. Validation of the VERITAS-Pro treatment adherence scale in a Spanish sample population with hemophilia.

    PubMed

    Cuesta-Barriuso, Rubén; Torres-Ortuño, Ana; Galindo-Piñana, Pilar; Nieto-Munuera, Joaquín; Duncan, Natalie; López-Pina, José Antonio

    2017-01-01

    We aimed to conduct a validation in Spanish of the Validated Hemophilia Regimen Treatment Adherence Scale - Prophylaxis (VERITAS-Pro) questionnaire for use in patients with hemophilia under prophylactic treatment. The VERITAS-Pro scale was adapted through a process of back translation from English to Spanish. A bilingual native Spanish translator translated the scale from English to Spanish. Subsequently, a bilingual native English translator translated the scale from Spanish to English. The disagreements were resolved by agreement between the research team and translators. Seventy-three patients with hemophilia, aged 13-62 years, were enrolled in the study. The scale was applied twice (2 months apart) to evaluate the test-retest reliability. Internal consistency reliability was lower on the Spanish VERITAS-Pro than on the English version. Test-retest reliability was high, ranging from 0.83 to 0.92. No significant differences ( P >0.05) were found between test and retest scores in subscales of VERITAS-Pro. In general, Spanish patients showed higher rates of nonadherence than American patients in all subscales. The Spanish version of the VERITAS-Pro has high levels of consistency and empirical validity. This scale can be administered to assess the degree of adherence of prophylactic treatment in patients with hemophilia.

  13. Leopold: the "bleeder prince" and public knowledge about hemophilia in Victorian Britain.

    PubMed

    Rushton, Alan R

    2012-07-01

    Hemophilia is a rare bleeding disorder inherited by males born of unaffected female carriers of the trait. British physicians became knowledgeable about this hereditary disease early in the nineteenth century as they investigated families transmitting the character through several generations. Prince Leopold (b. 1853), the fourth son of Queen Victoria, experienced recurrent bleeding episodes and was diagnosed with hemophilia during childhood. His hemorrhagic attacks were first described in the medical journals during 1868, and subsequently in the London and provincial newspapers. The royal family carefully managed news about health matters, and many newspapers reported widespread public sympathy for the travails of the queen and her children. But the republican press argued that the disaffected working classes resented the hyperbole connecting the health of royal individuals with the political future of the entire nation. Public discussion of hemophilia transformed it from a rare medical phenomenon to a matter of national news. Practicing physicians, the royal family, and the general public all came to understand the clinical features and the hereditary nature of the problem. Members of the royal family subsequently utilized this information to guide the marriages of their own children to prevent the spread of this dreaded bleeding disorder.

  14. In Vivo Gene Therapy of Hemophilia B: Sustained Partial Correction in Factor IX-Deficient Dogs

    NASA Astrophysics Data System (ADS)

    Kay, Mark A.; Rothenberg, Steven; Landen, Charles N.; Bellinger, Dwight A.; Leland, Frances; Toman, Carol; Finegold, Milton; Thompson, Arthur R.; Read, M. S.; Brinkhous, Kenneth M.; Woo, Savio L. C.

    1993-10-01

    The liver represents a model organ for gene therapy. A method has been developed for hepatic gene transfer in vivo by the direct infusion of recombinant retroviral vectors into the portal vasculature, which results in the persistent expression of exogenous genes. To determine if these technologies are applicable for the treatment of hemophilia B patients, preclinical efficacy studies were done in a hemophilia B dog model. When the canine factor IX complementary DNA was transduced directly into the hepatocytes of affected dogs in vivo, the animals constitutively expressed low levels of canine factor IX for more than 5 months. Persistent expression of the clotting. factor resulted in reductions of whole blood clotting and partial thromboplastin times of the treated animals. Thus, long-term treatment of hemophilia B patients may be feasible by direct hepatic gene therapy in vivo.

  15. Design and characterization of an APC-specific serpin for the treatment of hemophilia

    PubMed Central

    Polderdijk, Stéphanie G. I.; Adams, Ty E.; Ivanciu, Lacramioara; Camire, Rodney M.; Baglin, Trevor P.

    2017-01-01

    Hemophilia is a bleeding disorder caused by deficiency in factors VIII or IX, the two components of the intrinsic Xase complex. Treatment with replacement factor can lead to the development of inhibitory antibodies, requiring the use of bypassing agents such as factor VIIa and factor concentrates. An alternative approach to bypass the Xase complex is to inhibit endogenous anticoagulant activities. Activated protein C (APC) breaks down the complex that produces thrombin by proteolytically inactivating factor Va. Defects in this mechanism (eg, factor V Leiden) are associated with thrombosis but result in less severe bleeding when co-inherited with hemophilia. Selective inhibition of APC might therefore be effective for the treatment of hemophilia. The endogenous inhibitors of APC are members of the serpin family: protein C inhibitor (PCI) and α1-antitrypsin (α1AT); however, both exhibit poor reactivity and selectivity for APC. We mutated residues in and around the scissile P1-P1′ bond in PCI and α1AT, resulting in serpins with the desired specificity profile. The lead candidate was shown to promote thrombin generation in vitro and to restore fibrin and platelet deposition in an intravital laser injury model in hemophilia B mice. The power of targeting APC was further demonstrated by the complete normalization of bleeding after a severe tail clip injury in these mice. These results demonstrate that the protein C anticoagulant system can be successfully targeted by engineered serpins and that administration of such agents is effective at restoring hemostasis in vivo. PMID:27789479

  16. An innovative outcome-based care and procurement model of hemophilia management.

    PubMed

    Gringeri, Alessandro; Doralt, Jennifer; Valentino, Leonard A; Crea, Roberto; Reininger, Armin J

    2016-06-01

    Hemophilia is a rare bleeding disorder associated with spontaneous and post-traumatic bleeding. Each hemophilia patient requires a personalized approach to episodic or prophylactic treatment, but self-management can be challenging for patients, and avoidable bleeding may occur. Patient-tailored care may provide more effective prevention of bleeding, which in turn, may decrease the likelihood of arthropathy and associated chronic pain, missed time from school or work, and progressive loss of mobility. A strategy is presented here aiming to reduce or eliminate bleeding altogether through a holistic approach based on individual patient characteristics. In an environment of budget constraints, this approach would link procurement to patient outcome, adding incentives for all stakeholders to strive for optimal care and, ultimately, a bleed-free world.

  17. Declining trends in invasive orthopedic interventions for people with hemophilia enrolled in the Universal Data Collection program (2000-2010).

    PubMed

    Tobase, P; Lane, H; Siddiqi, A-E-A; Ingram-Rich, R; Ward, R S

    2016-07-01

    Recurrent joint hemarthroses due to hemophilia (Factor VIII and Factor IX deficiency) often lead to invasive orthopedic interventions to decrease frequency of bleeding and/or to alleviate pain associated with end-stage hemophilic arthropathy. Identify trends in invasive orthopedic interventions among people with hemophilia who were enrolled in the Universal Data Collection (UDC) program during the period 2000-2010. Data were collected from 130 hemophilia treatment centers in the United States annually during the period 2000-2010, in collaboration with the Centers for Disease Control and Prevention (CDC). The number of visits in which an invasive orthopedic intervention was reported was expressed as a proportion of the total visits in each year of the program. Invasive orthopedic interventions consisted of arthroplasty, arthrodesis, and synovectomy. Joints included in this study were the shoulder, elbow, hip, knee, and ankle. A 5.6% decrease in all invasive orthopedic interventions in all joints of people with hemophilia enrolled in the UDC program over the 11-year study period was observed. These data reflect a declining trend in invasive orthopedic interventions in people with hemophilia. Further research is needed to understand the characteristics that may influence invasive orthopedic interventions. © 2016 John Wiley & Sons Ltd.

  18. Demographic and clinical data in acquired hemophilia A: results from the European Acquired Haemophilia Registry (EACH2).

    PubMed

    Knoebl, P; Marco, P; Baudo, F; Collins, P; Huth-Kühne, A; Nemes, L; Pellegrini, F; Tengborn, L; Lévesque, H

    2012-04-01

    Acquired hemophilia A (AHA) is a rare autoimmune disease caused by autoantibodies against coagulation factor VIII and characterized by spontaneous hemorrhage in patients with no previous family or personal history of bleeding. Although data on several AHA cohorts have been collected, limited information is available on the optimal management of AHA. The European Acquired Hemophilia Registry (EACH2) was established to generate a prospective, large-scale, pan-European database on demographics, diagnosis, underlying disorders, bleeding characteristics, treatment and outcome of AHA patients. Five hundred and one (266 male, 235 female) patients from 117 centers and 13 European countries were included in the registry between 2003 and 2008. In 467 cases, hemostasis investigations and AHA diagnosis were triggered by a bleeding event. At diagnosis, patients were a median of 73.9 years. AHA was idiopathic in 51.9%; malignancy or autoimmune diseases were associated with 11.8% and 11.6% of cases. Fifty-seven per cent of the non-pregnancy-related cases were male. Four hundred and seventy-four bleeding episodes were reported at presentation, and hemostatic therapy initiated in 70.5% of patients. Delayed diagnosis significantly impacted treatment initiation in 33.5%. Four hundred and seventy-seven patients underwent immunosuppression, and 72.6% achieved complete remission. Representing the largest collection of consecutive AHA cases to date, EACH2 facilitates the analysis of a variety of open questions in AHA. © 2012 International Society on Thrombosis and Haemostasis.

  19. Improving the management of chronic diseases using web-based technologies: an application in hemophilia care.

    PubMed

    Teixeira, Leonor; Saavedra, Vasco; Ferreira, Carlos; Sousa Santos, Beatriz

    2010-01-01

    Modern methods of information and communication that use web technologies provide an opportunity to facilitate closer communication between patients and healthcare providers, allowing a joint management of chronic diseases. This paper describes a web-based technological solution to support the management of inherited bleeding disorders integrating, diffusing and archiving large sets of data relating to the clinical practice of hemophilia care, more specifically the clinical practice at the Hematology Service of Coimbra Hospital Center (a Hemophilia Treatment Center located in Portugal).

  20. Delays in maturation among adolescents with hemophilia and a history of inhibitors

    PubMed Central

    Lynn, Henry S.; Lail, Alice E.; Hoots, W. Keith; Berntorp, Erik; Gomperts, Edward D.

    2007-01-01

    Inhibitory antibodies to factors VIII or IX have the potential to affect a broad range of outcomes among people with hemophilia; however, their possible effect on growth and maturation has not been explored. We evaluated skeletal maturation (bone age), pubertal progression, serum testosterone levels, height velocity, and stature in the multicenter Hemophilia Growth and Development Study. A total of 333 children and adolescents (mean age, 12.4 years) were enrolled from 1989 to 1990 and followed for 7 years. Of these, 18% (n = 60) had a history of inhibitors. Bone age among HIV− adolescents with a history of inhibitors lagged 9 or more months behind those without inhibitors at every age from 12 to 15 years. Those with a history of inhibitors were older at every Tanner stage transition, attained a lower maximum growth velocity, and their serum testosterone levels were significantly lower compared with those without inhibitors. Delays were greater among HIV+ patients with a history of inhibitors compared with those without inhibitors; however, the differences were generally small and not statistically significant. The results of this investigation underscore the importance of monitoring the growth and maturation of children and adolescents with hemophilia, particularly those with inhibitors. PMID:17715388

  1. Inhibitor Risk Stratification and Individualized Treatment in Patients With Nonsevere Hemophilia A: A Single-Institution Practice Audit.

    PubMed

    Sun, Haowei Linda; Chan, Stella; Yenson, Paul; Jackson, Shannon

    2018-03-01

    Inhibitor risk in nonsevere hemophilia A increases with cumulative factor VIII (FVIII) exposure days and high-risk mutations. A standardized approach to minimize inhibitor risk is warranted. Following establishment of a systematic approach to reduce inhibitor risk in nonsevere hemophilia, we evaluated the uptake of these strategies into clinical practice. All adult males with nonsevere hemophilia A followed by British Columbia Adult Hemophilia Program from 2004 to 2016 were included in this retrospective audit. Quality-of-care indicators on inhibitor prevention were examined. Of 108 patients, 18 patients had high-risk FVIII mutations for inhibitor development. Rates of FVIII genotyping and 1-deamino-8-d-arginine-vasopressin (DDAVP) testing in mild patients without contraindications were both over 90%, although DDAVP was used for surgical prophylaxis in only 70% of procedures. Inhibitor testing and clinic visits occurred at a median interval of 22 months. Over 80% of patients with high-risk mutations had documentation and education on their inhibitor risk. Our practice audit demonstrated a high level of recognition and patient education of individual inhibitor risk. Impact of our standardized approach on the incidence of inhibitor development is yet to be determined.

  2. Longitudinal changes in health-related quality of life for chronic diseases: an example in hemophilia A.

    PubMed

    Poon, Jiat-Ling; Doctor, Jason N; Nichol, Michael B

    2014-08-01

    Patients with well-managed rare chronic diseases such as hemophilia maintain a stable health state and health-related quality of life (HrQoL) that may be affected by acute events. Longitudinal HrQoL assessments analyzed using multivariate multilevel (MVML) modelling can determine the impact of such events on individuals (within-person effect) and identify factors influencing within-population differences (between-person effect). To demonstrate the application of MVML modelling in a longitudinal study of HrQoL in hemophilia A. Using data on 136 adults and 125 children from a two-year observational cohort study of burden of illness in US hemophilia A patients, MVML modelling determined the effect of time-invariant (sociodemographic and clinical characteristics) and time-varying factors (bleeding frequency, emergency room visits, and missed work/school days) on within-person and between-person HrQoL changes. HrQoL was assessed using the SF-12 health survey (adults) and PedsQL inventory (children) at baseline, then every 6 months. In children, within-person (p < 0.0001) and between-person (p < 0.0001) psychosocial functioning was reduced by each additional bleed and missed day (within-person: p = 0.0089; between-person: p = 0.0060). Within-person physical functioning was reduced by each additional bleed (p < 0.0001), emergency room (ER) visit (p = 0.0284), and missed day (p = 0.0473). Between-persons, additional missed days (p < 0.0001) significantly decreased physical functioning. In adults, each additional missed day reduced SF-12 Health Survey mental (p = 0.0025) and physical (p = 0.0093) component summary scores. Each additional bleed also decreased physical component summary (PCS) significantly (p = 0.0093). This study demonstrated the applicability of MVML modelling in identifying time-invariant and time-varying factors influencing HrQoL in a rare chronic disease population. Small but significant within-person and

  3. CANINE HEMOPHILIA

    PubMed Central

    Graham, John B.; Buckwalter, Joseph A.; Hartley, L. J.; Brinkhous, Kenneth M.

    1949-01-01

    A study was made of the clotting defect and the course of the malady in a group of male dogs with an inherited, sex-linked bleeding disease. The clotting defect is characterized by a prolonged clotting time and a delayed prothrombin utilization, and is corrected by the addition either of thromboplastin or of normal plasma. A plasma protein fraction, fraction I, also corrects the defect. The defect appears to be due to a deficiency of a plasma factor, which normally, in the presence of platelets, makes thromboplastin available in shed blood. The clotting anomaly appears to be identical with that found in human hemophilia. The hemostatic defect is characterized by repeated hemorrhages, usually without obvious relationship to trauma. Hemarthroses occur frequently and may result in permanent joint deformity. The animals usually die early in life from massive hemorrhage. Transfusions with normal blood or plasma correct the clotting defect and readily control the hemorrhagic phenomena. By the use of transfusions, these dogs have been reared to maturity. PMID:18136192

  4. Characterization of a genetically engineered mouse model of hemophilia A with complete deletion of the F8 gene.

    PubMed

    Chao, B N; Baldwin, W H; Healey, J F; Parker, E T; Shafer-Weaver, K; Cox, C; Jiang, P; Kanellopoulou, C; Lollar, P; Meeks, S L; Lenardo, M J

    2016-02-01

    ESSENTIALS: Anti-factor VIII (FVIII) inhibitory antibody formation is a severe complication in hemophilia A therapy. We genetically engineered and characterized a mouse model with complete deletion of the F8 coding region. F8(TKO) mice exhibit severe hemophilia, express no detectable F8 mRNA, and produce FVIII inhibitors. The defined background and lack of FVIII in F8(TKO) mice will aid in studying FVIII inhibitor formation. The most important complication in hemophilia A treatment is the development of inhibitory anti-Factor VIII (FVIII) antibodies in patients after FVIII therapy. Patients with severe hemophilia who express no endogenous FVIII (i.e. cross-reacting material, CRM) have the greatest incidence of inhibitor formation. However, current mouse models of severe hemophilia A produce low levels of truncated FVIII. The lack of a corresponding mouse model hampers the study of inhibitor formation in the complete absence of FVIII protein. We aimed to generate and characterize a novel mouse model of severe hemophilia A (designated the F8(TKO) strain) lacking the complete coding sequence of F8 and any FVIII CRM. Mice were created on a C57BL/6 background using Cre-Lox recombination and characterized using in vivo bleeding assays, measurement of FVIII activity by coagulation and chromogenic assays, and anti-FVIII antibody production using ELISA. All F8 exonic coding regions were deleted from the genome and no F8 mRNA was detected in F8(TKO) mice. The bleeding phenotype of F8(TKO) mice was comparable to E16 mice by measurements of factor activity and tail snip assay. Similar levels of anti-FVIII antibody titers after recombinant FVIII injections were observed between F8(TKO) and E16 mice. We describe a new C57BL/6 mouse model for severe hemophilia A patients lacking CRM. These mice can be directly bred to the many C57BL/6 strains of genetically engineered mice, which is valuable for studying the impact of a wide variety of genes on FVIII inhibitor formation on a

  5. The CDC Hemophilia A Mutation Project (CHAMP) Mutation List: a New Online Resource

    PubMed Central

    Payne, Amanda B.; Miller, Connie H.; Kelly, Fiona M.; Soucie, J. Michael; Hooper, W. Craig

    2015-01-01

    Genotyping efforts in hemophilia A (HA) populations in many countries have identified large numbers of unique mutations in the Factor VIII gene (F8). To assist HA researchers conducting genotyping analyses, we have developed a listing of F8 mutations including those listed in existing locus-specific databases as well as those identified in patient populations and reported in the literature. Each mutation was reviewed and uniquely identified using Human Genome Variation Society (HGVS) nomenclature standards for coding DNA and predicted protein changes as well as traditional nomenclature based on the mature, processed protein. Listings also include the associated hemophilia severity classified by International Society of Thrombosis and Haemostasis (ISTH) criteria, associations of the mutations with inhibitors, and reference information. The mutation list currently contains 2,537 unique mutations known to cause HA. HA severity caused by the mutation is available for 2,022 mutations (80%) and information on inhibitors is available for 1,816 mutations (72%). The CDC Hemophilia A Mutation Project (CHAMP) Mutation List is available at http://www.cdc.gov/hemophiliamutations for download and search and will be updated quarterly based on periodic literature reviews and submitted reports. PMID:23280990

  6. 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

  7. An extra X does not prevent acquired hemophilia - Pregnancy-associated acquired hemophilia A.

    PubMed

    Barg, Assaf A; Livnat, Tami; Kenet, Gili

    2017-03-01

    Acquired hemophilia A (AHA) is a severe bleeding disorder caused by autoantibodies against clotting factor VIII (FVIII). With an estimated annual incidence of 1.3 to 1.5 per million, AHA is a rare disease. An extremely rare form of AHA has been described among women in the peripartum period, and may present with peripartum hemorrhage. Notably, although hemorrhagic symptoms commonly present 1-4 months around delivery, they may occur up to 1 year after parturition. When caring for a mother with AHA it is important to note that Factor VIII inhibitor may be transferred via the placenta from the mother to the fetus. Hence the newborn may also be affected. It is important to increase the awareness of Gynecologists for clinical symptoms and laboratory signs of AHA in order to avoid delayed diagnosis. Treatment may involve use of bypass agents to control hemorrhage, despite the risk of thrombosis, while immunomodulation (with increasing role for Rituximab) may be required to eradicate the inhibiting antibodies. Our review will evaluate the epidemiology, diagnosis, clinical course and treatment of peripartum AHA, focusing upon mother and infant care. © 2017 Elsevier Ltd. All rights reserved.

  8. Declining trends in invasive orthopedic interventions for people with hemophilia enrolled in the Universal Data Collection program (2000–2010)

    PubMed Central

    TOBASE, P.; LANE, H.; SIDDIQI, A.-E-A.; INGRAM-RICH, R.; WARD, R. S.

    2016-01-01

    Introduction Recurrent joint hemarthroses due to hemophilia (Factor VIII and Factor IX deficiency) often lead to invasive orthopedic interventions to decrease frequency of bleeding and/or to alleviate pain associated with end-stage hemophilic arthropathy. Aim Identify trends in invasive orthopedic interventions among people with hemophilia who were enrolled in the Universal Data Collection (UDC) program during the period 2000–2010. Methods Data were collected from 130 hemophilia treatment centers in the United States annually during the period 2000–2010, in collaboration with the Centers for Disease Control and Prevention (CDC). The number of visits in which an invasive orthopedic intervention was reported was expressed as a proportion of the total visits in each year of the program. Invasive orthopedic interventions consisted of arthroplasty, arthrodesis, and synovectomy. Joints included in this study were the shoulder, elbow, hip, knee, and ankle. Results A 5.6% decrease in all invasive orthopedic interventions in all joints of people with hemophilia enrolled in the UDC program over the 11-year study period was observed. Conclusions These data reflect a declining trend in invasive orthopedic interventions in people with hemophilia. Further research is needed to understand the characteristics that may influence invasive orthopedic interventions. PMID:27030396

  9. Spontaneous omental bleeding in a 20-year old patient with hemophilia A. A rare cause for emergency laparotomy.

    PubMed

    Aumann, V; Chiapponi, C; Meyer, F; Wybranski, C; Bruns, C J; Jannasch, O

    2016-11-08

    Spontaneous intraabdominal hemorrhage is a very rare event even in patients with bleeding disorders like hemophilia. Nevertheless this rare case must be considered in patients with coagulopathies presenting with abdominal pain. Prompt radiologic imaging and surgical consultation are of highest priority. Here we report on a 20-year-old patient with moderate hemophilia A, who underwent emergency laparotomy for a spontaneous idiopathic bleeding of the omentum majus. There are few cases in the literature on this sort of event in patients with hemophilia, who mostly suffer from spontaneous joint bleedings. These patients require an intensive, interdisciplinary perioperative care, involving haematologists, surgeons, radiologists and anesthesists. Finally we discuss, whether an optimized, individually adapted treatment with coagulation factors might possibly have prevented this bleeding event in this patient.

  10. Using the Hemophilia Joint Health Score for assessment of children: Reliability of the Spanish version.

    PubMed

    R, Cuesta-Barriuso; A, Torres-Ortuño; S, Pérez-Alenda; J, Carrasco Juan; F, Querol; J, Nieto-Munuera; Ja, López-Pina

    2018-02-27

    Numerous measuring instruments for the evaluation of hemophilic arthropathy have been developed. One of the most used systems is the Hemophilia Joint Health Score (HJHS) given its sensitivity to clinical changes appearing in the joints because of recurrent hemarthrosis. Assessing the interrater reliability, using the Spanish version of the HJHS (version 2.1) in children with hemophilia. Reliability study to assess the interrater reliability of the Spanish version of HJHS. A sample of 36 children aged 7-13 years diagnosed with hemophilia A or B was used. Two physiotherapists performed physical assessments with the Spanish version of the HJHS. Descriptive statistics (range, mean, standard deviation) and the analysis of interrater reliability were calculated. The interrater reliability was heterogeneous since the Kappa coefficient range (ĸ), although significant (p < 0.001), ranged 0.31-1.00 in the variables of HJHS (swelling, duration of swelling, muscle atrophy, crepitus on motion, flexion loss, extension loss, joint pain, strength, and global gait). In assessing the bias of observers with the Bland and Altman method, the observer 1 scored 0.41 (CI [-0.67, 1.49]) units above observer 2, and the difference between the two was significant (t(36) = 4.48), p < 0.001). The interrater reliability of the Spanish population version of the HJHS is high. This scale should be used generically in evaluating musculoskeletal pediatric patients with hemophilia.

  11. Problems of Hemophilia and the Role of the Rehabilitation Counselor.

    ERIC Educational Resources Information Center

    Carrai, Edward B.; Handford, H. Allen

    1983-01-01

    Because of the multiple problems associated with hemophilia, optimal treatment is usually provided in a comprehensive care setting by a team of medical and nonmedical professionals. The rehabilitation counselor contributes expertise to that of other team members in development and implementation of an individual rehabilitation plan for…

  12. [A Jehovah's Witness child with hemophilia B and factor IX inhibitors undergoing scoliosis surgery].

    PubMed

    Chau, Anthony; Wu, John; Ansermino, Mark; Tredwell, Stephen; Purdy, Robert

    2008-01-01

    To describe the successful perioperative hemostatic management of a Jehovah's Witness patient with hemophilia B and anaphylactic inhibitors to factor IX, undergoing scoliosis surgery. A 14 (1/2)-yr-old boy with severe hemophilia B who had a history of anaphylactic inhibitors to factor IX was scheduled to undergo corrective scoliosis surgery. He was initially started on epoetin alfa and iron supplementation to maximize preoperative red cell mass. Additionally, he was placed on a desensitization protocol of recombinant coagulation factor IX (rFIX) and was then treated with activated recombinant coagulation factor VII (rFVIIa) during the postoperative period. Tranexamic acid was given concomitantly. The intraoperative blood loss was approximately 350 mL. The nadir hemoglobin concentration was 111 g.L(-1) on postoperative days one and two. On postoperative day 11, the patient was stable and discharged home with a hemoglobin of 138 g.L(-1). He did not require blood transfusion and no adverse events were observed. The use of rFIX, rFVIIa, erythropoetin, iron, and tranexamic acid before, during and after scoliosis surgery may be a viable and safe option for hemophilia patients with inhibitors, who refuse blood products.

  13. Successful Phenotype Improvement following Gene Therapy for Severe Hemophilia A in Privately Owned Dogs.

    PubMed

    Callan, Mary Beth; Haskins, Mark E; Wang, Ping; Zhou, Shangzhen; High, Katherine A; Arruda, Valder R

    2016-01-01

    Severe hemophilia A (HA) is an inherited bleeding disorder characterized by <1% of residual factor VIII (FVIII) clotting activity. The disease affects several mammals including dogs, and, like humans, is associated with high morbidity and mortality. In gene therapy using adeno-associated viral (AAV) vectors, the canine model has been one of the best predictors of the therapeutic dose tested in clinical trials for hemophilia B (factor IX deficiency) and other genetic diseases, such as congenital blindness. Here we report our experience with liver gene therapy with AAV-FVIII in two outbred, privately owned dogs with severe HA that resulted in sustained expression of 1-2% of normal FVIII levels and prevented 90% of expected bleeding episodes. A Thr62Met mutation in the F8 gene was identified in one dog. These data recapitulate the improvement of the disease phenotype in research animals, and in humans, with AAV liver gene therapy for hemophilia B. Our experience is a novel example of the benefits of a relevant preclinical canine model to facilitate both translational studies in humans and improved welfare of privately owned dogs.

  14. Successful Phenotype Improvement following Gene Therapy for Severe Hemophilia A in Privately Owned Dogs

    PubMed Central

    Callan, Mary Beth; Haskins, Mark E.; Wang, Ping; Zhou, Shangzhen; High, Katherine A.; Arruda, Valder R.

    2016-01-01

    Severe hemophilia A (HA) is an inherited bleeding disorder characterized by <1% of residual factor VIII (FVIII) clotting activity. The disease affects several mammals including dogs, and, like humans, is associated with high morbidity and mortality. In gene therapy using adeno-associated viral (AAV) vectors, the canine model has been one of the best predictors of the therapeutic dose tested in clinical trials for hemophilia B (factor IX deficiency) and other genetic diseases, such as congenital blindness. Here we report our experience with liver gene therapy with AAV-FVIII in two outbred, privately owned dogs with severe HA that resulted in sustained expression of 1–2% of normal FVIII levels and prevented 90% of expected bleeding episodes. A Thr62Met mutation in the F8 gene was identified in one dog. These data recapitulate the improvement of the disease phenotype in research animals, and in humans, with AAV liver gene therapy for hemophilia B. Our experience is a novel example of the benefits of a relevant preclinical canine model to facilitate both translational studies in humans and improved welfare of privately owned dogs. PMID:27011017

  15. Development of a Web-Accessible Population Pharmacokinetic Service—Hemophilia (WAPPS-Hemo): Study Protocol

    PubMed Central

    Foster, Gary; Navarro-Ruan, Tamara; McEneny-King, Alanna; Edginton, Andrea N; Thabane, Lehana

    2016-01-01

    Background Individual pharmacokinetic assessment is a critical component of tailored prophylaxis for hemophilia patients. Population pharmacokinetics allows using individual sparse data, thus simplifying individual pharmacokinetic studies. Implementing population pharmacokinetics capacity for the hemophilia community is beyond individual reach and requires a system effort. Objective The Web-Accessible Population Pharmacokinetic Service—Hemophilia (WAPPS-Hemo) project aims to assemble a database of patient pharmacokinetic data for all existing factor concentrates, develop and validate population pharmacokinetics models, and integrate these models within a Web-based calculator for individualized pharmacokinetic estimation in patients at participating treatment centers. Methods Individual pharmacokinetic studies on factor VIII and IX concentrates will be sourced from pharmaceutical companies and independent investigators. All factor concentrate manufacturers, hemophilia treatment centers (HTCs), and independent investigators (identified via a systematic review of the literature) having on file pharmacokinetic data and willing to contribute full or sparse pharmacokinetic data will be eligible for participation. Multicompartmental modeling will be performed using a mixed-model approach for derivation and Bayesian forecasting for estimation of individual sparse data. NONMEM (ICON Development Solutions) will be used as modeling software. Results The WAPPS-Hemo research network has been launched and is currently joined by 30 HTCs from across the world. We have gathered dense individual pharmacokinetic data on 878 subjects, including several replicates, on 21 different molecules from 17 different sources. We have collected sparse individual pharmacokinetic data on 289 subjects from the participating centers through the testing phase of the WAPPS-Hemo Web interface. We have developed prototypal population pharmacokinetics models for 11 molecules. The WAPPS-Hemo website

  16. 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

  17. Transient blockade of the inducible costimulator pathway generates long-term tolerance to factor VIII after nonviral gene transfer into hemophilia A mice.

    PubMed

    Peng, Baowei; Ye, Peiqing; Blazar, Bruce R; Freeman, Gordon J; Rawlings, David J; Ochs, Hans D; Miao, Carol H

    2008-09-01

    Formation of inhibitory antibodies is a common problem encountered in clinical treatment for hemophilia. Human factor VIII (hFVIII) plasmid gene therapy in hemophilia A mice also leads to strong humoral responses. We demonstrate that short-term therapy with an anti-ICOS monoclonal antibody to transiently block the inducible costimulator/inducible costimulator ligand (ICOS/ICOSL) signaling pathway led to sustained tolerance to hFVIII in hFVIII plasmid-treated hemophilia A mice and allowed persistent, high-level FVIII functional activity (100%-300% of normal). Anti-ICOS treatment resulted in depletion of ICOS(+)CD4(+) T cells and activation of CD25(+)Foxp3(+) Tregs in the peripheral blood, spleen, and lymph nodes. CD4(+) T cells from anti-ICOS-treated mice did not proliferate in response to hFVIII stimulation and produced high levels of regulatory cytokines, including interleukin-10 and transforming growth factor-beta. Moreover, CD4(+)CD25(+) Tregs from tolerized mice adoptively transferred dominant tolerance in syngeneic hFVIII plasmid-treated hemophilia A mice and reduced the production of antibodies against FVIII. Anti-ICOS-treated mice tolerized to hFVIII generated normal primary and secondary antibody responses after immunization with the T-dependent antigen, bacteriophage Phix 174, indicating maintenance of immune competency. Our data indicate that transient anti-ICOS monoclonal antibody treatment represents a novel single-agent immunomodulatory strategy to overcome the immune responses against transgene product after gene therapy.

  18. The important role of von Willebrand factor in platelet-derived FVIII gene therapy for murine hemophilia A in the presence of inhibitory antibodies.

    PubMed

    Shi, Q; Schroeder, J A; Kuether, E L; Montgomery, R R

    2015-07-01

    Our previous studies have demonstrated that targeting FVIII expression to platelets results in FVIII storage together with von Willebrand factor (VWF) in platelet α-granules and that platelet-derived FVIII (2bF8) corrects the murine hemophilia A phenotype even in the presence of high-titer anti-FVIII inhibitory antibodies (inhibitors). To explore how VWF has an impact on platelet gene therapy for hemophilia A with inhibitors. 2bF8 transgenic mice in the FVIII(-/-) background (2bF8(tg+/-) F8(-/-) ) with varying VWF phenotypes were used in this study. Animals were analyzed by VWF ELISA, FVIII activity assay, Bethesda assay and tail clip survival test. Only 18% of 2bF8(tg+/-) F8(-/-) VWF(-/-) animals, in which VWF was deficient, survived the tail clip challenge with inhibitor titers of 3-8000 BU mL(-1) . In contrast, 82% of 2bF8(tg+/-) F8(-/-) VWF(+/+) mice, which had normal VWF levels, survived tail clipping with inhibitor titers of 10-50,000 BU mL(-1) . All 2bF8(tg+/-) F8(-/-) VWF(-/-) mice without inhibitors survived tail clipping and no VWF(-/-) F8(-/-) mice survived this challenge. Because VWF is synthesized by endothelial cells and megakaryocytes and is distributed in both plasma and platelets in peripheral blood, we further investigated the effect of each compartment of VWF on platelet-FVIII gene therapy for hemophilia A with inhibitors. In the presence of inhibitors, 42% of animals survived tail clipping in the group with plasma-VWF and 50% survived in the platelet-VWF group. VWF is essential for platelet gene therapy for hemophilia A with inhibitors. Both platelet-VWF and plasma-VWF are required for optimal platelet-derived FVIII gene therapy for hemophilia A in the presence of inhibitors. © 2015 International Society on Thrombosis and Haemostasis.

  19. Lentivirus-mediated platelet gene therapy of murine hemophilia A with pre-existing anti-FVIII immunity

    PubMed Central

    Kuether, E. L.; Schroeder, J. A.; Fahs, S. A.; Cooley, B. C.; Chen, Y.; Montgomery, R. R.; Wilcox, D. A.; Shi, Q.

    2012-01-01

    Summary Background The development of inhibitory antibodies, referred to as inhibitors, against exogenous FVIII in a significant subset of patients with hemophilia A remains a persistent challenge to the efficacy of protein replacement therapy. Our previous studies using the transgenic approach provided proof-of-principle that platelet-specific expression could be successful for treating hemophilia A in the presence of inhibitory antibodies. Objective To investigate a clinically translatable approach for platelet gene therapy of hemophilia A with pre-existing inhibitors. Methods Platelet-FVIII expression in pre-immunized FVIIInull mice was introduced by transplantation of lentivirus-transduced bone marrow or enriched hematopoietic stem cells. FVIII expression was determined by a chromogenic assay. The transgene copy number per cell was quantitated by real time PCR. Inhibitor titer was measured by Bethesda assay. Phenotypic correction was assessed by the tail clipping assay and an electrolytic-induced venous injury model. Integration sites were analyzed by LAM-PCR. Results Therapeutic levels of platelet-FVIII expression were sustained long-term without evoking an anti-FVIII memory response in the transduced pre-immunized recipients. The tail clip survival test and the electrolytic injury model confirmed that hemostasis was improved in the treated animals. Sequential bone marrow transplants showed sustained platelet-FVIII expression resulting in phenotypic correction in pre-immunized secondary and tertiary recipients. Conclusions Lentivirus-mediated platelet-specific gene transfer improves hemostasis in hemophilic A mice with pre-existing inhibitors, indicating that this approach may be a promising strategy for gene therapy of hemophilia A even in the high-risk setting of pre-existing inhibitory antibodies. PMID:22632092

  20. The Effect of Aquatic Exercise Therapy on Muscle Strength and Joint's Range of Motion in Hemophilia Patients.

    PubMed

    Kargarfard, Mehdi; Dehghadani, Mehdi; Ghias, Reza

    2013-01-01

    This study was to evaluate the effect of a period of aquatic exercise therapy on muscle strength and joints range of motion in hemophilia patients. This was a semiexperimental, pretest, post-test study with a control group. This semi-experimental study comprised twenty men suffering moderate hemophilia were selected by convenience sampling method from patients of a referral hospital. They were randomly assigned to intervention and control groups of equal number. The hemophilia patients who were referred to Sayedo-Shohada Hospital enrolled in this study. Twenty men suffering moderate hemophilia were selected using convenience sampling method and then divided randomly into intervention and control groups (10 patients in each group). Subjects of aquatic exercise therapy group underwent activity in water in three sessions (45-60 minutes) per week for 8 weeks, while the control group was only under follow-up and during this period did not experience any effective physical activity. The patients' muscle strength and joint range of motion were evaluated through standard laboratory tools, using an isokinetic dynamometer (Biodex, Systems III) and a standard goniometer in the beginning and at end of the study. Finally, data was analyzed using analysis of covariance (ANCOVA). The strength of the muscles around the knee joint (to perform extension and flexion movements) increased significantly in the case group while the control group experienced a significant reduction of strength in left leg, but in right leg remarkable change was observed. Range of motion in all joints was improved in the case group, while the control group did not improve significantly. The results showed that aquatic exercise therapy can be a useful method to improve joints' strength and range of motion in hemophilia patients in order to improve their daily functioning and quality of life.

  1. The Effect of Aquatic Exercise Therapy on Muscle Strength and Joint's Range of Motion in Hemophilia Patients

    PubMed Central

    Kargarfard, Mehdi; Dehghadani, Mehdi; Ghias, Reza

    2013-01-01

    Background: This study was to evaluate the effect of a period of aquatic exercise therapy on muscle strength and joints range of motion in hemophilia patients. Methods: This was a semiexperimental, pretest, post-test study with a control group. This semi-experimental study comprised twenty men suffering moderate hemophilia were selected by convenience sampling method from patients of a referral hospital. They were randomly assigned to intervention and control groups of equal number. The hemophilia patients who were referred to Sayedo-Shohada Hospital enrolled in this study. Twenty men suffering moderate hemophilia were selected using convenience sampling method and then divided randomly into intervention and control groups (10 patients in each group). Subjects of aquatic exercise therapy group underwent activity in water in three sessions (45-60 minutes) per week for 8 weeks, while the control group was only under follow-up and during this period did not experience any effective physical activity. The patients’ muscle strength and joint range of motion were evaluated through standard laboratory tools, using an isokinetic dynamometer (Biodex, Systems III) and a standard goniometer in the beginning and at end of the study. Finally, data was analyzed using analysis of covariance (ANCOVA). Results: The strength of the muscles around the knee joint (to perform extension and flexion movements) increased significantly in the case group while the control group experienced a significant reduction of strength in left leg, but in right leg remarkable change was observed. Range of motion in all joints was improved in the case group, while the control group did not improve significantly. Conclusion: The results showed that aquatic exercise therapy can be a useful method to improve joints’ strength and range of motion in hemophilia patients in order to improve their daily functioning and quality of life. PMID:23412736

  2. Targeted genome engineering in human induced pluripotent stem cells from patients with hemophilia B using the CRISPR-Cas9 system.

    PubMed

    Lyu, Cuicui; Shen, Jun; Wang, Rui; Gu, Haihui; Zhang, Jianping; Xue, Feng; Liu, Xiaofan; Liu, Wei; Fu, Rongfeng; Zhang, Liyan; Li, Huiyuan; Zhang, Xiaobing; Cheng, Tao; Yang, Renchi; Zhang, Lei

    2018-04-06

    Replacement therapy for hemophilia remains a lifelong treatment. Only gene therapy can cure hemophilia at a fundamental level. The clustered regularly interspaced short palindromic repeats-CRISPR associated nuclease 9 (CRISPR-Cas9) system is a versatile and convenient genome editing tool which can be applied to gene therapy for hemophilia. A patient's induced pluripotent stem cells (iPSCs) were generated from their peripheral blood mononuclear cells (PBMNCs) using episomal vectors. The AAVS1-Cas9-sgRNA plasmid which targets the AAVS1 locus and the AAVS1-EF1α-F9 cDNA-puromycin donor plasmid were constructed, and they were electroporated into the iPSCs. When insertion of F9 cDNA into the AAVS1 locus was confirmed, whole genome sequencing (WGS) was carried out to detect the off-target issue. The iPSCs were then differentiated into hepatocytes, and human factor IX (hFIX) antigen and activity were measured in the culture supernatant. Finally, the hepatocytes were transplanted into non-obese diabetic/severe combined immunodeficiency disease (NOD/SCID) mice through splenic injection. The patient's iPSCs were generated from PBMNCs. Human full-length F9 cDNA was inserted into the AAVS1 locus of iPSCs of a hemophilia B patient using the CRISPR-Cas9 system. No off-target mutations were detected by WGS. The hepatocytes differentiated from the inserted iPSCs could secrete hFIX stably and had the ability to be transplanted into the NOD/SCID mice in the short term. PBMNCs are good somatic cell choices for generating iPSCs from hemophilia patients. The iPSC technique is a good tool for genetic therapy for human hereditary diseases. CRISPR-Cas9 is versatile, convenient, and safe to be used in iPSCs with low off-target effects. Our research offers new approaches for clinical gene therapy for hemophilia.

  3. Two-incision laparoscopic appendectomy for a severe hemophilia A child patient with coagulation factor VII deficiency: Case report and review of literature.

    PubMed

    He, Jin Peng; Feng, Jie Xiong

    2017-10-01

    The main complication of patients with severe hemophilia is recurrent bleeding events that usually affected musculoskeletal contractures. And replacement therapy methods were continuously improved to minimize adverse impacts brought by those complications. However, only several cases reported about the appendectomy for hemophilia A. We report a case of acute appendicitis treated by two-incision laparoscopy in a boy with hemophilia A and coagulation factor VII deficiency for the first time. An 8y7m-old Chinese boy presented with half a day of right sided abdominal pain, fever, nausea, and vomiting. He received a computed tomography (CT) scan which revealed an enlarged appendix, thickened wall and appendiceal fecalith, and had received a conservative anti-bacterial treatment for his acute appendicitis but failed. He was diagnosed with hemophilia A and coagulation factor VII deficiency. Two-incision laparoscopic appendectomy was made in success with a careful management of perioperative period. We monitored the clotting factor FVIII level and gave him a replacement therapy. The patient had an uneventful recovery. It is important to exclude intraabdominal or retroperitoneal hemorrhage in patients suffering from hemophilia and acute abdominal pain. Pre-operative evaluation of validity of the FVIII replacement therapy is another effective strategy to assess the safety and feasibility of applying an operation procedure. The two-incision laparoscopic appendectomy is an effective treatment for this kind of patients for its minimal trauma and fast recovery characteristics. Our report shows that laparoscopic appendectomy is feasible in a child suffering from hemophilia after adequate blood clotting factor replacement treatment.

  4. Strategies to encourage physical activity in patients with hemophilia to improve quality of life

    PubMed Central

    Goto, Miwa; Takedani, Hideyuki; Yokota, Kazuhiko; Haga, Nobuhiko

    2016-01-01

    Hemophilia is a bleeding disorder caused by a congenital abnormality of blood coagulation. Until the mid-1970s, patients with hemophilia (PWH) were advised to refrain from physical activity (PA) because of a perceived increased risk of bleeding. Since then, PA, which is recognized as being essential for health maintenance, is now recommended by the World Federation of Hemophilia. Moreover, a number of studies reported that PA can improve treatment efficacy and prevent bleeding in PWH. Physical assessment and intervention in PA are currently used in clinical practice. However, the necessity of PA is not emphasized, and many PWH generally have low- to- no PA. Therefore, a behavior change approach to encourage patient motivation is becoming ever more important. In this article, we review articles addressing PA in PWH and discuss strategies to encourage PA through a behavior change approach by focusing on factors relevant to hemophilia, such as benefits and bleeding risk of PA, risk management of bleeding, PA characteristics, and difficulty with exercise adherence. The trust relationship between clinicians and patients, a transtheoretical model of behavior change, and motivation theory as approaches to promote PA are introduced. Finally, we review a case report of the clinical success of a behavior change approach to promote PA. Many PWH find it difficult to continue PA because of aging, fear of bleeding, insufficient recognition of PA benefits, and psychological problems. Therefore, it is essential and important to perform prophylaxis with PWH and to heighten their understanding of the benefits and risks of PA, before initiating the exercise regimen. For those patients who find it difficult to participate in PA, it is necessary to plan individual-based behavior change approach and encourage self-efficacy. PMID:27274330

  5. Successful medical management of a neonate with spontaneous splenic rupture and severe hemophilia A.

    PubMed

    Badawy, Sherif M; Rossoff, Jenna; Yallapragada, Sushmita; Liem, Robert I; Sharathkumar, Anjali A

    2017-03-01

    Splenic rupture in neonates is a rare event, usually occurring in the setting of underlying predisposing conditions. Here, we present the case of a term neonate who presented with worsening anemia in the setting of known hemolytic disease during the newborn period and was later found to have a spontaneous splenic rupture. He was subsequently diagnosed with severe hemophilia A, and was managed medically with recombinant factor VIII replacement therapy without any surgical intervention. This is the first reported case of a neonate who had spontaneous splenic rupture and severe hemophilia A, and underwent successful medical treatment without any surgical intervention. Copyright © 2016 King Faisal Specialist Hospital & Research Centre. Published by Elsevier Ltd. All rights reserved.

  6. Knee and Ankle Arthroplasty in Hemophilia

    PubMed Central

    Solimeno, Luigi Piero; Pasta, Gianluigi

    2017-01-01

    Today, major surgical procedures can be safely performed in hemophilic patients with chronic arthropathy, using available factor concentrates. In this setting, total knee replacement is considered the “gold standard”, while the use of total ankle replacement is still debated. Indeed, the unsatisfactory results obtained with the previous available design of implants did not raise enthusiasm as knee or hip replacement. Recently, the introduction of new implant designs and better reported outcomes have renewed the interest in total ankle replacement in people with hemophilia. In this review, the role of replacement surgery in the treatment of chronic hemophilic arthropathy will be described. PMID:29165342

  7. Safety, efficacy and pharmacokinetics of rVIII-SingleChain in children with severe hemophilia A: results of a multicenter clinical trial.

    PubMed

    Stasyshyn, O; Djambas Khayat, C; Iosava, G; Ong, J; Abdul Karim, F; Fischer, K; Veldman, A; Blackman, N; St Ledger, K; Pabinger, I

    2017-04-01

    Essentials rVIII-SingleChain is a novel recombinant factor VIII with covalently bonded heavy and light chains. Efficacy, safety and pharmacokinetics were studied in pediatric patients with severe hemophilia A. Across all prophylaxis regimens, the median annualized spontaneous bleeding rate was 0.00. rVIII-SingleChain showed excellent hemostatic efficacy and a favorable safety profile. Background rVIII-SingleChain is a novel B-domain truncated recombinant factor VIII (rFVIII) comprised of covalently bonded FVIII heavy and light chains, demonstrating a high binding affinity to von Willebrand factor. Objectives This phase III study investigated the safety, efficacy and pharmacokinetics of rVIII-SingleChain in previously treated pediatric patients < 12 years of age with severe hemophilia A. Patients/Methods Patients could be assigned to prophylaxis or on-demand therapy by the investigator. For patients assigned to prophylaxis, the treatment regimen and dose were based on the bleeding phenotype. For patients receiving on-demand therapy, dosing was guided by World Federation of Hemophilia recommendations. The primary endpoint was treatment success, defined as a rating of 'excellent' or 'good' on the investigator's clinical assessment of hemostatic efficacy for all treated bleeding events. Results The study enrolled 84 patients (0 to < 6 years, n = 35; ≥ 6 to < 12 years, n = 49); 81 were assigned to prophylaxis and three to an on-demand regimen. Patients accumulated a total of 5239 exposure days (EDs), with 65 participants reaching > 50 EDs. In the 347 bleeds treated and evaluated by the investigator, hemostatic efficacy was rated as excellent or good in 96.3%. The median annualized spontaneous bleeding rate was 0.00 (Q1, Q3: 0.00, 2.20), and the median annualized bleeding rate was 3.69 (Q1, Q3: 0.00, 7.20) across all prophylaxis regimens. No participant developed an inhibitor. Conclusions rVIII-SingleChain is a novel rFVIII molecule showing excellent hemostatic

  8. Development of a Web-Accessible Population Pharmacokinetic Service-Hemophilia (WAPPS-Hemo): Study Protocol.

    PubMed

    Iorio, Alfonso; Keepanasseril, Arun; Foster, Gary; Navarro-Ruan, Tamara; McEneny-King, Alanna; Edginton, Andrea N; Thabane, Lehana

    2016-12-15

    Individual pharmacokinetic assessment is a critical component of tailored prophylaxis for hemophilia patients. Population pharmacokinetics allows using individual sparse data, thus simplifying individual pharmacokinetic studies. Implementing population pharmacokinetics capacity for the hemophilia community is beyond individual reach and requires a system effort. The Web-Accessible Population Pharmacokinetic Service-Hemophilia (WAPPS-Hemo) project aims to assemble a database of patient pharmacokinetic data for all existing factor concentrates, develop and validate population pharmacokinetics models, and integrate these models within a Web-based calculator for individualized pharmacokinetic estimation in patients at participating treatment centers. Individual pharmacokinetic studies on factor VIII and IX concentrates will be sourced from pharmaceutical companies and independent investigators. All factor concentrate manufacturers, hemophilia treatment centers (HTCs), and independent investigators (identified via a systematic review of the literature) having on file pharmacokinetic data and willing to contribute full or sparse pharmacokinetic data will be eligible for participation. Multicompartmental modeling will be performed using a mixed-model approach for derivation and Bayesian forecasting for estimation of individual sparse data. NONMEM (ICON Development Solutions) will be used as modeling software. The WAPPS-Hemo research network has been launched and is currently joined by 30 HTCs from across the world. We have gathered dense individual pharmacokinetic data on 878 subjects, including several replicates, on 21 different molecules from 17 different sources. We have collected sparse individual pharmacokinetic data on 289 subjects from the participating centers through the testing phase of the WAPPS-Hemo Web interface. We have developed prototypal population pharmacokinetics models for 11 molecules. The WAPPS-Hemo website (available at www.wapps-hemo.org, version

  9. CRISPR/Cas9-mediated somatic correction of a novel coagulator factor IX gene mutation ameliorates hemophilia in mouse.

    PubMed

    Guan, Yuting; Ma, Yanlin; Li, Qi; Sun, Zhenliang; Ma, Lie; Wu, Lijuan; Wang, Liren; Zeng, Li; Shao, Yanjiao; Chen, Yuting; Ma, Ning; Lu, Wenqing; Hu, Kewen; Han, Honghui; Yu, Yanhong; Huang, Yuanhua; Liu, Mingyao; Li, Dali

    2016-05-01

    The X-linked genetic bleeding disorder caused by deficiency of coagulator factor IX, hemophilia B, is a disease ideally suited for gene therapy with genome editing technology. Here, we identify a family with hemophilia B carrying a novel mutation, Y371D, in the human F9 gene. The CRISPR/Cas9 system was used to generate distinct genetically modified mouse models and confirmed that the novel Y371D mutation resulted in a more severe hemophilia B phenotype than the previously identified Y371S mutation. To develop therapeutic strategies targeting this mutation, we subsequently compared naked DNA constructs versus adenoviral vectors to deliver Cas9 components targeting the F9 Y371D mutation in adult mice. After treatment, hemophilia B mice receiving naked DNA constructs exhibited correction of over 0.56% of F9 alleles in hepatocytes, which was sufficient to restore hemostasis. In contrast, the adenoviral delivery system resulted in a higher corrective efficiency but no therapeutic effects due to severe hepatic toxicity. Our studies suggest that CRISPR/Cas-mediated in situ genome editing could be a feasible therapeutic strategy for human hereditary diseases, although an efficient and clinically relevant delivery system is required for further clinical studies. © 2016 The Authors. Published under the terms of the CC BY 4.0 license.

  10. Rationale for a randomized controlled trial comparing two prophylaxis regimens in adults with severe hemophilia A: the Hemophilia Adult Prophylaxis Trial

    PubMed Central

    Ragni, Margaret V

    2011-01-01

    A major goal of comprehensive hemophilia care is to prevent occurrence of bleeds by prophylaxis or regular preventive factor, one or more times weekly. Although prophylaxis is effective in reducing bleeding and joint damage in children, whether it is necessary to continue into adulthood is not known. The purpose of this article is to describe a Phase III randomized controlled trial to evaluate prophylaxis comparing two dose regimens in adults with severe hemophilia A. I hypothesize that adults with mature cartilage and joints are less susceptible to joint bleeds and joint damage, and that once-weekly recombinant factor VIII prophylaxis, with up to two rescue doses per week, is as effective as thrice-weekly prophylaxis in reducing bleeding frequency, but less costly and more acceptable, with higher quality of life. The ultimate goal of this project is to determine whether once-weekly prophylaxis is any worse than thrice-weekly prophylaxis in reducing joint bleeding frequency, while potentially utilizing less factor, at lower cost, leading to a better quality of life. This is an innovative concept, as it challenges the current paradigm of thrice-weekly prophylaxis in adults, which is based on dosing in children. Furthermore, this trial will assess interdose thrombin generation, a novel tissue factor-based assay of hemostasis, to determine if individualized thrombin generation can predict more individualized prophylaxis dosing, which would be practice changing. PMID:21939418

  11. Pharmacokinetics and pharmacodynamics of SCT800, a new recombinant FVIII, in hemophilia A mice

    PubMed Central

    Gu, Ruo-lan; Liu, Liang; Xie, Liang-zhi; Gai, Wen-lin; Cao, Si-shuo; Meng, Zhi-yun; Gan, Hui; Wu, Zhuo-na; Li, Jian; Zheng, Ying; Zhu, Xiao-xia; Dou, Gui-fang

    2016-01-01

    Aim: SCT800 is a new third-generation recombinant FVIII agent that is undergoing promising preclinical study. This study aimed to investigate the pharmacokinetic and pharmacodynamic profiles of SCT800 in hemophilia A mice. Methods: After hemophilia A mice were intravenously injected with single dose of SCT800 (80, 180, and 280 IU/kg) or the commercially available product Xyntha (280 IU/kg), pharmacokinetics profiles were evaluated based on measuring plasma FVIII: C. For pharmacodynamics study, dose-response curves of SCT800 and Xyntha (1–200 IU/kg) were constructed using a tail bleeding model monitoring both bleeding time and blood loss. Results: Pharmacokinetics profile analysis showed a dose independency of SCT800 ranging from 80 to 280 IU/kg and comparable pharmacokinetic profiles between SCT800 and Xyntha at the doses tested. Pharmacodynamics study revealed comparable ED50 values of SCT800 and Xyntha in the tail bleeding model: 14.78 and 15.81 IU/kg for bleeding time, respectively; 13.50 and 13.58 IU/kg for blood loss, respectively. Moreover, at the doses tested, the accompanying dose-related safety evaluation in the tail bleeding model showed lower hypercoagulable tendency and wider dosage range potential for SCT800 than Xyntha. Conclusion: In hemophilia A mice, SCT800 shows comparable pharmacokinetics and pharmacodynamics to Xyntha at the doses tested, and possibly with better safety properties. PMID:26806305

  12. Perioperative treatment of hemophilia A patients: blood group O patients are at risk of bleeding complications.

    PubMed

    Hazendonk, H C A M; Lock, J; Mathôt, R A A; Meijer, K; Peters, M; Laros-van Gorkom, B A P; van der Meer, F J M; Driessens, M H E; Leebeek, F W G; Fijnvandraat, K; Cnossen, M H

    2016-03-01

    ESSENTIALS: Targeting of factor VIII values is a challenge during perioperative replacement therapy in hemophilia. This study aims to identify the extent and predictors of factor VIII underdosing and overdosing. Blood group O predicts underdosing and is associated with perioperative bleeding. To increase quality of care and cost-effectiveness of treatment, refining of dosing is obligatory. Perioperative administration of factor VIII (FVIII) concentrate in hemophilia A may result in both underdosing and overdosing, leading to respectively a risk of bleeding complications and unnecessary costs. This retrospective observational study aims to identify the extent and predictors of underdosing and overdosing in perioperative hemophilia A patients (FVIII levels < 0.05 IU mL(-1)). One hundred nineteen patients undergoing 198 elective, minor, or major surgical procedures were included (median age 40 years, median body weight 75 kg). Perioperative management was evaluated by quantification of perioperative infusion of FVIII concentrate and achieved FVIII levels. Predictors of underdosing and (excessive) overdosing were analyzed by logistic regression analysis. Excessive overdosing was defined as upper target level plus ≥ 0.20 IU mL(-1). Depending on postoperative day, 7-45% of achieved FVIII levels were under and 33-75% were above predefined target ranges as stated by national guidelines. A potential reduction of FVIII consumption of 44% would have been attained if FVIII levels had been maintained within target ranges. Blood group O and major surgery were predictive of underdosing (odds ratio [OR] 6.3, 95% confidence interval [CI] 2.7-14.9; OR 3.3, 95% CI 1.4-7.9). Blood group O patients had more bleeding complications in comparison to patients with blood group non-O (OR 2.02, 95% CI 1.00-4.09). Patients with blood group non-O were at higher risk of overdosing (OR 1.5, 95% CI 1.1-1.9). Additionally, patients treated with bolus infusions were at higher risk of excessive

  13. Role of CCL3L1-CCR5 Genotypes in the Epidemic Spread of HIV-1 and Evaluation of Vaccine Efficacy

    DTIC Science & Technology

    2008-08-01

    S) 12. DISTRIBUTION/AVAILABILITY STATEMENT Approved for public release; distribution unlimited 13 . SUPPLEMENTARY NOTES 14. ABSTRACT Background...GRG-defined population groups to the overall epidemic varied significantly (0 to 13 %). Consistent with findings shown in Figure 2c, the highest AFs...Multicenter AIDS Cohort Study (MACS), Multicenter Hemophilia Cohort Study (MHCS), San Francisco City Cohort (SFCC). Science 279: 389–393. 13 . Gonzalez E

  14. Understanding adherence to treatment and physical activity in children with hemophilia: The role of psychosocial factors.

    PubMed

    Bérubé, Sarah; Cloutier-Bergeron, Audrey; Amesse, Claudine; Sultan, Serge

    2017-02-01

    The objective of this study was to identify psychosocial factors to explain intentions of children and adolescents with hemophilia to adhere to recommendations for self-care. Twenty-four patients with hemophilia A and B, aged 6-18 years old, and their parents, completed a survey. Measures assessed factors from the theory of planned behavior, physical activity, and medical treatment adherence. The results indicate that past behaviors, attitudes, and subjective norms explained a large proportion of the intention to engage in future nonrecommended physical activity. This study supports the need to investigate motivational factors underlying behaviors in larger scale studies and identifies targets for future interventions.

  15. Assessment of healthcare measures, healthcare resource use, and cost of care among severe hemophilia A patients in Mumbai region of India.

    PubMed

    Jadhav, U; Mukherjee, K

    2017-10-23

    In India, the low public health priority given to rare disorders such as hemophilia hinders their management and optimal care, leading to relatively poor health outcomes. This study aims to profile the multidimensional health status of patients with severe hemophilia A, and its association with the use of healthcare resources and the cost of care in Mumbai region of India. A cross-sectional, single-center study was conducted during January-May 2011, among 160 patients diagnosed with severe hemophilia A in Mumbai region of India. Their health status was documented using the Hemophilia Utilization Group Study's validated instrument of Functional Health Status Measure (FHS) and a single item of Self-care Measure. Of 160 patients, 55% (n = 88) scored on the lower side on the FHS, with an average score of 6.65 ± 2.85. The use of healthcare resources and cost of treatment were considerable for patients with a lower mean rank score on the FHS and a higher mean rank score on the self-care measure. The consumption of clotting factor concentrates (CFCs), number of visits to a health facility and incidence of inpatient episodes were significantly associated with a relatively low score on the FHS. Similarly, a higher cost of treatment, in terms of the cost of CFCs, direct cost, emergency room cost, and indirect cost, were significantly associated with a lower score on the FHS. The health status of patients with severe hemophilia A is compromised and has a significant impact on the use of healthcare resources and the cost of treatment.

  16. Long distance PCR in detection of inversion mutations of F8C gene in hemophilia A patients.

    PubMed

    Poláková, H; Zmetáková, I; Kádasi, L'

    2003-06-01

    In the present paper, the experience with detection of intron 22 inversion of F8C gene in severe hemophilia A patients using a recently described long-distance PCR (LD-PCR) method was reported. To test the sensitivity and the specifity of the LD-PCR, analysis of 46 DNA samples of patients and their family members, previously tested by Southern hybridization, was performed. In addition, 16 DNA samples of severe hemophilia A patients in which causative mutation was unknown, were included in analysis. Four-primers, P, Q, A&B, which are able to differentiate between the affected males with or without the inversion, and in female carriers, were used in LD-PCR. Two primers, P&Q, are located within the F8C gene flanking int22h1. Two further primers, A&B, flank int22h2 and int22h3, extragene homologs of int22h1. Nine combinations of four primers were used to identify the optimal one. Four-primers (P, Q, A&B), three-primers (P,Q & B;P, A & B; A, B & Q;P, Q & A) and two-primers (A & B; P & Q; A & Q; P & B) PCR amplifications were performed in the hemophilia A patients as well as in obligate carriers DNA samples. Successful amplification required introduction of some modifications of the original protocol. The most reproducible and uniform results were obtained using two-primers PCR, performed in four single reactions. Thus, a total of 46 DNA samples, 22 were hemizygous for inversion, 6 without the inversion, 14 carriers and 4 non-carriers of inversion. Perfect correlation between genotypes determined using Southern hybridization and LD-PCR was achieved. The optimalized two-primers LD-PCR protocol was used for analysis of 16 DNA samples of severe hemophilia A patients with unknown mutation. Ten cases of inversions and six cases without them were detected. Thus in additional 10 severe hemophilic patients DNA diagnosis was completed. The most successful and reproducible results were obtained performing four single LD-PCR reactions with combinations of two-primers A & B; P & Q

  17. Vedolizumab Treatment for Ulcerative Colitis in an Elderly Multimorbid Patient with Hemophilia A.

    PubMed

    Schäffler, Holger; Huth, Astrid; Lamprecht, Georg; Anders, Olaf

    2017-01-01

    The treatment of inflammatory bowel diseases (IBD) can be challenging, especially in elderly multimorbid patients. Since incidence and prevalence rates of IBD are rising steadily, treatment of older patients with relevant and also rare comorbidities will be of increasing relevancy for caregivers. Here we report on a 74-year-old multimorbid patient with severe ulcerative colitis (UC) and hemophilia A. Because of the chronic active disease, therapy with a tumor necrosis factor-α inhibitor was started. He suffered from a severe infectious complication (pneumonia) under therapy with infliximab. The therapy was changed to vedolizumab, with which the patient stayed in long-term clinical and endoscopic remission. Because the patient had a non-ST-segment elevation myocardial infarction in April 2016, he received dual platelet inhibitor therapy with aspirin and clopidogrel. Because of consecutive aspirin intolerance, the therapy was changed to clopidogrel monotherapy. Although the UC was treated appropriately with vedolizumab and the patient was in endoscopic mucosal remission, recurrent bleeding episodes from multiple inflammatory pseudopolyps occurred. The bleeding episodes resolved quickly after immediate treatment with factor VIII (Kogenate®). In conclusion, we describe the first patient in the literature with UC and hemophilia A who stayed in long-term remission under therapy with vedolizumab. From our point of view, vedolizumab can be safely administered in the setting of UC and hemophilia A. Antiplatelet drugs which inhibit primary hemostasis must be used with caution in this setting. Bleeding episodes can be treated safely and effectively with factor VIII (Kogenate®).

  18. 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.

  19. Inhibitors in Hemophilia B.

    PubMed

    Santoro, Cristina; Quintavalle, Gabriele; Castaman, Giancarlo; Baldacci, Erminia; Ferretti, Antonietta; Riccardi, Federica; Tagliaferri, Annarita

    2018-06-20

    Hemophilia B (HB) is an X-linked bleeding disorder caused by deficiency of factor IX (FIX). Patients with the severe form (FIX <1%) account approximately for 30 to 45% of persons with HB and usually suffer from recurrent joint, soft-tissue, and muscle bleeds. The availability of safe plasma-derived and recombinant products has virtually abolished the risk of viral infections and the adoption of prophylactic regimens has attenuated the impact of hemophilic arthropathy. Therefore, the development of an inhibitor against FIX is currently the most serious complication that can still occur in the new generations of HB patients. The development of an inhibitor in HB is a rare event (1.5-3% of all patients) but is associated with a significant morbidity, related not only to the bleeding risk but also to the frequent occurrence of allergic/anaphylactic reactions and nephrotic syndrome. Due to the relative rarity of this event, few data exist about risk factors, pathophysiology, and clinical aspects of inhibitors in HB. The induction of immune tolerance is often unsuccessful and can be otherwise affected by many complications in patients with history of allergy or anaphylaxis. Therefore, alternative therapeutic strategies and new approaches are developing. The aim of this narrative review is to discuss current knowledge about risk factors, pathophysiology, and clinical aspects of this rare but serious complication. Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

  20. Effectiveness of the Medtep Hemophilia online platform for adherence to prophylactic treatment in haemophilia patients: Results from a 1-year observational study.

    PubMed

    Cuesta-Barriuso, R; López-Pina, J A; Nieto-Munuera, J; Sagarra-Valls, G; Panisello-Royo, J M; Torres-Ortuño, A

    2018-03-01

    Medtep Hemophilia platform is an online tool that allows patients with congenital coagulopathies to keep track of their daily condition-related events with the objective of ensuring successful adherence to therapy. To assess the effectiveness of Medtep Hemophilia in improving adherence to prophylactic treatment in haemophilia A and B patients in a 1-year prospective observational study, as well as its impact on the patient's disease status. Patients (>13 years old) received support material to familiarize themselves with Medtep Hemophilia. Adherence to treatment, quality of life (QoL) and illness perception were assessed. Values at baseline, 1, 6 and 12 months, and changes from baseline value were analysed. The Hemophilia Joint Health Score (HJHS) test was applied at baseline and study completion. Forty-six patients were enrolled (43 evaluable). After 1 year, 56.4% patients showed continued use of the platform (100% compliance) whereas 25.6% were inactive. Treatment adherence increased both significantly (P < .001) and progressively during the study. Similarly, improved QoL and illness perception were observed with respect to baseline in most of the questionnaire components (P < .05 after 12 months). A patient's age had no influence on the results, whereas compliant patients (>80% of platform use) tended to score better than noncompliant. The HJHS test values remained similar during the study. The Medtep Hemophilia online platform helped the studied patients with haemophilia to improve their adherence to prophylactic treatment, while increasing their QoL and illness perception, as well as joint arthropathies stabilization. © 2018 John Wiley & Sons Ltd.

  1. Eighteen Years of Molecular Genotyping the Hemophilia Inversion Hotspot: From Southern Blot to Inverse Shifting-PCR

    PubMed Central

    Rossetti, Liliana C.; Radic, Claudia P.; Abelleyro, Miguel M.; Larripa, Irene B.; De Brasi, Carlos D.

    2011-01-01

    The factor VIII gene (F8) intron 22 inversion (Inv22) is a paradigmatic duplicon-mediated rearrangement, found in about one half of patients with severe hemophilia A worldwide. The identification of this prevalent cause of hemophilia was delayed for nine years after the F8 characterization in 1984. The aim of this review is to present the wide diversity of practical approaches that have been developed for genotyping the Inv22 (and related int22h rearrangements) since discovery in 1993. The sequence— Southern blot, long distance-PCR and inverse shifting-PCR—for Inv22 genotyping is an interesting example of scientific ingenuity and evolution in order to resolve challenging molecular diagnostic problems. PMID:22072947

  2. Effect of whole body vibration training on quadriceps strength, bone mineral density, and functional capacity in children with hemophilia: a randomized clinical trial.

    PubMed

    El-Shamy, S

    2017-06-01

    The objective was to evaluate the effects of whole body vibration training on quadriceps strength, bone mineral density, and functional capacity in children with hemophilia. Thirty children with hemophilia with age ranging from 9 to 13 years were selected and randomly assigned to either the study group that received whole body vibration training (30-40 Hz, 2-4 mm of peak-to-peak vertical plate displacement for 15 minutes/day, 3 days/week/ 12 weeks) plus the conventional physical therapy program or the control group that performed a conventional physical therapy program only. Outcomes included quadriceps strength, bone mineral density, and the functional capacity. Children in the study group showed a significant improvement in all outcomes compared with the control group. The quadriceps peak torque after treatment was 70.26 and 56.46 Nm for the study and control group, respectively (p⟨0.001). The lumbar spine bone mineral density after treatment was 0.85 and 0.72 g/cm 2 for the study and control group, respectively (p⟨0.001). The functional capacity after treatment was 325 and 290 m for the study and control group, respectively (p=0.006). Whole body vibration training is an effective modality in increasing quadriceps strength, bone mineral density, and functional capacity in children with hemophilia.

  3. An Analysis of the hemophilia of the royal families of Europe, its startling implication and dentistry's role in treating the hemophiliac patient.

    PubMed

    Maloney, William James; Raymond, George; Hershkowitz, David; Rochlen, Glenn

    2015-03-01

    Hemophilia is an inherited x-linked recessive disorder. It is known popularly as "The Royal Disease," as it has affected many of the royal families of Europe by virtue of Queen Victoria being a carrier for the gene and, subsequently, passing it on to her offspring. They, in turn, married and had children with other royal families of Europe. Hemophilia is certainly not limited to royalty. There are many hemophiliacs living in our communities, and they must receive both proper dental home-care education and dental treatment in order to prevent possibly life-threatening emergency dental episodes. Individuals with hemophilia pose different management issues to the dental professional. The various precautions and modifications that must be taken in order to ensure the safe delivery of dental care to hemophiliac dental patients are discussed.

  4. 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

  5. Challenges and open issues in the management of acquired hemophilia A (AHA).

    PubMed

    Shetty, Shrimati D; Ghosh, Kanjaksha

    2015-03-01

    Acquired hemophilia A (AHA) is a rare autoimmune bleeding disorder caused by antibodies which neutralize the function of factor VIII (FVIII). The disease presents a complex clinical challenge to the treating Physicians and Hematologists. As the disease is associated with high mortality, prompt management is necessary. Early recognition, quick diagnosis and timely referral to a specialized center are important for better management of these patients. The different clinical manifestations, underlying pathology, inhibitor kinetics and the associated age related comorbidities do not allow extrapolation of the treatment protocols of congenital hemophilia to AHA. The basic strategies of the management of AHA patients involve maintaining hemostasis, suppression or eradication of antibodies, diagnosis and treatment of underlying pathology and avoid treatment related complications like thrombosis. The efficiency of hemostatic agents which are generally used to treat AHA is unpredictable. Due to the rarity of the disease, there are no randomized clinical trials on the management of this disorder and thus the expertise and experience of the treating Physicians' guide treatment strategies. Copyright © 2014 Elsevier Inc. All rights reserved.

  6. The CDC Hemophilia B mutation project mutation list: a new online resource.

    PubMed

    Li, Tengguo; Miller, Connie H; Payne, Amanda B; Craig Hooper, W

    2013-11-01

    Hemophilia B (HB) is caused by mutations in the human gene F9. The mutation type plays a pivotal role in genetic counseling and prediction of inhibitor development. To help the HB community understand the molecular etiology of HB, we have developed a listing of all F9 mutations that are reported to cause HB based on the literature and existing databases. The Centers for Disease Control and Prevention (CDC) Hemophilia B Mutation Project (CHBMP) mutation list is compiled in an easily accessible format of Microsoft Excel and contains 1083 unique mutations that are reported to cause HB. Each mutation is identified using Human Genome Variation Society (HGVS) nomenclature standards. The mutation types and the predicted changes in amino acids, if applicable, are also provided. Related information including the location of mutation, severity of HB, the presence of inhibitor, and original publication reference are listed as well. Therefore, our mutation list provides an easily accessible resource for genetic counselors and HB researchers to predict inhibitors. The CHBMP mutation list is freely accessible at http://www.cdc.gov/hemophiliamutations.

  7. Hepatitis C treatment with triple therapy in a patient with hemophilia A

    PubMed Central

    Singh, Gurshawn; Sass, Reuben; Alamiry, Rayan; Zein, Nizar; Alkhouri, Naim

    2013-01-01

    We report a case of successful treatment of chronic hepatitis C infection with telaprevir-based triple therapy in a patient with hemophilia A complicated by factor VIII inhibitor. A twenty-two years old male with hereditary hemophilia A and high-titer factor VIII inhibitor was taking maintenance doses of recombinant factor VIII. He visited our clinic for treatment of his chronic hepatitis C with the newly instituted protease inhibitor based therapy. He was diagnosed with hepatitis C genotype 1a at one year of age. He was initiated on telaprevir, ribavirin and peg-interferon for treatment of hepatitis C and qualified for response-guided therapy. He completed treatment at 24 wk with minimal adverse effects. Notably, after 4 wk of hepatitis C treatment, his factor VIII inhibitor screen was negative and the dose for recombinant factor VIII decreased by half of the initial dosing before he was treated for hepatitis C. We suspect that suppressing hepatitis C may help decrease factor VIII inhibitor level and the need for recombinant factor VIII. PMID:24303477

  8. 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

  9. High-affinity, noninhibitory pathogenic C1 domain antibodies are present in patients with hemophilia A and inhibitors.

    PubMed

    Batsuli, Glaivy; Deng, Wei; Healey, John F; Parker, Ernest T; Baldwin, W Hunter; Cox, Courtney; Nguyen, Brenda; Kahle, Joerg; Königs, Christoph; Li, Renhao; Lollar, Pete; Meeks, Shannon L

    2016-10-20

    Inhibitor formation in hemophilia A is the most feared treatment-related complication of factor VIII (fVIII) therapy. Most inhibitor patients with hemophilia A develop antibodies against the fVIII A2 and C2 domains. Recent evidence demonstrates that the C1 domain contributes to the inhibitor response. Inhibitory anti-C1 monoclonal antibodies (mAbs) have been identified that bind to putative phospholipid and von Willebrand factor (VWF) binding epitopes and block endocytosis of fVIII by antigen presenting cells. We now demonstrate by competitive enzyme-linked immunosorbent assay and hydrogen-deuterium exchange mass spectrometry that 7 of 9 anti-human C1 mAbs tested recognize an epitope distinct from the C1 phospholipid binding site. These mAbs, designated group A, display high binding affinities for fVIII, weakly inhibit fVIII procoagulant activity, poorly inhibit fVIII binding to phospholipid, and exhibit heterogeneity with respect to blocking fVIII binding to VWF. Another mAb, designated group B, inhibits fVIII procoagulant activity, fVIII binding to VWF and phospholipid, fVIIIa incorporation into the intrinsic Xase complex, thrombin generation in plasma, and fVIII uptake by dendritic cells. Group A and B epitopes are distinct from the epitope recognized by the canonical, human-derived inhibitory anti-C1 mAb, KM33, whose epitope overlaps both groups A and B. Antibodies recognizing group A and B epitopes are present in inhibitor plasmas from patients with hemophilia A. Additionally, group A and B mAbs increase fVIII clearance and are pathogenic in a hemophilia A mouse tail snip bleeding model. Group A anti-C1 mAbs represent the first identification of pathogenic, weakly inhibitory antibodies that increase fVIII clearance. © 2016 by The American Society of Hematology.

  10. High-affinity, noninhibitory pathogenic C1 domain antibodies are present in patients with hemophilia A and inhibitors

    PubMed Central

    Batsuli, Glaivy; Deng, Wei; Healey, John F.; Parker, Ernest T.; Baldwin, W. Hunter; Cox, Courtney; Nguyen, Brenda; Kahle, Joerg; Königs, Christoph; Li, Renhao; Lollar, Pete

    2016-01-01

    Inhibitor formation in hemophilia A is the most feared treatment-related complication of factor VIII (fVIII) therapy. Most inhibitor patients with hemophilia A develop antibodies against the fVIII A2 and C2 domains. Recent evidence demonstrates that the C1 domain contributes to the inhibitor response. Inhibitory anti-C1 monoclonal antibodies (mAbs) have been identified that bind to putative phospholipid and von Willebrand factor (VWF) binding epitopes and block endocytosis of fVIII by antigen presenting cells. We now demonstrate by competitive enzyme-linked immunosorbent assay and hydrogen-deuterium exchange mass spectrometry that 7 of 9 anti-human C1 mAbs tested recognize an epitope distinct from the C1 phospholipid binding site. These mAbs, designated group A, display high binding affinities for fVIII, weakly inhibit fVIII procoagulant activity, poorly inhibit fVIII binding to phospholipid, and exhibit heterogeneity with respect to blocking fVIII binding to VWF. Another mAb, designated group B, inhibits fVIII procoagulant activity, fVIII binding to VWF and phospholipid, fVIIIa incorporation into the intrinsic Xase complex, thrombin generation in plasma, and fVIII uptake by dendritic cells. Group A and B epitopes are distinct from the epitope recognized by the canonical, human-derived inhibitory anti-C1 mAb, KM33, whose epitope overlaps both groups A and B. Antibodies recognizing group A and B epitopes are present in inhibitor plasmas from patients with hemophilia A. Additionally, group A and B mAbs increase fVIII clearance and are pathogenic in a hemophilia A mouse tail snip bleeding model. Group A anti-C1 mAbs represent the first identification of pathogenic, weakly inhibitory antibodies that increase fVIII clearance. PMID:27381905

  11. 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.

  12. Hemostatic effect of a monoclonal antibody mAb 2021 blocking the interaction between FXa and TFPI in a rabbit hemophilia model.

    PubMed

    Hilden, Ida; Lauritzen, Brian; Sørensen, Brit Binow; Clausen, Jes Thorn; Jespersgaard, Christina; Krogh, Berit Olsen; Bowler, Andrew Neil; Breinholt, Jens; Gruhler, Albrecht; Svensson, L Anders; Petersen, Helle Heibroch; Petersen, Lars Christian; Balling, Kristoffer W; Hansen, Lene; Hermit, Mette Brunsgaard; Egebjerg, Thomas; Friederichsen, Birgitte; Ezban, Mirella; Bjørn, Søren Erik

    2012-06-14

    Hemophilia is treated by IV replacement therapy with Factor VIII (FVIII) or Factor IX (FIX), either on demand to resolve bleeding, or as prophylaxis. Improved treatment may be provided by drugs designed for subcutaneous and less frequent administration with a reduced risk of inhibitor formation. Tissue factor pathway inhibitor (TFPI) down-regulates the initiation of coagulation by inhibition of Factor VIIa (FVIIa)/tissue factor/Factor Xa (FVIIa/TF/FXa). Blockage of TFPI inhibition may facilitate thrombin generation in a hemophilic setting. A high-affinity (K(D) = 25pM) mAb, mAb 2021, against TFPI was investigated. Binding of mAb 2021 to TFPI effectively prevented inhibition of FVIIa/TF/FXa and improved clot formation in hemophilia blood and plasma. The binding epitope on the Kunitz-type protease inhibitor domain 2 of TFPI was mapped by crystallography, and showed an extensive overlap with the FXa contact region highlighting a structural basis for its mechanism of action. In a rabbit hemophilia model, an intravenous or subcutaneous dose significantly reduced cuticle bleeding. mAb 2021 showed an effect comparable with that of rFVIIa. Cuticle bleeding in the model was reduced for at least 7 days by a single intravenous dose of mAb 2021. This study suggests that neutralization of TFPI by mAb 2021 may constitute a novel treatment option in hemophilia.

  13. Predictors of retention among HIV/hemophilia health care professionals.

    PubMed

    Brown, Larry K; Schultz, Janet R; Forsberg, Ann D; King, Gary; Kocik, Susan M; Butler, Regina B

    2002-01-01

    Health care professionals working with individuals with chronic medical illness, especially those infected with the Human Immunodeficiency Virus (HIV), may be at risk for burnout and departure due to various job stresses such as the death of patients and social stigma. Factors that prevent burnout and employee attrition are seldom studied. Two hundred thirteen staff (doctors, nurses and mental health workers) at a representative sample of Hemophilia Treatment Centers (HTC) completed instruments to measure Burnout (Maslach Burnout Inventory), and perceived job stresses and satisfaction (job tasks, interactions with colleagues and patient care). The staff were surveyed again after two years and their job status determined after 4 years. After 4 years, 35% of the staff had left the field of Hemophilia/HIV care. Univariate tests found that retention was significantly associated with initial job satisfaction, being married and low levels of stress with colleagues. Burnout, as measured by the Maslach Burnout Inventory, at baseline, was unrelated to job retention over 4 years. An adjusted multiple logistic regression of all significant variables found that colleague support was most related to retention (OR=2.8, CI=1.49,5.1). We conclude that attrition of highly trained staff is a significant issue for patients and HTCs. These data suggest the important role that a well-functioning team can have in buffering the inevitable stresses associated with HIV care. Mental Health professionals have considerable expertise in addressing these issues.

  14. The value of usability testing for Internet-based adolescent self-management interventions: "Managing Hemophilia Online".

    PubMed

    Breakey, Vicky R; Warias, Ashley V; Ignas, Danial M; White, Meghan; Blanchette, Victor S; Stinson, Jennifer N

    2013-10-04

    As adolescents with hemophilia approach adulthood, they are expected to assume responsibility for their disease management. A bilingual (English and French) Internet-based self-management program, "Teens Taking Charge: Managing Hemophilia Online," was developed to support adolescents with hemophilia in this transition. This study explored the usability of the website and resulted in refinement of the prototype. A purposive sample (n=18; age 13-18; mean age 15.5 years) was recruited from two tertiary care centers to assess the usability of the program in English and French. Qualitative observations using a "think aloud" usability testing method and semi-structured interviews were conducted in four iterative cycles, with changes to the prototype made as necessary following each cycle. This study was approved by research ethics boards at each site. Teens responded positively to the content and appearance of the website and felt that it was easy to navigate and understand. The multimedia components (videos, animations, quizzes) were felt to enrich the experience. Changes to the presentation of content and the website user-interface were made after the first, second and third cycles of testing in English. Cycle four did not result in any further changes. Overall, teens found the website to be easy to use. Usability testing identified end-user concerns that informed improvements to the program. Usability testing is a crucial step in the development of Internet-based self-management programs to ensure information is delivered in a manner that is accessible and understood by users.

  15. An integrated knowledge system for the Space Shuttle hazardous gas detection system

    NASA Technical Reports Server (NTRS)

    Lo, Ching F.; Shi, George Z.; Bangasser, Carl; Fensky, Connie; Cegielski, Eric; Overbey, Glenn

    1993-01-01

    A computer-based integrated Knowledge-Based System, the Intelligent Hypertext Manual (IHM), was developed for the Space Shuttle Hazardous Gas Detection System (HGDS) at NASA Marshall Space Flight Center (MSFC). The IHM stores HGDS related knowledge and presents it in an interactive and intuitive manner. This manual is a combination of hypertext and an expert system which store experts' knowledge and experience in hazardous gas detection and analysis. The IHM's purpose is to provide HGDS personnel with the capabilities of: locating applicable documentation related to procedures, constraints, and previous fault histories; assisting in the training of personnel; enhancing the interpretation of real time data; and recognizing and identifying possible faults in the Space Shuttle sub-systems related to hazardous gas detection.

  16. Effect of whole body vibration training on quadriceps strength, bone mineral density, and functional capacity in children with hemophilia: a randomized clinical trial

    PubMed Central

    El-Shamy, S.

    2017-01-01

    Objectives: The objective was to evaluate the effects of whole body vibration training on quadriceps strength, bone mineral density, and functional capacity in children with hemophilia. Methods: Thirty children with hemophilia with age ranging from 9 to 13 years were selected and randomly assigned to either the study group that received whole body vibration training (30-40 Hz, 2-4 mm of peak-to-peak vertical plate displacement for 15 minutes/day, 3 days/week/ 12 weeks) plus the conventional physical therapy program or the control group that performed a conventional physical therapy program only. Outcomes included quadriceps strength, bone mineral density, and the functional capacity. Results: Children in the study group showed a significant improvement in all outcomes compared with the control group. The quadriceps peak torque after treatment was 70.26 and 56.46 Nm for the study and control group, respectively (p<0.001). The lumbar spine bone mineral density after treatment was 0.85 and 0.72 g/cm2 for the study and control group, respectively (p<0.001). The functional capacity after treatment was 325 and 290 m for the study and control group, respectively (p=0.006). Conclusions: Whole body vibration training is an effective modality in increasing quadriceps strength, bone mineral density, and functional capacity in children with hemophilia. PMID:28574408

  17. Combination of hemostatic therapies for treatment of patients with hemophilia A and inhibitors.

    PubMed

    Livnat, Tami; Budnik, Ivan; Levy-Mendelovich, Sarina; Avishai, Einat; Misgav, Mudi; Barg, Assaf Arie; Lubetsky, Aharon; Brutman-Barazani, Tami; Kenet, Gili

    2017-07-01

    Therapy application and monitoring of patients with hemophilia A (HA) and inhibitors are challenging. In the current study, combined FVIII - bypass therapy was implemented for a cohort of severe HA patients with inhibitors. Plasma of 15 HA patients with inhibitors was spiked ex vivo with FVIII, rFVIIa, FEIBA and their combinations and thrombin generation (TG) was studied. Some patients who experienced hemarthroses or required minor surgeries were treated by a combined concomitant administration of FVIII+FEIBA as IV bolus doses. TG spiking studies showed individual responses not correlated to inhibitor titer. Combinations of agents augmented TG as compared to any single agent, while combined FVIII+FEIBA yielded the highest TG, supporting it as a potential treatment. Following emergent successful surgery of child treated by concomitant FVIII+FEIBA, a total of 396 episodes in 7/15 patients were treated with concomitant FVIII+FEIBA. Five patients were treated for bleeding episodes only, whereas 2 were children undergoing immune tolerance induction (ITI) with FEIBA prophylaxis. Four minor surgeries were performed on FVIII+FEIBA repeated infusions. Neither thrombosis nor any other adverse events were documented. A combination of FVIII+FEIBA may be effective and safe as an alternative treatment option for some high-responding inhibitor patients. Copyright © 2017 Elsevier Inc. All rights reserved.

  18. The value of HEAD-US system in detecting subclinical abnormalities in joints of patients with hemophilia.

    PubMed

    De la Corte-Rodriguez, Hortensia; Rodriguez-Merchan, E Carlos; Alvarez-Roman, M Teresa; Martin-Salces, Mónica; Martinoli, Carlo; Jimenez-Yuste, Víctor

    2018-03-01

    Prevention of hemarthrosis is the key factor in the adequate management of people with hemophilia (PWH). If hemarthrosis occurs, early diagnosis of joint damage is essential to make personalized treatments. This study is aimed at gaining an understanding of the ability of point-of-care ultrasound (US) using the `Hemophilia Early Arthropathy Detection with Ultrasound´ (HEAD-US) protocol to detect abnormalities in joints without history of hemarthrosis and clinically asymptomatic joints of PWH. The sample included 976 joints from 167 PWH (mean age 24.86 years). Data were collected from routine practice over a 3-year period and analyzed based on history of hemarthrosis and results of clinical (HJHS 2.1) and HEAD-US examinations. In our series, 14% of patients exhibited HEAD-US signs of incipient arthropathy in joints with no history of bleeding and with a HJHS 2.1 score of 0. The most severely involved joint was the right ankle. Synovitis, articular cartilage and subchondral bone damage scores in joints with subclinical findings were slower than in joints with previous hemarthroses or HJHS 2.1 > 1 Conclusions: Our study demonstrates that HEAD-US is better than hemarthrosis records and the HJHS 2.1 scale in detecting the early signs of joint damage in PWH.

  19. An Open-label, Single-dose, Pharmacokinetic Study of Factor VIII Activity After Administration of Moroctocog Alfa (AF-CC) in Male Chinese Patients With Hemophilia A.

    PubMed

    Liu, Hongzhong; Wu, Runhui; Hu, Pei; Sun, Feifei; Xu, Lihong; Liang, Yali; Nepal, Sunil; Qu, Peng Roger; Huard, Francois; Korth-Bradley, Joan M

    2017-07-01

    Hemophilia A represents up to 80% of all hemophilia cases in China. In patients with this condition, bleeding can be prevented and controlled by administering clotting factor VIII (FVIII). Since their initial availability, recombinant FVIII products have undergone several iterations to enhance their safety. Moroctocog alfa albumin-free cell culture (AF-CC) is among the third generation of recombinant FVIII products and received regulatory approval in China in August 2012. The present study characterizes the single-dose pharmacokinetic parameters of FVIII activity (FVIII:C) after administration of moroctocog alfa (AF-CC) in male Chinese patients with hemophilia A. This multicenter, open-label, single-dose study enrolled 13 male Chinese patients diagnosed with severe hemophilia A (FVIII:C <1%) and a history of at least 150 exposure-days to any FVIII-containing product. Eligible patients received a single dose of moroctocog alfa (AF-CC) 50 IU/kg IV within 10 minutes. Blood samples were collected within 2 hours before administration and through 72 hours after dosing. Pharmacokinetic parameters were assessed based on FVIII:C and were analyzed by age groups: ages 6 to <12 years (n = 3) and ≥12 years (n = 10). The mean plasma concentration-time profile for FVIII:C activity was consistently lower in patients aged 6 to <12 years compared with those aged ≥12 years. Geometric AUC 0-∞ and C max were approximately 57% and 28% lower in the younger patients relative to the older patients, respectively. A total of 4 adverse events occurred in 4 patients. Low-titer, transient FVIII inhibitors were observed in 2 patients and were considered serious adverse events. Neither case resulted in clinical manifestations nor required treatment. This is the first report of the pharmacokinetic parameters of FVIII:C after moroctocog alfa (AF-CC) in an all-Chinese population of males with hemophilia A. The pharmacokinetic profile in older patients was similar to that previously reported

  20. 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

  1. Transitioning issues in adolescent to young adult hemophilia patients with inhibitors: an approach for a growing population.

    PubMed

    Young, Guy

    2010-09-01

    The major adverse effect of factor replacement therapy in patients with hemophilia is the development of neutralizing antibodies termed inhibitors. This complication renders standard factor replacement therapy ineffective resulting in increased morbidity and mortality. Until recently, the population of adults with inhibitors was relatively small due to the death of many of the patients from HIV that they contracted from contaminated factor in the early 1980s. With the advent of factor products with reduced risks for deadly infections in the mid-1980s to early 1990s, a cohort of inhibitor patients is now beginning to enter adulthood thus raising the issues regarding the transition of these patients into adulthood. It is, therefore, expected that adult hematologists will be seeing more inhibitor patients and that pediatric hematologists will be faced with managing this transition process, which may not necessarily include transition to an adult facility or adult hematologist. This review will discuss the various issues ranging from choice of medical provider to a discussion of psychosocial and financial issues facing this specific patient population.

  2. Hemophilia A Pseudoaneurysm in a Patient with High Responding Inhibitors Complicating Total Knee Arthroplasty: Embolization: A Cost-Reducing Alternative to Medical Therapy

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

    Kickuth, Ralph, E-mail: ralph.kickuth@insel.ch; Anderson, Suzanne; Peter-Salonen, Kristiina

    2006-12-15

    Joint hemorrhages are very common in patients with severe hemophilia. Inhibitors in patients with hemophilia are allo-antibodies that neutralize the activity of the clotting factor. After total knee replacement, rare intra-articular bleeding complications might occur that do not respond to clotting factor replacement. We report a 40-year-old male with severe hemophilia A and high responding inhibitors presenting with recurrent knee joint hemorrhage after bilateral knee prosthetic surgery despite adequate clotting factor treatment. There were two episodes of marked postoperative hemarthrosis requiring extensive use of subsititution therapy. Eleven days postoperatively, there was further hemorrhage into the right knee. Digital subtraction angiographymore » diagnosed a complicating pseudoaneurysm of the inferior lateral geniculate artery and embolization was successfully performed. Because clotting factor replacement therapy has proved to be excessively expensive and prolonged, especially in patients with inhibitors, we recommend the use of cost-effective early angiographic embolization.« less

  3. 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

  4. 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

    compared on-demand treatment to prophylaxis with bypassing agents. In one study (34 males) prophylaxis significantly reduced mean overall bleeding rates, MD - 7.27 (95% CI -9.92 to -4.62) (low quality evidence), mean number of overall bleeding events per month, MD -1.10 (95% CI -1.54 to -0.66), mean number of hemarthrosis, MD -6.60 (95% CI -9.32 to -3.88) (low quality evidence) and mean number of joints that had hemarthrosis, MD -0.90 (95% CI -1.36 to -0.44). The meta-analysis did not conclusively demonstrate significant benefit of prophylaxis on health-related quality of life as measured by Haem-A-QoL score, EQ-5D total score and utility score, EQ-5D VAS and SF-36 physical summary and mental summary score (low quality evidence for all health-related quality of life analyses).The remaining two studies compared dose regimens. The results from one study (22 males) did not conclusively demonstrate benefit or harm of high-dose versus low-dose recombinant activated factor VIIa (rFVIIa) as a prophylaxis for overall bleeding rate, MD -0.82 (95% CI -2.27 to 0.63) (moderate quality evidence), target joint bleeding rate, MD -3.20 (95% CI -7.23 to 0.83) (moderate quality evidence) and serious adverse events, RR 9.00 (95% CI, 0.54 to 149.50) (moderate quality evidence).The overall quality of evidence was moderate to low due to imprecision from limited information provided by studies with small sample sizes and incomplete outcome data in one study. The evidence suggests that prophylaxis with bypassing agents may be effective in reducing bleeding in males with hemophilia with inhibitors. However, there is a lack of evidence for the superiority of one agent over the other or for the optimum dosage regimen. Further studies are needed to evaluate the benefits and harms of prophylaxis treatment on health-related quality of life, as well as the effects of dose of bypassing agents on the outcomes.

  5. 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.

  6. The value of usability testing for Internet-based adolescent self-management interventions: “Managing Hemophilia Online”

    PubMed Central

    2013-01-01

    Background As adolescents with hemophilia approach adulthood, they are expected to assume responsibility for their disease management. A bilingual (English and French) Internet-based self-management program, “Teens Taking Charge: Managing Hemophilia Online,” was developed to support adolescents with hemophilia in this transition. This study explored the usability of the website and resulted in refinement of the prototype. Methods A purposive sample (n=18; age 13–18; mean age 15.5 years) was recruited from two tertiary care centers to assess the usability of the program in English and French. Qualitative observations using a “think aloud” usability testing method and semi-structured interviews were conducted in four iterative cycles, with changes to the prototype made as necessary following each cycle. This study was approved by research ethics boards at each site. Results Teens responded positively to the content and appearance of the website and felt that it was easy to navigate and understand. The multimedia components (videos, animations, quizzes) were felt to enrich the experience. Changes to the presentation of content and the website user-interface were made after the first, second and third cycles of testing in English. Cycle four did not result in any further changes. Conclusions Overall, teens found the website to be easy to use. Usability testing identified end-user concerns that informed improvements to the program. Usability testing is a crucial step in the development of Internet-based self-management programs to ensure information is delivered in a manner that is accessible and understood by users. PMID:24094082

  7. Risk Factors for Inhibitor Formation in Hemophilia: A Prevalent Case-Control Study

    PubMed Central

    Ragni, Margaret V.; Ojeifo, Oluseyi; Feng, Jinong; Yan, Jin; Hill, Kathleen A.; Sommer, Steve S.; Trucco, Massimo N.; Brambilla, Donald J.

    2009-01-01

    Background Inhibitor formation is a major complication of hemophilia treatment. Aim In a prevalent case-control study, we evaluated blood product exposure, genotype, and HLA type on hemophilia A inhibitor formation. Methods Product exposure was extracted from medical records. Genotype was determined on stored DNA samples by detection of virtually all mutations-SSCP (DOVAM-S) and subcycling PCR. HLA typing was performed by PCR amplification and exonuclease-released fluorescence. Results Cases experienced higher intensity factor, 455 vs. 200 U per exposure, p<0.005, more frequent central nervous system (CNS) bleeding, 7 of 20 (35.0%) vs. 1 of 57 (1.7%), p=0.001, and more commonly from inhibitor families, 7 of 20 (35.0%) vs. 0 of 57 (0%), p<0.001, and African-American, 12 of 63 (19.0%) vs. 6 of 117 (5.1%), p=0.015. Among the latter, CNS bleeding was more commonly the initial bleed, 60% vs. 0%, p<0.001, and survival was shorter, 14 vs. 38 yr, p=0.025. Inhibitor formation was uncommon in those with missense mutations, 2 of 65 (3.1%) vs. 31 of 119 (26.0%), p=0.008, and unrelated to factor VIII immunogenic epitope, p=0.388, or HLA type, p>0.100. Genotype was not associated with race. Time to immune tolerance was shorter for titers < 120 vs. ≥ 120 BU/ml, 6 vs. 16 months, p<0.01, but unaffected by tolerizing dose regimen, p>0.50. Conclusions Inhibitor formation is associated with high intensity product exposure, CNS bleeding, African-American race, and low frequency of missense mutations. The ideal time to initiate prophylaxis to reduce CNS bleeding and inhibitor formation will require prospective studies. PMID:19563499

  8. Coronary artery bypass grafting in a patient with hemophilia B: continuous recombinant factor IX infusion as per the Japanese guidelines for replacement therapy.

    PubMed

    Suzuki, Tomoyuki; Kawamoto, Shunsuke; Kumagai, Kiichiro; Adachi, Osamu; Kanda, Keisuke; Ishikawa, Masaaki; Okitsu, Yoko; Harigae, Hideo; Kurosawa, Shin; Saiki, Yoshikatsu

    2016-08-01

    We herein report our experience of successfully managing the hemostatic system by controlling serum factor IX levels throughout the perioperative period in a patient with hemophilia B. Coronary artery bypass grafting with cardiopulmonary bypass was planned for a 52-year-old man with moderate severity of hemophilia B. During surgery, recombinant factor IX (rFIX; BeneFIX(®) Pfizer Japan inc., Tokyo, Japan) was administered by bolus infusion followed by continuous infusion as per the guidelines of the Japanese Society on Thrombosis and Hemostasis. The operative course was uneventful without any considerable bleeding or complications.

  9. [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.

  10. Health economic review of recombinant activated factor VII for treatment of bleeding episodes in hemophilia patients with inhibitors.

    PubMed

    Stephens, Jennifer M; Joshi, Ashish V; Sumner, Michael; Botteman, Marc F

    2007-06-01

    Severe hemophilia with inhibitors is a rare disease with substantial clinical, humanistic and economic consequences. This review provides an overview of the role of recombinant activated factor VII (rFVIIa) versus plasma-derived bypassing agents for hemophilia with inhibitors and summarizes the 13 formal economic analyses (6 burden of illness and 7 comparative studies) that have been published in this indication. The findings suggest that the economic impact of rFVIIa has occurred primarily during hospitalization to manage major bleeding episodes and to allow for elective orthopedic surgeries that would not have been attempted prior to rFVIIa. Comparative analyses for on-demand treatment suggest that the total cost of treating a bleeding episode with rFVIIa may be lower than with plasma-based agents due to faster bleeding resolution, higher initial efficacy rates and avoidance of second and third lines of treatment.

  11. 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

  12. International recommendations on the diagnosis and treatment of patients with acquired hemophilia A

    PubMed Central

    Huth-Kühne, Angela; Baudo, Francesco; Collins, Peter; Ingerslev, Jørgen; Kessler, Craig M.; Lévesque, Hervé; Castellano, Maria Eva Mingot; Shima, Midori; St-Louis, Jean

    2009-01-01

    Acquired hemophilia A (AHA) is a rare bleeding disorder characterized by autoantibodies directed against circulating coagulation factor (F) VIII. Typically, patients with no prior history of a bleeding disorder present with spontaneous bleeding and an isolated prolonged aPTT. AHA may, however, present without any bleeding symptoms, therefore an isolated prolonged aPTT should always be investigated further irrespective of the clinical findings. Control of acute bleeding is the first priority, and we recommend first-line therapy with bypassing agents such as recombinant activated FVII or activated prothrombin complex concentrate. Once the diagnosis has been achieved, immediate autoantibody eradication to reduce subsequent bleeding risk should be performed. We recommend initial treatment with corticosteroids or combination therapy with corticosteroids and cyclophosphamide and suggest second-line therapy with rituximab if first-line therapy fails or is contraindicated. In contrast to congenital hemophilia, no comparative studies exist to support treatment recommendations for patients with AHA, therefore treatment guidance must rely on the expertise and clinical experience of specialists in the field. The aim of this document is to provide a set of international practice guidelines based on our collective clinical experience in treating patients with AHA and contribute to improved care for this patient group. PMID:19336751

  13. Massive adrenal vein aneurysm mimicking an adrenal tumor in a patient with hemophilia A: a case report and review of the literature.

    PubMed

    Sleightholm, Richard; Wahlmeier, Steven; Carson, Jeffrey S; Drincic, Andjela; Lazenby, Audrey; Foster, Jason M

    2016-12-01

    Visceral venous aneurysms are exceedingly rare, and until now, there have been no reports of this phenomenon in the adrenal vasculature. This report details the first adrenal venous aneurysm reported in the literature. The aneurysm presented as an 18-cm mass that was initially suspected to be a hematoma or tumor on the basis of the complex medical history of the patient, which included hemophilia A and testicular cancer. After surgical excision, pathologic examination confirmed this mass to be a 15.9-cm adrenal vein aneurysm, the largest aneurysm of any type or location recorded in the medical literature. A 58-year-old caucasian male with hemophilia A presented to the emergency room of another institution with abdominal pain, blood in the stool, and a history of diverticulosis and symptomatic hemorrhoids. A large, left-sided adrenal mass was detected by computed tomography, and because of the patient's hemophilia A and imaging consistent with a hemorrhagic mass, a hematoma was initially suspected. The patient was transferred to our institution, monitored for further bleeding with a stable hospital course, and discharged from the hospital under close monitoring. After 7-8 weeks with no change in the size of the mass, concerns grew regarding increasing symptoms of both satiety and mass effects from the large anomaly, as well as about the patient's complicated medical history, which also included cancer. Surgical excision was recommended because of the concerns about increasing symptoms and the possibility of a malignancy. Correction and maintenance of factor VIII levels were incorporated pre-, intra-, and postoperatively, and en bloc surgical resection was performed to minimize bleeding and provide oncologic extirpation of the mass. A bowling ball-sized mass was removed, and careful pathologic examination revealed the mass to be a venous adrenal aneurysm. After a brief hospital stay, the patient made a full recovery. Extensive review of the literature revealed 11

  14. Special features of total knee replacement in hemophilia.

    PubMed

    Rodriguez-Merchan, Emerito Carlos

    2013-12-01

    Total knee replacement is an operation frequently needed by hemophilia patients, which greatly improves their quality of life. This operation, however, carries a higher risk of bleeding and infection for hemophiliacs than it does for osteoarthritis sufferers. It is advisable to implant prosthetic components using antibiotic-loaded cement. It is essential to maintain a level of 100% of the replacement clotting factor for 2 weeks. Hematological treatment must be established, depending on the patient's factor levels and other pharmacokinetic parameters such as recovery and half-life, optimal doses and treatment time. It is preferable to use general anesthesia due to the risk of spinal bleeding. The lifespan of total knee replacement in hemophilic patients is shorter than in patients with osteoarthritis because of the increased risk of infection.

  15. Acquired Hemophilia A in an advanced age patient of hispanic origin: a case report.

    PubMed

    Rivera Cora, Nalyssa I; Irizarry Delgado, Freddie; Merle Ramírez, Santa M; Vera Quiñones, Jorge

    2017-09-04

    Acquired Hemophilia A (AHA) is a rare hematological disorder that exhibits an incidence of approximately 1.5 cases per million patients a year. It is characterized by the development of autoantibodies against circulating Factor VIII coagulation proteins which, in turn, which in turn lead to potentially life-threatening hemorrhagic episodes. The incidence of AHA increases with age; with 80% of the affected patient population encompassing men and women that are 65 years or older. Some of the challenges that are highlighted in managing this disorder relate to the delayed diagnosis of this condition due to the rarity of the latter, the difficulty in establishing reliable hemostasis, and the secondary complications that are found when using immunosuppressive and hemostatic treatments in tandem with the elderly population afflicted with this disease. A 90-year-old female of Hispanic origin presented with a 2-week history of generalized weakness, dizziness, shortness of breath and extensive purpuric formations that involved the left arm towards the lateral aspect of the thorax with the inclusion of a small right lateral neck hematoma formation. Upon initial laboratory screening, a hemoglobin level of 7.9, a hematocrit level of 21.9 and a PTT value of 70.9 were discovered. Despite conventional hemostatic treatment approaches, the patient did not show marked improvement of the laboratory values. Ongoing specialized laboratory reports, combined with the clinical presentation of the patient, led to the diagnosis of Acquired Hemophilia A. Treatment with recombinant porcine Factor VIII was initiated, which led to rapid improvement of clinical symptoms and laboratory values. The patient was discharged with current treatment plan and emergent follow/up with a hematologist was scheduled. Acquired Hemophilia A is an elusive bleeding disorder that has been seldom encountered in the demographics of Puerto Rico. The prompt detection of this diagnosis based on the clinical

  16. Co-Infection of the Hepatitis C Virus With Other Blood-Borne and Hepatotropic Viruses Among Hemophilia Patients in Poland.

    PubMed

    Kucharska, Marta; Inglot, Malgorzata; Szymczak, Aleksandra; Rymer, Weronika; Zalewska, Malgorzata; Malyszczak, Krzysztof; Zaleska-Dorobisz, Urszula; Kuliszkiewicz-Janus, Malgorzata

    2016-09-01

    The prevalence of HCV infection in people with hemophilia is substantially higher than that in the general population (63% - 98%). Multiple transfusions and substitutive therapy have also been linked to a high risk of HBV and HIV transmission. However, the prevalence of other blood-borne viral infections in this population is less well known. This study aimed to assess the prevalence of co-infection with HBV and other blood-borne viruses in Polish HCV-infected hemophiliacs. Seventy-one individuals, the majority of whom were male (94.36%), who had congenital bleeding disorders (60 had hemophilia A, five had hemophilia B, and six had other factor deficiencies) and HCV infection, which was defined as the presence of positive anti-HCV antibodies, were included in this study. The study group was divided into two subgroups according to the year in which blood donors were first tested for HBsAg in Poland. The serological markers were screened using commercially available enzyme immunoassays according to the manufacturer's instructions. The molecular tests were performed using real-time PCR technology with commercial assays according to the manufacturer's instructions. The spontaneous elimination rate of HCV RNA was 29.6%. The HCV genotype 1 was detected in 28 patients (65.1%), genotype 2 in one patient (2.3%), genotype 3 in 11 patients (25.6%), genotype 4 in two patients (4.7%), and a mixed infection with genotypes 1 and 4 was detected in one person (2.3%). Fifty-three patients (74.6%) were anti-HBc positive. Among the seven HBsAg(+) patients, three individuals were HBV-DNA positive. No occult hepatitis B was detected. In six HBsAg positive patients, the HCV RNA was positive, while one patient was also infected with HIV. The prevalence rate of past infection with HAV in the study group was 30.9%, with a tendency for a higher prevalence in older patients. The prevalence of CMV and EBV infection was high and similar to that seen in the general population. All the patients

  17. Co-Infection of the Hepatitis C Virus With Other Blood-Borne and Hepatotropic Viruses Among Hemophilia Patients in Poland

    PubMed Central

    Kucharska, Marta; Inglot, Malgorzata; Szymczak, Aleksandra; Rymer, Weronika; Zalewska, Malgorzata; Malyszczak, Krzysztof; Zaleska-Dorobisz, Urszula; Kuliszkiewicz-Janus, Malgorzata

    2016-01-01

    Background The prevalence of HCV infection in people with hemophilia is substantially higher than that in the general population (63% - 98%). Multiple transfusions and substitutive therapy have also been linked to a high risk of HBV and HIV transmission. However, the prevalence of other blood-borne viral infections in this population is less well known. Objectives This study aimed to assess the prevalence of co-infection with HBV and other blood-borne viruses in Polish HCV-infected hemophiliacs. Methods Seventy-one individuals, the majority of whom were male (94.36%), who had congenital bleeding disorders (60 had hemophilia A, five had hemophilia B, and six had other factor deficiencies) and HCV infection, which was defined as the presence of positive anti-HCV antibodies, were included in this study. The study group was divided into two subgroups according to the year in which blood donors were first tested for HBsAg in Poland. The serological markers were screened using commercially available enzyme immunoassays according to the manufacturer’s instructions. The molecular tests were performed using real-time PCR technology with commercial assays according to the manufacturer’s instructions. Results The spontaneous elimination rate of HCV RNA was 29.6%. The HCV genotype 1 was detected in 28 patients (65.1%), genotype 2 in one patient (2.3%), genotype 3 in 11 patients (25.6%), genotype 4 in two patients (4.7%), and a mixed infection with genotypes 1 and 4 was detected in one person (2.3%). Fifty-three patients (74.6%) were anti-HBc positive. Among the seven HBsAg(+) patients, three individuals were HBV-DNA positive. No occult hepatitis B was detected. In six HBsAg positive patients, the HCV RNA was positive, while one patient was also infected with HIV. The prevalence rate of past infection with HAV in the study group was 30.9%, with a tendency for a higher prevalence in older patients. The prevalence of CMV and EBV infection was high and similar to that seen in

  18. Child-Rearing Practices toward Children with Hemophilia: The Relative Importance of Clinical Characteristics and Parental Emotional Reactions.

    ERIC Educational Resources Information Center

    Banis, S.; Suurmeijer, Th. P. B. M.; van Peer, D. R.

    1999-01-01

    Addresses the relative importance of clinical characteristics of the child and parental emotional reactions, to child-rearing practices towards children with hemophilia. Results indicate that mother's emotional reactions appear to have a stronger influence on child-rearing uncertainty and overprotection than clinical characteristics of the child.…

  19. 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

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

    PubMed Central

    Lane, Jérôme; McLaren, Paul J.; Dorrell, Lucy; Shianna, Kevin V.; Stemke, Amanda; Pelak, Kimberly; Moore, Stephen; Oldenburg, Johannes; Alvarez-Roman, Maria Teresa; Angelillo-Scherrer, Anne; Boehlen, Francoise; Bolton-Maggs, Paula H.B.; Brand, Brigit; Brown, Deborah; Chiang, Elaine; Cid-Haro, Ana Rosa; Clotet, Bonaventura; Collins, Peter; Colombo, Sara; Dalmau, Judith; Fogarty, Patrick; Giangrande, Paul; Gringeri, Alessandro; Iyer, Rathi; Katsarou, Olga; Kempton, Christine; Kuriakose, Philip; Lin, Judith; Makris, Mike; Manco-Johnson, Marilyn; Tsakiris, Dimitrios A.; Martinez-Picado, Javier; Mauser-Bunschoten, Evelien; Neff, Anne; Oka, Shinichi; Oyesiku, Lara; Parra, Rafael; Peter-Salonen, Kristiina; Powell, Jerry; Recht, Michael; Shapiro, Amy; Stine, Kimo; Talks, Katherine; Telenti, Amalio; Wilde, Jonathan; Yee, Thynn Thynn; Wolinsky, Steven M.; Martinson, Jeremy; Hussain, Shehnaz K.; Bream, Jay H.; Jacobson, Lisa P.; Carrington, Mary; Goedert, James J.; Haynes, Barton F.; McMichael, Andrew J.; Goldstein, David B.; Fellay, Jacques

    2013-01-01

    Human genetic variation contributes to differences in susceptibility to HIV-1 infection. To search for novel host resistance factors, we performed a genome-wide association study (GWAS) in hemophilia patients highly exposed to potentially contaminated factor VIII infusions. Individuals with hemophilia A and a documented history of factor VIII infusions before the introduction of viral inactivation procedures (1979–1984) were recruited from 36 hemophilia treatment centers (HTCs), and their genome-wide genetic variants were compared with those from matched HIV-infected individuals. Homozygous carriers of known CCR5 resistance mutations were excluded. Single nucleotide polymorphisms (SNPs) and inferred copy number variants (CNVs) were tested using logistic regression. In addition, we performed a pathway enrichment analysis, a heritability analysis, and a search for epistatic interactions with CCR5 Δ32 heterozygosity. A total of 560 HIV-uninfected cases were recruited: 36 (6.4%) were homozygous for CCR5 Δ32 or m303. After quality control and SNP imputation, we tested 1 081 435 SNPs and 3686 CNVs for association with HIV-1 serostatus in 431 cases and 765 HIV-infected controls. No SNP or CNV reached genome-wide significance. The additional analyses did not reveal any strong genetic effect. Highly exposed, yet uninfected hemophiliacs form an ideal study group to investigate host resistance factors. Using a genome-wide approach, we did not detect any significant associations between SNPs and HIV-1 susceptibility, indicating that common genetic variants of major effect are unlikely to explain the observed resistance phenotype in this population. PMID:23372042

  1. Patient preferences in the treatment of hemophilia A: impact of storage conditions on product choice.

    PubMed

    Tischer, Bernd; Marino, Renato; Napolitano, Mariasanta

    2018-01-01

    To gain insights into the usage of factor VIII (FVIII) products by patients diagnosed with moderate/severe hemophilia A, and to assess the impact and perceived importance of product storage. In this study, 200 patients diagnosed with moderate or severe hemophilia A across seven countries participated. Data were collected via a 30-minute, face-to-face interview in six countries and via a web-based survey in the seventh country. The questionnaire evaluated the effect of six features associated with FVIII products on the choice of the product; the structure and flow of data collection was designed to eliminate potential bias. Two-thirds of the respondents were using recombinant FVIII products. Only 17% were generally dissatisfied with current FVIII products, whereas >40% of the respondents were dissatisfied with frequency of administration and storage issues when traveling. The majority noted restrictions in their daily activities, particularly travel and sports. Most of them (85%), stored their product in the refrigerator and of these, 88% believed that it should always be stored there. These patients were also less satisfied with the product overall, more concerned about storage temperature, more restricted in daily activities, and spent more time on preparation and injection compared with patients who stored their product at room temperature. Conjoint analysis revealed that origin of FVIII (plasma-derived vs recombinant) was the strongest driver of product choice among all respondents, followed by storage flexibility (temperature), reconstitution device, and administration frequency. In this study, we did not investigate the efficacy and safety of the product. Not refrigerating FVIII products was associated with greater patient satisfaction and less restriction on daily activities. If efficacy and safety are unaffected, then storing FVIII at room temperature might have a positive impact on product choice. Few patients were aware that FVIII can be stored without

  2. Patient preferences in the treatment of hemophilia A: impact of storage conditions on product choice

    PubMed Central

    Tischer, Bernd; Marino, Renato; Napolitano, Mariasanta

    2018-01-01

    Objectives To gain insights into the usage of factor VIII (FVIII) products by patients diagnosed with moderate/severe hemophilia A, and to assess the impact and perceived importance of product storage. Methods In this study, 200 patients diagnosed with moderate or severe hemophilia A across seven countries participated. Data were collected via a 30-minute, face-to-face interview in six countries and via a web-based survey in the seventh country. The questionnaire evaluated the effect of six features associated with FVIII products on the choice of the product; the structure and flow of data collection was designed to eliminate potential bias. Results Two-thirds of the respondents were using recombinant FVIII products. Only 17% were generally dissatisfied with current FVIII products, whereas >40% of the respondents were dissatisfied with frequency of administration and storage issues when traveling. The majority noted restrictions in their daily activities, particularly travel and sports. Most of them (85%), stored their product in the refrigerator and of these, 88% believed that it should always be stored there. These patients were also less satisfied with the product overall, more concerned about storage temperature, more restricted in daily activities, and spent more time on preparation and injection compared with patients who stored their product at room temperature. Conjoint analysis revealed that origin of FVIII (plasma-derived vs recombinant) was the strongest driver of product choice among all respondents, followed by storage flexibility (temperature), reconstitution device, and administration frequency. In this study, we did not investigate the efficacy and safety of the product. Conclusion Not refrigerating FVIII products was associated with greater patient satisfaction and less restriction on daily activities. If efficacy and safety are unaffected, then storing FVIII at room temperature might have a positive impact on product choice. Few patients were

  3. 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

  4. Hemorrhagic pericardial effusion as the debut of acquired hemophilia in a chronic lymphocytic leukemia patient

    PubMed Central

    Bastida, José María; Cano-Mozo, María Teresa; Lopez-Cadenas, Felix; Vallejo, Victor Eduardo; Merchán, Soraya; Santos-Montón, Cecilia; González-Calle, David; Carrillo, Javier; Martín, Ana Africa; Torres-Hernández, Jose Angel; González, Marcos; Martín-Herrero, Francisco; Pabón, Pedro; González-Porras, Jose Ramon

    2017-01-01

    Abstract Background: Acquired hemophilia A (AHA) is a rare bleeding disease caused by autoantibodies against factor VIII. Spontaneous bleeding symptoms usually affect the skin and muscle, while pericardial effusion is an extremely rare manifestation. In the elderly, anticoagulant treatment is frequent and bleeding symptoms are usually associated with this. Clinical findings: We report a hemorrhagic pericardial effusion as the AHA debut in a patient with untreated chronic lymphocytic leukemia and anticoagulated with apixaban for atrial fibrillation and chronic arterial ischemia. The patient was treated with recombinant activated factor VII to control the active bleeding and corticosteroids and cyclophosphamide to eradicate the inhibitor. In addition, a briefly review of hematological malignancies associated to acquired hemophilia was performed. Particularities: a) anticoagulant treatment may confuse the suspicion of AHA and its diagnosis; b) hemorrhagic pericardial effusion is an extremely rare presentation; c) bypassing agents raise the risk of thromboembolism; d) hematological malignancies rarely cause AHA (<20% of cases). Conclusion: A multidisciplinary team is needed to diagnose and manage AHA effectively. The use of anticoagulants may lead to the misdiagnosis of clinical symptoms. Chronic lymphocytic leukemia is one of the main causes of hematological malignancies associated. The specific treatment of CLL is still recommended in the event of active disease. PMID:29381944

  5. 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.

  6. 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...

  7. [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.

  8. Acquired hemophilia A: a review of recent data and new therapeutic options.

    PubMed

    Franchini, Massimo; Vaglio, Stefania; Marano, Giuseppe; Mengoli, Carlo; Gentili, Sara; Pupella, Simonetta; Liumbruno, Giancarlo Maria

    2017-10-01

    Acquired hemophilia A (AHA) is a rare, but potentially life-threatening, bleeding disorder caused by an autoantibody against factor VIII that interferes with its coagulant function. We performed a narrative review focusing on the diagnostic aspects of AHA and on the current treatment strategies with particular regard to new data and therapeutic developments. The management of this severe hemorrhagic disorder is based on the control of bleeding with the use of bypassing agents and on the utilization of a variety of immunosuppressant agents with the goal of eliminating the autoantibody permanently. The optimal management of AHA should be multidisciplinary and requires a close collaboration between physicians from various specialties.

  9. Impact of the underlying mutation and the route of vector administration on immune responses to factor IX in gene therapy for hemophilia B.

    PubMed

    Cao, Ou; Hoffman, Brad E; Moghimi, Babak; Nayak, Sushrusha; Cooper, Mario; Zhou, Shangzhen; Ertl, Hildegund C J; High, Katherine A; Herzog, Roland W

    2009-10-01

    Immune responses to factor IX (F.IX), a major concern in gene therapy for hemophilia, were analyzed for adeno-associated viral (AAV-2) gene transfer to skeletal muscle and liver as a function of the F9 underlying mutation. Vectors identical to those recently used in clinical trials were administered to four lines of hemophilia B mice on a defined genetic background [C3H/HeJ with deletion of endogenous F9 and transgenic for a range of nonfunctional human F.IX (hF.IX) variants]. The strength of the immune response to AAV-encoded F.IX inversely correlated with the degree of conservation of endogenous coding information and levels of endogenous antigen. Null mutation animals developed T- and B-cell responses in both protocols. However, inhibitor titers were considerably higher upon muscle gene transfer (or protein therapy). Transduced muscles of Null mice had strong infiltrates with CD8+ cells, which were much more limited in the liver and not seen for the other mutations. Sustained expression was achieved with liver transduction in mice with crm(-) nonsense and missense mutations, although they still formed antibodies upon muscle gene transfer. Therefore, endogenous expression prevented T-cell responses more effectively than antibody formation, and immune responses varied substantially depending on the protocol and the underlying mutation.

  10. 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.

  11. Economic evaluation of major knee surgery with recombinant activated factor VII in hemophilia patients with high titer inhibitors and advanced knee arthropathy: exploratory results via literature-based modeling.

    PubMed

    Ballal, Rahul D; Botteman, Marc F; Foley, Isaac; Stephens, Jennifer M; Wilke, Caitlyn T; Joshi, Ashish V

    2008-03-01

    People with severe hemophilia suffer from frequent intra-articular hemorrhages, leading to pain, swelling, reduced flexion, and arthropathy. Elective orthopedic surgery using factor VIII (FVIII) replacement to prevent uncontrolled bleeding has been endorsed as an effective treatment option for patients with severe or advanced hemophilic arthropathy. These surgeries reduce pain, restore mobility and function, and reduce the frequency of recurrent joint bleeds. Unfortunately, some patients with hemophilia develop inhibitors to FVIII, which neutralize FVIII activity and render the use of even massive amounts of FVIII replacement ineffective and surgery very risky. For this reason, elective surgical procedures in high-titer inhibitor patients had largely been abandoned until the introduction of new agents, such as recombinant activated factor VII (rFVIIa, NovoSeven, Novo Nordisk A/S, Denmark). rFVIIa has been shown effective for prophylaxis during elective surgery and has therefore improved the feasibility of orthopedic surgery in hemophilia patients with high-titer inhibitors. The present research explored, from a modified US payer perspective, the direct economic and quality of life benefits of four different elective knee surgeries (total knee replacement [TKR], knee arthrodesis [KA], proximal tibial osteotomy, and distal femoral osteotomy) with rFVIIa coverage in hemophilia patients with high-titer inhibitors. An exploratory literature-based life-table model was developed to compare the direct medical costs and quality of life of two hypothetical cohorts of high-titer inhibitor patients with frequent bleeding episodes: one undergoing and the other not undergoing elective knee surgery. Knee surgery costs included perioperative rFVIIa costs, inpatient and rehabilitation care, and repeat procedures due to surgery failure, prosthesis loosening or deep infection. Based on efficacy studies, knee surgery was assumed to reduce mean annual bleeding episodes at the affected

  12. Hazardous Gas Leak Analysis in the Space Shuttle

    NASA Technical Reports Server (NTRS)

    Barile, Ronald G.

    1991-01-01

    Helium tests of the main propulsion system in the Space Shuttle and on hydrogen leaks are examined. The hazardous gas detection system (HGDS) in the mobile launch pad uses mass spectrometers (MS) to monitor the shuttle environment for leaks. The mass spectrometers are fed by long tubes to sample gas from the payload bay, mid-body, aft engine compartment, and external tank. The purpose is to improve the HGDS, especially in its potential for locating cryogen leaks. Pre-existing leak data was analyzed for transient information to determine if the leak location could be pinpointed from test data. A rapid response leak detection experiment was designed, built, and tested. Large eddies and vortices were visually seen with Schlieren imaging, and they were detected in the time plots of the various instruments. The response time of the MS was found in the range of 0.05 to 0.1 sec. Pulsed concentration waves were clearly detected at 25 cycles per sec by spectral analysis of MS data. One conclusion is that the backup HGDS sampling frequency should be increased above the present rate of 1 sample per second.

  13. Effects of Therapeutic Exercise and Hydrotherapy on Pain Severity and Knee Range of Motion in Patients with Hemophilia: A Randomized Controlled Trial

    PubMed Central

    Mazloum, Vahid; Rahnama, Nader; Khayambashi, Khalil

    2014-01-01

    Background: Pain and limited range of motion (ROM) are the crucial subsequent results of joint hemorrhages in individuals with bleeding disorders and hemophilia. Exercise interventions are particularly recommended in treatment of such patients. The purpose of this study was to detect the influences of conventional exercise therapy and hydrotherapy on the knee joint complications in patients with hemophilia. Methods: A total of 40 patients engaging hemophilia A were randomized into one of three groups: Therapeutic exercise (N = 13), hydrotherapy (N = 14) or control (N = 13). While the first two groups followed their specific programs for 4 weeks, routine life-style was maintained by subjects in the control group in this period. To evaluate the pain level and knee ROM the visual analog scale and standard goniometer were utilized, respectively. The outcome was measured at baseline and after completing the prescribed protocols. Data analysis was performed using one-way analysis of variance and Scheffe statistical tests (P < 0.05). Results: Both experimental groups experienced more significant decreasing in pain level (P < 0.001) and knee flexion and extension ROM (P < 0.001) in comparison to the control group. Although the pain was significantly (P < 0.01) more alleviated in participants treated through hydrotherapy in comparison to exercise therapy, the difference in ROM improvement was not statistically significant (P > 0.05). Conclusions: Using hydrotherapy in addition to usual rehabilitation training can result in beneficial effect in terms of pain and knee joint ROM. However, it appears that hydrotherapy is more effective in reducing pain. PMID:24554996

  14. Effects of therapeutic exercise and hydrotherapy on pain severity and knee range of motion in patients with hemophilia: a randomized controlled trial.

    PubMed

    Mazloum, Vahid; Rahnama, Nader; Khayambashi, Khalil

    2014-01-01

    Pain and limited range of motion (ROM) are the crucial subsequent results of joint hemorrhages in individuals with bleeding disorders and hemophilia. Exercise interventions are particularly recommended in treatment of such patients. The purpose of this study was to detect the influences of conventional exercise therapy and hydrotherapy on the knee joint complications in patients with hemophilia. A total of 40 patients engaging hemophilia A were randomized into one of three groups: Therapeutic exercise (N = 13), hydrotherapy (N = 14) or control (N = 13). While the first two groups followed their specific programs for 4 weeks, routine life-style was maintained by subjects in the control group in this period. To evaluate the pain level and knee ROM the visual analog scale and standard goniometer were utilized, respectively. The outcome was measured at baseline and after completing the prescribed protocols. Data analysis was performed using one-way analysis of variance and Scheffe statistical tests (P < 0.05). Both experimental groups experienced more significant decreasing in pain level (P < 0.001) and knee flexion and extension ROM (P < 0.001) in comparison to the control group. Although the pain was significantly (P < 0.01) more alleviated in participants treated through hydrotherapy in comparison to exercise therapy, the difference in ROM improvement was not statistically significant (P > 0.05). Using hydrotherapy in addition to usual rehabilitation training can result in beneficial effect in terms of pain and knee joint ROM. However, it appears that hydrotherapy is more effective in reducing pain.

  15. Radiosynovectomy in rheumatology, orthopedics, and hemophilia.

    PubMed

    Schneider, Peter; Farahati, Jamshid; Reiners, Christoph

    2005-01-01

    Radiosynovectomy (RSV) is a local intraarticular injection of radionuclides in colloidal form for radiotherapy. First used by Fellinger et al. in 1952, the technique has now been applied for more than 50 y for treatment of resistant synovitis of individual joints after failure of long-term systemic pharmacotherapy and intraarticular steroid injections. RSV relieves pain and inflammation from rheumatoid arthritis (RA), for which it initially was used, and is accepted as an alternative to surgical synovectomy in cases of RA or other inflammatory arthropathies such as osteoarthritis and hemophiliac arthropathy. A good understanding of the clinical pathophysiology of the disease processes is mandatory, and close interdisciplinary collaboration with other clinicians who diagnose and treat patients is strongly suggested. Reported success rates range from 40% to 90% for the different joints and underlying diseases. A few well-designed prospective double-blind trials have evaluated the efficacy of RSV and justified the procedure as a viable option for treating chronic synovitis in RA or secondary to inflammatory arthropathies. In comparison with surgical synovectomy, RSV produces equivalent results, costs less, allows the patient to remain ambulatory, and is repeatable. RSV has to be considered the initial procedure of choice for the treatment of patients with hemarthrosis in hemophilia. In addition, local instillation of radiopharmaceuticals can effectively reduce effusions after implantation of a prosthesis.

  16. 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

  17. 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

  18. Genetic Correction and Hepatic Differentiation of Hemophilia B-specific Human Induced Pluripotent Stem Cells.

    PubMed

    He, Qiong; Wang, Hui-Hui; Cheng, Tao; Yuan, Wei-Ping; Ma, Yu-Po; Jiang, Yong-Ping; Ren, Zhi-Hua

    2017-09-27

    Objective To genetically correct a disease-causing point mutation in human induced pluripotent stem cells (iPSCs) derived from a hemophilia B patient. Methods First, the disease-causing mutation was detected by sequencing the encoding area of human coagulation factor IX (F IX) gene. Genomic DNA was extracted from the iPSCs, and the primers were designed to amplify the eight exons of F IX. Next, the point mutation in those iPSCs was genetically corrected using CRISPR/Cas9 technology in the presence of a 129-nucleotide homologous repair template that contained two synonymous mutations. Then, top 8 potential off-target sites were subsequently analyzed using Sanger sequencing. Finally, the corrected clones were differentiated into hepatocyte-like cells, and the secretion of F IX was validated by immunocytochemistry and ELISA assay. Results The cell line bore a missense mutation in the 6 th coding exon (c.676 C>T) of F IX gene. Correction of the point mutation was achieved via CRISPR/Cas9 technology in situ with a high efficacy at about 22% (10/45) and no off-target effects detected in the corrected iPSC clones. F IX secretion, which was further visualized by immunocytochemistry and quantified by ELISA in vitro, reached about 6 ng/ml on day 21 of differentiation procedure. Conclusions Mutations in human disease-specific iPSCs could be precisely corrected by CRISPR/Cas9 technology, and corrected cells still maintained hepatic differentiation capability. Our findings might throw a light on iPSC-based personalized therapies in the clinical application, especially for hemophilia B.

  19. The story of a unique molecule in hemophilia A: recombinant single-chain factor VIII.

    PubMed

    Pabinger-Fasching, Ingrid

    2016-05-01

    For patients with hemophilia A, replacement of deficient factor VIII (FVIII) using plasma-derived or recombinant FVIII (rFVIII) products to restore hemostatic control can reduce bleeding complications and preserve musculoskeletal function. Despite the clinical availability of several of these products, challenges remain in the treatment of hemophilia A, the most notable of which are the risk of inhibitor development and the limited half-life of existing FVIII concentrates, which can make prophylaxis burdensome for patients. The use of recombinant protein technology may lead to novel FVIII products with improved properties. This article describes the story of a unique recombinant FVIII protein, rVIII-SingleChain, which is currently in development. In contrast to native FVIII and other commercially available rFVIII preparations, rVIII-SingleChain uses a strong, covalent bond to connect the light and heavy chains, thereby creating a stable, single-chain rFVIII. It has enhanced intrinsic stability, better integrity after reconstitution, and a higher binding affinity to von Willebrand factor. The physicochemical profile of rVIII-SingleChain and preclinical data on its activity and phamacokinetics strengthened the rationale for its clinical investigation. Available data from the AFFINITY clinical trial program are promising; indicating that it has good hemostatic efficacy when used on demand, for prophylaxis, and in the surgical setting, and is also very well tolerated. A pediatric study and an extension study are ongoing as part of the AFFINITY program. © 2016 Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

  20. Efficacy and safety of rVIII-SingleChain: results of a phase 1/3 multicenter clinical trial in severe hemophilia A

    PubMed Central

    Mahlangu, Johnny; Kuliczkowski, Kazimierz; Karim, Faraizah Abdul; Stasyshyn, Oleksandra; Kosinova, Marina V.; Lepatan, Lynda Mae; Skotnicki, Aleksander; Boggio, Lisa N.; Klamroth, Robert; Oldenburg, Johannes; Hellmann, Andrzej; Santagostino, Elena; Baker, Ross I.; Fischer, Kathelijn; Gill, Joan C.; P’Ng, Stephanie; Chowdary, Pratima; Escobar, Miguel A.; Khayat, Claudia Djambas; Rusen, Luminita; Bensen-Kennedy, Debra; Blackman, Nicole; Limsakun, Tharin; Veldman, Alex; St. Ledger, Katie

    2016-01-01

    Recombinant VIII (rVIII)-SingleChain is a novel B-domain–truncated recombinant factor VIII (rFVIII), comprised of covalently bonded factor VIII (FVIII) heavy and light chains. It was designed to have a higher binding affinity for von Willebrand factor (VWF). This phase 1/3 study investigated the efficacy and safety of rVIII-SingleChain in the treatment of bleeding episodes, routine prophylaxis, and surgical prophylaxis. Participants were ≥12 years of age, with severe hemophilia A (endogenous FVIII <1%). The participants were allocated by the investigator to receive rVIII-SingleChain in either an on-demand or prophylaxis regimen. Of the 175 patients meeting study eligibility criteria, 173 were treated with rVIII-SingleChain, prophylactically (N = 146) or on-demand (N = 27). The total cumulative exposure was 14 306 exposure days (EDs), with 120 participants reaching ≥50 EDs and 52 participants having ≥100 EDs. Hemostatic efficacy was rated by the investigator as excellent or good in 93.8% of the 835 bleeds treated and assessed. Across all prophylaxis regimens, the median annualized spontaneous bleeding rate was 0.00 (Q1, Q3: 0.0, 2.4) and the median overall annualized bleeding rate (ABR) was 1.14 (Q1, Q3: 0.0, 4.2). Surgical hemostasis was rated as excellent/good in 100% of major surgeries by the investigator. No participant developed FVIII inhibitors. In conclusion, rVIII-SingleChain is a novel rFVIII molecule showing excellent hemostatic efficacy in surgery and in the control of bleeding events, low ABR in patients on prophylaxis, and a favorable safety profile in this large clinical study. This trial was registered at www.clinicaltrials.gov as #NCT01486927. PMID:27330001

  1. Efficacy and safety of rVIII-SingleChain: results of a phase 1/3 multicenter clinical trial in severe hemophilia A.

    PubMed

    Mahlangu, Johnny; Kuliczkowski, Kazimierz; Karim, Faraizah Abdul; Stasyshyn, Oleksandra; Kosinova, Marina V; Lepatan, Lynda Mae; Skotnicki, Aleksander; Boggio, Lisa N; Klamroth, Robert; Oldenburg, Johannes; Hellmann, Andrzej; Santagostino, Elena; Baker, Ross I; Fischer, Kathelijn; Gill, Joan C; P'Ng, Stephanie; Chowdary, Pratima; Escobar, Miguel A; Khayat, Claudia Djambas; Rusen, Luminita; Bensen-Kennedy, Debra; Blackman, Nicole; Limsakun, Tharin; Veldman, Alex; St Ledger, Katie; Pabinger, Ingrid

    2016-08-04

    Recombinant VIII (rVIII)-SingleChain is a novel B-domain-truncated recombinant factor VIII (rFVIII), comprised of covalently bonded factor VIII (FVIII) heavy and light chains. It was designed to have a higher binding affinity for von Willebrand factor (VWF). This phase 1/3 study investigated the efficacy and safety of rVIII-SingleChain in the treatment of bleeding episodes, routine prophylaxis, and surgical prophylaxis. Participants were ≥12 years of age, with severe hemophilia A (endogenous FVIII <1%). The participants were allocated by the investigator to receive rVIII-SingleChain in either an on-demand or prophylaxis regimen. Of the 175 patients meeting study eligibility criteria, 173 were treated with rVIII-SingleChain, prophylactically (N = 146) or on-demand (N = 27). The total cumulative exposure was 14 306 exposure days (EDs), with 120 participants reaching ≥50 EDs and 52 participants having ≥100 EDs. Hemostatic efficacy was rated by the investigator as excellent or good in 93.8% of the 835 bleeds treated and assessed. Across all prophylaxis regimens, the median annualized spontaneous bleeding rate was 0.00 (Q1, Q3: 0.0, 2.4) and the median overall annualized bleeding rate (ABR) was 1.14 (Q1, Q3: 0.0, 4.2). Surgical hemostasis was rated as excellent/good in 100% of major surgeries by the investigator. No participant developed FVIII inhibitors. In conclusion, rVIII-SingleChain is a novel rFVIII molecule showing excellent hemostatic efficacy in surgery and in the control of bleeding events, low ABR in patients on prophylaxis, and a favorable safety profile in this large clinical study. This trial was registered at www.clinicaltrials.gov as #NCT01486927. © 2016 by The American Society of Hematology.

  2. Direct Acting Antiviral Agents in Korean Patients with Chronic Hepatitis C and Hemophilia Who Are Treatment-Naïve or Treatment-Experienced.

    PubMed

    Lee, Hyun Woong; Yoo, Ki Young; Won, Joung Won; Kim, Hyung Joon

    2017-09-15

    Chronic hepatitis C (CHC) is a major comorbidity in patients with hemophilia. Patients (n=30) were enrolled between September 2015 and April 2016. Twenty-six patients were genotype 1 (1b, n=21; 1a, n=5) and four patients were genotype 2a/2b. Among 21 patients with genotype 1b, Y93H resistance-associated variants (RAVs) were detected in three patients (14.3%). We evaluated sustained virologic response (SVRs) at 12 weeks, as well as relapse and safety. Five patients with genotype 1a and three patients with genotype 1b (RAV positive) received ledipasvir/sofosbuvir for 12 weeks. SVR12 rate was 100% (8/8). Eleven patients with genotype 1b were treatment-naïve and received daclatasvir plus asunaprevir for 24 weeks. SVR12 rate was 91% (10/11). One patient experienced viral breakthrough without RAV at 12 weeks. Seven treatment-experienced patients with genotype 1b received daclatasvir plus asunaprevir for 24 weeks. SVR12 rate was 85.7% (6/7). One patient experienced viral breakthrough with RAV (L31M, Y93H) at 12 weeks. Four patients with genotype 2a/2b received sofosbuvir plus ribavirin for 12 weeks. SVR12 rate was 100% (4/4). No serious adverse event-related discontinuations were noted. New direct acting antiviral treatment achieved high SVRs rates at 12 weeks in CHC patients with hemophilia without serious adverse events.

  3. Direct Acting Antiviral Agents in Korean Patients with Chronic Hepatitis C and Hemophilia Who Are Treatment-Naïve or Treatment-Experienced

    PubMed Central

    Lee, Hyun Woong; Yoo, Ki Young; Won, Joung Won; Kim, Hyung Joon

    2017-01-01

    Background/Aims Chronic hepatitis C (CHC) is a major comorbidity in patients with hemophilia. Methods Patients (n=30) were enrolled between September 2015 and April 2016. Twenty-six patients were genotype 1 (1b, n=21; 1a, n=5) and four patients were genotype 2a/2b. Among 21 patients with genotype 1b, Y93H resistance-associated variants (RAVs) were detected in three patients (14.3%). We evaluated sustained virologic response (SVRs) at 12 weeks, as well as relapse and safety. Results Five patients with genotype 1a and three patients with genotype 1b (RAV positive) received ledipasvir/sofosbuvir for 12 weeks. SVR12 rate was 100% (8/8). Eleven patients with genotype 1b were treatment-naïve and received daclatasvir plus asunaprevir for 24 weeks. SVR12 rate was 91% (10/11). One patient experienced viral breakthrough without RAV at 12 weeks. Seven treatment-experienced patients with genotype 1b received daclatasvir plus asunaprevir for 24 weeks. SVR12 rate was 85.7% (6/7). One patient experienced viral breakthrough with RAV (L31M, Y93H) at 12 weeks. Four patients with genotype 2a/2b received sofosbuvir plus ribavirin for 12 weeks. SVR12 rate was 100% (4/4). No serious adverse event-related discontinuations were noted. Conclusions New direct acting antiviral treatment achieved high SVRs rates at 12 weeks in CHC patients with hemophilia without serious adverse events. PMID:28874040

  4. A Pharmacometric Approach to Substitute for a Conventional Dose-Finding Study in Rare Diseases: Example of Phase III Dose Selection for Emicizumab in Hemophilia A.

    PubMed

    Yoneyama, Koichiro; Schmitt, Christophe; Kotani, Naoki; Levy, Gallia G; Kasai, Ryu; Iida, Satofumi; Shima, Midori; Kawanishi, Takehiko

    2017-12-06

    Emicizumab (ACE910) is a bispecific antibody mimicking the cofactor function of activated coagulation factor VIII. In phase I-I/II studies, emicizumab reduced the bleeding frequency in patients with severe hemophilia A, regardless of the presence of factor VIII inhibitors, at once-weekly subcutaneous doses of 0.3, 1, and 3 mg/kg. Using the phase I-I/II study data, population pharmacokinetic and repeated time-to-event (RTTE) modeling were performed to quantitatively characterize the relationship between the pharmacokinetics of emicizumab and reduction in bleeding frequency. Simulations were then performed to identify the minimal exposure expected to achieve zero bleeding events for 1 year in at least 50% of patients and to select the dosing regimens to be tested in phase III studies. The RTTE model adequately predicted the bleeding onset over time as a function of plasma emicizumab concentration. Simulations suggested that plasma emicizumab concentrations of ≥  45 μg/mL should result in zero bleeding events for 1 year in at least 50% of patients. This efficacious exposure provided the basis for selecting previously untested dosing regimens of 1.5 mg/kg once weekly, 3 mg/kg every 2 weeks, and 6 mg/kg every 4 weeks for phase III studies. A pharmacometric approach guided the phase III dose selection of emicizumab in hemophilia A, without conducting a conventional dose-finding study. Phase III studies with the selected dosing regimens are currently ongoing. This case study indicates that a pharmacometric approach can substitute for a conventional dose-finding study in rare diseases and will streamline the drug development process.

  5. 42 CFR 130.3 - Amount of payments.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 42 Public Health 1 2010-10-01 2010-10-01 false Amount of payments. 130.3 Section 130.3 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES COMPASSIONATE PAYMENTS RICKY RAY HEMOPHILIA RELIEF FUND PROGRAM General Provisions § 130.3 Amount of payments. If there are sufficient amounts...

  6. Successful transduction of liver in hemophilia by AAV-Factor IX and limitations imposed by the host immune response.

    PubMed

    Manno, Catherine S; Pierce, Glenn F; Arruda, Valder R; Glader, Bertil; Ragni, Margaret; Rasko, John J; Rasko, John; Ozelo, Margareth C; Hoots, Keith; Blatt, Philip; Konkle, Barbara; Dake, Michael; Kaye, Robin; Razavi, Mahmood; Zajko, Albert; Zehnder, James; Rustagi, Pradip K; Nakai, Hiroyuki; Chew, Amy; Leonard, Debra; Wright, J Fraser; Lessard, Ruth R; Sommer, Jürg M; Tigges, Michael; Sabatino, Denise; Luk, Alvin; Jiang, Haiyan; Mingozzi, Federico; Couto, Linda; Ertl, Hildegund C; High, Katherine A; Kay, Mark A

    2006-03-01

    We have previously shown that a single portal vein infusion of a recombinant adeno-associated viral vector (rAAV) expressing canine Factor IX (F.IX) resulted in long-term expression of therapeutic levels of F.IX in dogs with severe hemophilia B. We carried out a phase 1/2 dose-escalation clinical study to extend this approach to humans with severe hemophilia B. rAAV-2 vector expressing human F.IX was infused through the hepatic artery into seven subjects. The data show that: (i) vector infusion at doses up to 2 x 10(12) vg/kg was not associated with acute or long-lasting toxicity; (ii) therapeutic levels of F.IX were achieved at the highest dose tested; (iii) duration of expression at therapeutic levels was limited to a period of approximately 8 weeks; (iv) a gradual decline in F.IX was accompanied by a transient asymptomatic elevation of liver transaminases that resolved without treatment. Further studies suggested that destruction of transduced hepatocytes by cell-mediated immunity targeting antigens of the AAV capsid caused both the decline in F.IX and the transient transaminitis. We conclude that rAAV-2 vectors can transduce human hepatocytes in vivo to result in therapeutically relevant levels of F.IX, but that future studies in humans may require immunomodulation to achieve long-term expression.

  7. Effectiveness of an Educational Physiotherapy and Therapeutic Exercise Program in Adult Patients With Hemophilia: A Randomized Controlled Trial.

    PubMed

    Cuesta-Barriuso, Rubén; Torres-Ortuño, Ana; Nieto-Munuera, Joaquín; López-Pina, José Antonio

    2017-05-01

    To assess the efficacy of an educational physiotherapy home exercise intervention for physical improvement, pain perception, quality of life, and illness behavior in patients with hemophilic arthropathy. Single-blind randomized controlled trial. Home. Patients with hemophilia (N=20) were randomly allocated to an educational intervention group or to a control group. The educational intervention was performed every 2 weeks over a 15-week period, and home exercises were carried out once a day, 6 days a week, over the same period. Joint status was evaluated using the Gilbert scale; pain was assessed using the visual analog scale; illness behavior was evaluated using the Illness Behavior Questionnaire; and the perception of the quality of life was evaluated using the A36 Hemophilia-QoL questionnaire. We observed significant differences in the intervention group and the control group for both quality of life and illness behavior. There was no significant improvement in joint status; however, an improvement was noted in terms of perception of pain in the ankle. A physiotherapy program based on educational sessions and home exercises can improve the perception of pain in patients with hemophilic arthropathy of the ankle. It improves some variables in the perception of the quality of life and illness behavior. Copyright © 2016 American Congress of Rehabilitation Medicine. Published by Elsevier Inc. All rights reserved.

  8. 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

  9. Long-term correction of canine hemophilia B by gene transfer of blood coagulation factor IX mediated by adeno-associated viral vector.

    PubMed

    Herzog, R W; Yang, E Y; Couto, L B; Hagstrom, J N; Elwell, D; Fields, P A; Burton, M; Bellinger, D A; Read, M S; Brinkhous, K M; Podsakoff, G M; Nichols, T C; Kurtzman, G J; High, K A

    1999-01-01

    Hemophilia B is a severe X-linked bleeding diathesis caused by the absence of functional blood coagulation factor IX, and is an excellent candidate for treatment of a genetic disease by gene therapy. Using an adeno-associated viral vector, we demonstrate sustained expression (>17 months) of factor IX in a large-animal model at levels that would have a therapeutic effect in humans (up to 70 ng/ml, adequate to achieve phenotypic correction, in an animal injected with 8.5x10(12) vector particles/kg). The five hemophilia B dogs treated showed stable, vector dose-dependent partial correction of the whole blood clotting time and, at higher doses, of the activated partial thromboplastin time. In contrast to other viral gene delivery systems, this minimally invasive procedure, consisting of a series of percutaneous intramuscular injections at a single timepoint, was not associated with local or systemic toxicity. Efficient gene transfer to muscle was shown by immunofluorescence staining and DNA analysis of biopsied tissue. Immune responses against factor IX were either absent or transient. These data provide strong support for the feasibility of the approach for therapy of human subjects.

  10. A Fully Redundant On-Line Mass Spectrometer System Used to Monitor Cryogenic Fuel Leaks on the Space Shuttle

    NASA Technical Reports Server (NTRS)

    Griffin, T. P.; Naylor, G. R.; Haskell, W. D.; Breznik, G. S.; Mizell, C. A.; Steinrock, Todd (Technical Monitor)

    2001-01-01

    This paper presents an on-line mass spectrometer designed to monitor for cryogenic leaks on the Space Shuttle. The topics include: 1) Hazardous Gas Detection Lab; 2) LASRE Test Support; 3) Background; 4) Location of Systems; 5) Sample Lines for Gas Detection; 6) Problems with Current Systems; 7) Requirements for New System (Nitrogen and Helium Background); and 8) HGDS 2000. This paper is in viewgraph form.

  11. Long-term efficacy and safety of prophylaxis with recombinant factor VIII in Chinese pediatric patients with hemophilia A: a multi-center, retrospective, non-interventional, phase IV (ReCARE) study.

    PubMed

    Li, Changgang; Zhang, Xinsheng; Zhao, Yongqiang; Wu, Runhui; Hu, Qun; Xu, Weiqun; Sun, Jing; Yang, Renchi; Li, Xiaojing; Zhou, Rongfu; Lian, Shinmei; Gu, Jian; Wu, Junde; Hou, Qingsong

    2017-07-01

    The first recombinant factor VIII (rFVIII) product was launched in China in 2007. However, until now, no study has been conducted to describe the efficacy and safety of prophylaxis with rFVIII in Chinese pediatric patients with hemophilia A (HA). To summarize the efficacy and safety data on prophylaxis with rFVIII in Chinese pediatric patients with HA. ReCARE (Retrospective study in Chinese pediatric hemophilia A patients with rFVIII contained regular prophylaxis) was a retrospective study conducted in 12 hemophilia treatment centers (HTCs) across China. The primary endpoints included reduction in annualized bleeding rate (ABR); the secondary endpoints included evaluation of joint function (number and sites of target joints) using Gilbert score and Hemophilia Joint Health Score (HJHS), quality of life (QoL) and factors affecting treatment choices. Safety assessment of rFVIII was also conducted. We analyzed a total of 183 male pediatric patients (mean age, 7.1 ± 4.23 years) who received prophylaxis between 1 November 2007 and 31 May 2013. Compared with baseline, prophylaxis with rFVIII significantly reduced overall annualized joint bleed rate (AJBR) (p < .001) and ABR (p < .001). Inhibitor formation was reported in 5 (2.7%) patients and hemarthrosis was reported in 1 patient. The mean number of target joints was positively related to age (p < .001) and weight (p = .003) at baseline. Responses from survey questionnaires reported that effective bleeding control, joint protection, improvement in quality of life, favorable medical insurance policies, and economic capability were reasons for choosing prophylaxis. Prophylaxis with rFVIII reduced bleeding and number of target joints, even with a low-dose regimen, in Chinese pediatric patients with HA. Other than the efficacy and safety, factors such as poor disease control, improved economic stability and stable financial support made prophylaxis as an attractive treatment option. ClinicalTrials.gov ID

  12. An interactive mutation database for human coagulation factor IX provides novel insights into the phenotypes and genetics of hemophilia B.

    PubMed

    Rallapalli, P M; Kemball-Cook, G; Tuddenham, E G; Gomez, K; Perkins, S J

    2013-07-01

    Factor IX (FIX) is important in the coagulation cascade, being activated to FIXa on cleavage. Defects in the human F9 gene frequently lead to hemophilia B. To assess 1113 unique F9 mutations corresponding to 3721 patient entries in a new and up-to-date interactive web database alongside the FIXa protein structure. The mutations database was built using MySQL and structural analyses were based on a homology model for the human FIXa structure based on closely-related crystal structures. Mutations have been found in 336 (73%) out of 461 residues in FIX. There were 812 unique point mutations, 182 deletions, 54 polymorphisms, 39 insertions and 26 others that together comprise a total of 1113 unique variants. The 64 unique mild severity mutations in the mature protein with known circulating protein phenotypes include 15 (23%) quantitative type I mutations and 41 (64%) predominantly qualitative type II mutations. Inhibitors were described in 59 reports (1.6%) corresponding to 25 unique mutations. The interactive database provides insights into mechanisms of hemophilia B. Type II mutations are deduced to disrupt predominantly those structural regions involved with functional interactions. The interactive features of the database will assist in making judgments about patient management. © 2013 International Society on Thrombosis and Haemostasis.

  13. The pharmacokinetics of a B-domain truncated recombinant factor VIII, turoctocog alfa (NovoEight®), in patients with hemophilia A.

    PubMed

    Jiménez-Yuste, V; Lejniece, S; Klamroth, R; Suzuki, T; Santagostino, E; Karim, F A; Saugstrup, T; Møss, J

    2015-03-01

    Turoctocog alfa (NovoEight(®)) is a human recombinant coagulation factor VIII (rFVIII) for the treatment of patients with hemophilia A. To evaluate the pharmacokinetics of turoctocog alfa in all age groups across clinical trials. Data from previously treated patients with severe hemophilia A (FVIII activity level of ≤ 1%) with no history of FVIII inhibitors, in a non-bleeding state, were included. The pharmacokinetics were assessed following a wash-out period and a subsequent single intravenous 50 IU kg(-1) dose of turoctocog alfa. Blood was sampled during a 48-h period postdose. Standard pharmacokinetic (PK) parameters were estimated on the basis of plasma FVIII activity vs. time (PK profiles) with non-compartmental methods. Furthermore, a population PK analysis was conducted. Data from 76 patients (aged 1-60 years) enrolled globally across six clinical trials were included, totaling 105 turoctocog alfa PK profiles. Single-dose PK results 3-6 months after the first dose of turoctocog alfa were comparable with the results obtained after the first dose. Similar PK characteristics were shown for different lots and strengths of the drug product. Overall, area under the plasma concentration (activity) curve from administration to infinity (AUC) and t1(/2) tended to increase with increasing age, with lower AUC and shorter t(1/2) being seen in children than in adolescents and adults. The PK profiles of turoctocog alfa and other commercially available plasma-derived FVIII and rFVIII products were similar in all age groups. The PK characteristics of turoctocog alfa have been thoroughly studied, and shown to be consistent over time, reproducible between different lots and strengths of drug product, and similar to those observed for other FVIII products. © 2014 International Society on Thrombosis and Haemostasis.

  14. Low cost industrial production of coagulation factor IX bioencapsulated in lettuce cells for oral tolerance induction in hemophilia B

    PubMed Central

    Su, Jin; Zhu, Liqing; Sherman, Alexandra; Wang, Xiaomei; Lin, Shina; Kamesh, Aditya; Norikane, Joey H.; Streatfield, Stephen J.; Herzog, Roland W.; Daniell, Henry

    2015-01-01

    Antibodies (inhibitors) developed by hemophilia B patients against coagulation factor IX (FIX) are challenging to eliminate because of anaphylaxis or nephrotic syndrome after continued infusion. To address this urgent unmet medical need, FIX fused with a transmucosal carrier (CTB) was produced in a commercial lettuce (Simpson Elite) cultivar using species specific chloroplast vectors regulated by endogenous psbA sequences. CTB-FIX (~1mg/g) in lyophilized cells was stable with proper folding, disulfide bonds and pentamer assembly when stored ~2 years at ambient temperature. Feeding lettuce cells to hemophilia B mice delivered CTB-FIX efficiently to the gut immune system, induced LAP+ regulatory T cells and suppressed inhibitor/IgE formation and anaphylaxis against FIX. Lyophilized cells enabled 10-fold dose escalation studies and successful induction of oral tolerance was observed in all tested doses. Induction of tolerance in such a broad dose range should enable oral delivery to patients of different age groups and diverse genetic background. Using Fraunhofer cGMP hydroponic system, ~870 kg fresh or 43.5 kg dry weight can be harvested per 1000 ft2 per annum yielding 24,000–36,000 doses for 20-kg pediatric patients, enabling first commercial development of an oral drug, addressing prohibitively expensive purification, cold storage/transportation and short shelf life of current protein drugs. PMID:26302233

  15. Real-World Analysis of Dispensed IUs of Coagulation Factor IX and Resultant Expenditures in Hemophilia B Patients Receiving Standard Half-life Versus Extended Half-life Products and Those Switching from Standard Half-life to Extended Half-life Products.

    PubMed

    Tortella, Bartholomew J; Alvir, José; McDonald, Margaret; Spurden, Dean; Fogarty, Patrick F; Chhabra, Amit; Pleil, Andreas M

    2018-01-24

    Hemophilia B requires replacement therapy with factor IX (FIX) coagulation products to treat and prevent bleeding episodes. A recently introduced extended half-life (EHL) recombinant FIX replacement product provided the opportunity to compare the amount of dispensed factor and expenditures for EHL treatment compared with a standard half-life (SHL) product. To determine factor international units (IUs) dispensed and expenditures associated with switching from nonacog alfa, the most commonly used SHL replacement product, to eftrenonacog alfa, an EHL FIX replacement product. Two U.S. claims databases were analyzed. A large national specialty pharmacy dispensation claims database was used to identify the number of IUs dispensed and monthly charges for all patients with hemophilia B from April 2015 to June 2016. Truven Health MarketScan Research Databases (January 2010-July 2016) were used to identify IUs and expenditures for patients with claims data for at least 3 months before and after switching from the SHL to the EHL product. Medians for IUs and expenditures are presented to accommodate for skewness of data distribution. The national specialty pharmacy database analysis included 296 patients with moderate or severe hemophilia B (233 on SHL; 94 on EHL). Median monthly factor dispensed was 11% lower (2,142 IU) in the EHL versus SHL cohort over the study period, while individual monthly reductions ranged from 32% to 47% (9,838 IU to 16,514 IU). Using the wholesale acquisition cost, the median per-patient monthly factor expenditures over the 15-month study period were 94% higher ($23,005) for the EHL than for the SHL product. Individual median monthly expenditure differences ranged from 15% ($6,562) to 49% ($19,624). In the Truven database, 14 patients switched from the SHL to the EHL product. The amount of factor dispensed was variable; in the 1-year period before and after the switch from the SHL to the EHL product, mean IUs dispensed decreased by 3,005 IU, while

  16. The upward spiral of drug costs: a time series analysis of drugs used in the treatment of hemophilia.

    PubMed

    Rogoff, Edward G; Guirguis, Hany S; Lipton, Richard A; Seremetis, Stephanie V; DiMichele, Donna M; Agnew, George M; Karpatkin, Margaret; Barish, Robert J; Jones, Robert L; Bianco, Celso; Knothe, Barbara D; Lee, Myung-Soo

    2002-10-01

    Hemophilia is an expensive disease because its treatment is heavily dependent on costly clotting factor drugs. Over the last nine years,a consortium of three Comprehensive Hemophilia Treatment Centers and other hospitals, which purchased clotting factors for their patients, has seen treatment costs escalate on average 17% annually. Currently, new, even more expensive drugs are entering the market. This study analyzes 3,244 purchases that were made over a nine-year period totaling nearly 500 million units of clotting factor, representing every product on the market. Purchases were made both apart from and under the Federal Public Health Service (PHS)discount pricing rules. The main cause of the increases was the move to newer, more expensive products. The average price of existing products increased less than 2%per year, but new products were priced, on average, 47% higher than existing products. Overall consumption increased by an average of 5% per year, likely reflecting prophylactic treatment modalities that require greater amounts of clotting factor. Government pricing programs, such as the PHS program, were ineffective or counterproductive at reducing costs. There is a notable absence of competition in this market, with a few dominant companies having a functional monopoly in the largest segments of the market. Prices of older products are not lowered, even when new products are brought to market. A few products that serve small patient groups have had their prices increased substantially. This escalation is likely to continue as new, more expensive clotting factor drugs are developed. Since these new products are not proven to be any safer or more effective than the current products, this situation creates a risk of intervention by government and insurers to address both treatment costs and exhaustion of patients' insurance caps. Drug companies are not serving the patients by pricing new, but often very similar, products so aggressively. The trends seen in

  17. Assessments of pain, functional impairment, anxiety, and depression in US adults with hemophilia across patient-reported outcome instruments in the Pain, Functional Impairment, and Quality of Life (P-FiQ) study.

    PubMed

    Buckner, Tyler W; Batt, Katharine; Quon, Doris; Witkop, Michelle; Recht, Michael; Kessler, Craig; Baumann, Kimberly; Hernandez, Grace; Wang, Michael; Cooper, David L; Kempton, Christine L

    2018-04-01

    Pain, functional impairment, anxiety, and depression associated with joint disease may affect health-related quality of life (HRQoL) in people with hemophilia. To report detailed patient-reported outcomes (PRO) assessments related to HRQoL in participants in the Pain, Functional Impairment, and Quality of Life (P-FiQ) study. Pain and HRQoL were assessed via PRO instruments in US adult males with hemophilia A or B and a history of joint pain or bleeding. PRO instruments included EQ-5D-5L with visual analog scale, Brief Pain Inventory v2 Short Form, SF-36v2, and Hemophilia Activities List. Instrument domain and item responses were described. Responses were collected from 381 adult males with a median age of 34 years. Pain was observed across instruments and affected daily activities and quality of life. Respondents reported functional impairment that limited the kind of work and activities they participated in, with activities involving the lower extremities being most affected. A high prevalence of mental health disorders was identified across instruments. Pain and HRQoL were evaluated using multiple PRO instruments, which vary in timescales of assessment and levels of detail. More consistent clinical assessments and patient dialog regarding pain and aspects of HRQoL may help drive improved outcomes. © 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  18. Low cost industrial production of coagulation factor IX bioencapsulated in lettuce cells for oral tolerance induction in hemophilia B.

    PubMed

    Su, Jin; Zhu, Liqing; Sherman, Alexandra; Wang, Xiaomei; Lin, Shina; Kamesh, Aditya; Norikane, Joey H; Streatfield, Stephen J; Herzog, Roland W; Daniell, Henry

    2015-11-01

    Antibodies (inhibitors) developed by hemophilia B patients against coagulation factor IX (FIX) are challenging to eliminate because of anaphylaxis or nephrotic syndrome after continued infusion. To address this urgent unmet medical need, FIX fused with a transmucosal carrier (CTB) was produced in a commercial lettuce (Simpson Elite) cultivar using species specific chloroplast vectors regulated by endogenous psbA sequences. CTB-FIX (∼1 mg/g) in lyophilized cells was stable with proper folding, disulfide bonds and pentamer assembly when stored ∼2 years at ambient temperature. Feeding lettuce cells to hemophilia B mice delivered CTB-FIX efficiently to the gut immune system, induced LAP(+) regulatory T cells and suppressed inhibitor/IgE formation and anaphylaxis against FIX. Lyophilized cells enabled 10-fold dose escalation studies and successful induction of oral tolerance was observed in all tested doses. Induction of tolerance in such a broad dose range should enable oral delivery to patients of different age groups and diverse genetic background. Using Fraunhofer cGMP hydroponic system, ∼870 kg fresh or 43.5 kg dry weight can be harvested per 1000 ft(2) per annum yielding 24,000-36,000 doses for 20-kg pediatric patients, enabling first commercial development of an oral drug, addressing prohibitively expensive purification, cold storage/transportation and short shelf life of current protein drugs. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

  19. [Remission of acquired hemophilia A following radiation therapy for esophageal cancer].

    PubMed

    Yanagisawa, Kunio; Ogawa, Yoshiyuki; Mitsui, Takeki; Noguchi, Hiroyuki; Shimizu, Hiroaki; Ishizaki, Takuma; Handa, Hiroshi; Ieko, Masahiro; Ichinose, Akitada; Nojima, Yoshihisa

    2016-04-01

    Although acquired hemophilia A (AHA) often develops in patients with neoplasms, there are few reports on the efficacy of radiation therapy during the bleeding phase of AHA in the prior literature. We herein present a case of AHA experiencing remission soon after radiation therapy for esophageal cancer. A man in his seventies, who had a history of radical nephrectomy for left renal cell carcinoma, received a diagnosis of esophageal cancer. Three months later, he noticed a right thigh hematoma, and was transferred to our hospital. Laboratory data revealed a marked reduction of coagulation factor VIII (FVIII) activity at 0.9% and the inhibitor to FVIII was detected in his serum at 21.8 BU/ml. Under a diagnosis of AHA, the patient received high-dose oral prednisolone, which failed to achieve disease remission. He then underwent radiation therapy to eradicate the underlying esophageal cancer. Despite tapering of the prednisolone dosage, FVIII inhibitor declined to undetectable levels. In this case, radiation therapy for the underlying cancer was associated with achieving complete remission of AHA.

  20. AI mass spectrometers for space shuttle health monitoring

    NASA Technical Reports Server (NTRS)

    Adams, F. W.

    1991-01-01

    The facility Hazardous Gas Detection System (HGDS) at Kennedy Space Center (KSC) is a mass spectrometer based gas analyzer. Two instruments make up the HGDS, which is installed in a prime/backup arrangement, with the option of using both analyzers on the same sample line, or on two different lines simultaneously. It is used for monitoring the Shuttle during fuel loading, countdown, and drainback, if necessary. The use of complex instruments, operated over many shifts, has caused problems in tracking the status of the ground support equipment (GSE) and the vehicle. A requirement for overall system reliability has been a major force in the development of Shuttle GSE, and is the ultimate driver in the choice to pursue artificial intelligence (AI) techniques for Shuttle and Advanced Launch System (ALS) mass spectrometer systems. Shuttle applications of AI are detailed.

  1. Management of bleeding in acquired hemophilia A: results from the European Acquired Haemophilia (EACH2) Registry.

    PubMed

    Baudo, Francesco; Collins, Peter; Huth-Kühne, Angela; Lévesque, Hervé; Marco, Pascual; Nemes, László; Pellegrini, Fabio; Tengborn, Lilian; Knoebl, Paul

    2012-07-05

    Acquired hemophilia A is a rare bleeding disorder caused by autoantibodies to coagulation FVIII. Bleeding episodes at presentation are spontaneous and severe in most cases. Optimal hemostatic therapy is controversial, and available data are from observational and retrospective studies only. The EACH2 registry, a multicenter, pan-European, Web-based database, reports current patient management. The aim was to assess the control of first bleeding episodes treated with a bypassing agent (rFVIIa or aPCC), FVIII, or DDAVP among 501 registered patients. Of 482 patients with one or more bleeding episodes, 144 (30%) received no treatment for bleeding; 31 were treated with symptomatic therapy only. Among 307 patients treated with a first-line hemostatic agent, 174 (56.7%) received rFVIIa, 63 (20.5%) aPCC, 56 (18.2%) FVIII, and 14 (4.6%) DDAVP. Bleeding was controlled in 269 of 338 (79.6%) patients treated with a first-line hemostatic agent or ancillary therapy alone. Propensity score matching was applied to allow unbiased comparison between treatment groups. Bleeding control was significantly higher in patients treated with bypassing agents versus FVIII/DDAVP (93.3% vs 68.3%; P = .003). Bleeding control was similar between rFVIIa and aPCC (93.0%; P = 1). Thrombotic events were reported in 3.6% of treated patients with a similar incidence between rFVIIa (2.9%) and aPCC (4.8%).

  2. Cohort Profile: The International Childhood Cardiovascular Cohort (i3C) Consortium

    PubMed Central

    Dwyer, Terence; Sun, Cong; Magnussen, Costan G; Raitakari, Olli T; Schork, Nicholas J; Venn, Alison; Burns, Trudy L; Juonala, Markus; Steinberger, Julia; Sinaiko, Alan R; Prineas, Ronald J; Davis, Patricia H; Woo, Jessica G; Morrison, John A; Daniels, Stephen R; Chen, Wei; Srinivasan, Sathanur R; Viikari, Jorma SA; Berenson, Gerald S

    2013-01-01

    This is a consortium of large children's cohorts that contain measurements of major cardiovascular disease (CVD) risk factors in childhood and had the ability to follow those cohorts into adulthood. The purpose of this consortium is to enable the pooling of data to increase power, most importantly for the follow-up of CVD events in adulthood. Within the consortium, we hope to be able to obtain data on the independent effects of childhood and early adult levels of CVD risk factors on subsequent CVD occurrence. PMID:22434861

  3. 34 CFR 694.3 - What are the requirements for a cohort?

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 34 Education 3 2010-07-01 2010-07-01 false What are the requirements for a cohort? 694.3 Section 694.3 Education Regulations of the Offices of the Department of Education (Continued) OFFICE OF POSTSECONDARY EDUCATION, DEPARTMENT OF EDUCATION GAINING EARLY AWARENESS AND READINESS FOR UNDERGRADUATE...

  4. Single-tube tetradecaplex panel of highly polymorphic microsatellite markers < 1 Mb from F8 for simplified preimplantation genetic diagnosis of hemophilia A.

    PubMed

    Zhao, M; Chen, M; Tan, A S C; Cheah, F S H; Mathew, J; Wong, P C; Chong, S S

    2017-07-01

    Essentials Preimplantation genetic diagnosis (PGD) of severe hemophilia A relies on linkage analysis. Simultaneous multi-marker screening can simplify selection of informative markers in a couple. We developed a single-tube tetradecaplex panel of polymorphic markers for hemophilia A PGD use. Informative markers can be used for linkage analysis alone or combined with mutation detection. Background It is currently not possible to perform single-cell preimplantation genetic diagnosis (PGD) to directly detect the common inversion mutations of the factor VIII (F8) gene responsible for severe hemophilia A (HEMA). As such, PGD for such inversion carriers relies on indirect analysis of linked polymorphic markers. Objectives To simplify linkage-based PGD of HEMA, we aimed to develop a panel of highly polymorphic microsatellite markers located near the F8 gene that could be simultaneously genotyped in a multiplex-PCR reaction. Methods We assessed the polymorphism of various microsatellite markers located ≤ 1 Mb from F8 in 177 female subjects. Highly polymorphic markers were selected for co-amplification with the AMELX/Y indel dimorphism in a single-tube reaction. Results Thirteen microsatellite markers located within 0.6 Mb of F8 were successfully co-amplified with AMELX/Y in a single-tube reaction. Observed heterozygosities of component markers ranged from 0.43 to 0.84, and ∼70-80% of individuals were heterozygous for ≥ 5 markers. The tetradecaplex panel successfully identified fully informative markers in a couple interested in PGD for HEMA because of an intragenic F8 point mutation, with haplotype phasing established through a carrier daughter. In-vitro fertilization (IVF)-PGD involved single-tube co-amplification of fully informative markers with AMELX/Y and the mutation-containing F8 amplicon, followed by microsatellite analysis and amplicon mutation-site minisequencing analysis. Conclusions The single-tube multiplex-PCR format of this highly polymorphic

  5. Immunoglobulin G4-related acquired hemophilia: A case report

    PubMed Central

    Li, Xiaoyan; Duan, Wei; Zhu, Xiang; Xu, Jianying

    2016-01-01

    Acquired hemophilia A (AHA) is a relatively rare and life-threatening bleeding disorder whose pathogenesis is not completely understood. The present study reports a rare case of immunogubulin (IgG)4-related AHA with multisystemic involvement. A 55-year old male patient presented with symptoms of bronchial asthma and multiple subdermal hematomas. Chest computed tomography showed multiple diffuse nodular lesions with thickening of bronchovascular bundles, and scattered high-density spots in both lung lobes. Laboratory investigations showed increased activated partial prothrombin time (120.0 sec), a markedly decreased factor VIII (FVIII) activity (0.5%), a high-titer of FVIII inhibitor (27.2 Bethesda units/ml) and a marked increase in serum IgG4 (>4.03 g/l) level. Left inguinal lymph node biopsy revealed capsular thickening with marked lymphoplasmacytic infiltration, occlusive phlebitis and irregular fibrosis. Immunostaining revealed numerous IgG4-positive plasma cells (>100 cells/human plasma fibronectin) in the nodular lesions, with an IgG4/IgG ratio of >40%. The symptoms were markedly alleviated following corticosteroid therapy. The current study presents the first reported case of a rare IgG4-related AHA that presented with unusual clinical features and multisystemic involvement. The patient responded well to corticosteroid therapy. Documentation of such rare cases will help in characterizing the pathogenesis, and prompt recognition and timely treatment of this rare disorder. PMID:28105131

  6. Cross-reacting Material-positive Hemophilia A Diagnosed in a Patient with a Spontaneous Thigh Hemorrhage

    PubMed Central

    Saito, Tatsuya; Mukae, Jyunichi; Nakamura, Yosuke; Inaba, Hiroshi; Nogami, Keiji; Koyama, Takatoshi; Fukutake, Katsuyuki; Yamamoto, Koh

    2017-01-01

    A 53-year-old man, who had been diagnosed with mild hemophilia A (HA) at 35 years of age, was hospitalized with a thigh hematoma. His bleeding continued despite the administration of recombinant factor VIII (FVIII). The results of an FVIII/von Willebrand factor binding assay were normal. The patient's FVIII coagulant activity (FVIII:C) was low, but his FVIII antigen levels were within the normal limits, suggesting FVIII protein dysfunction. The FVIII:C measurements obtained by one-stage clotting and chromogenic assays were different. An FVIII gene analysis revealed a missense mutation p.Ser308Leu, which is rare in Japan. This case highlights that gene analyses and chromogenic assays are necessary to interpret the discrepancies between FVIII:C and the bleeding phenotype of patients with mild HA. PMID:28674365

  7. Cross-reacting Material-positive Hemophilia A Diagnosed in a Patient with a Spontaneous Thigh Hemorrhage.

    PubMed

    Saito, Tatsuya; Mukae, Jyunichi; Nakamura, Yosuke; Inaba, Hiroshi; Nogami, Keiji; Koyama, Takatoshi; Fukutake, Katsuyuki; Yamamoto, Koh

    2017-01-01

    A 53-year-old man, who had been diagnosed with mild hemophilia A (HA) at 35 years of age, was hospitalized with a thigh hematoma. His bleeding continued despite the administration of recombinant factor VIII (FVIII). The results of an FVIII/von Willebrand factor binding assay were normal. The patient's FVIII coagulant activity (FVIII:C) was low, but his FVIII antigen levels were within the normal limits, suggesting FVIII protein dysfunction. The FVIII:C measurements obtained by one-stage clotting and chromogenic assays were different. An FVIII gene analysis revealed a missense mutation p.Ser308Leu, which is rare in Japan. This case highlights that gene analyses and chromogenic assays are necessary to interpret the discrepancies between FVIII:C and the bleeding phenotype of patients with mild HA.

  8. Association between ACTN3 R577X Polymorphism and Trunk Flexibility in 2 Different Cohorts.

    PubMed

    Kikuchi, Naoki; Zempo, Hirofumi; Fuku, Noriyuki; Murakami, Haruka; Sakamaki-Sunaga, Mikako; Okamoto, Takanobu; Nakazato, Koichi; Miyachi, Motohiko

    2017-05-01

    α-Actinin-3 (ACTN3) R577X polymorphism is associated with muscular strength and power. This study was performed to investigate the association between ACTN3 R577X polymorphisms and flexibility as another component of fitness in 2 cohorts. Cohort 1 consisted of 208 men and 568 women (ages 23-88), while Cohort 2 consisted of 529 men and 728 women (ages 23-87). All participants were recruited from the Tokyo metropolitan area and underwent a battery of tests to assess their grip strength and sit-and-reach flexibility. Genotyping results were analyzed for ACTN3 (rs1815739) polymorphism using the TaqMan approach. In Cohort 1, sit-and-reach in the RR genotype (35.3±0.7 cm) was significantly lower than those in the RX and XX genotypes (37.2±0.3 cm) even after adjusting for sex, age, and exercise habit as covariates (P<0.01). In Cohort 2, sit-and-reach tended to be lower in RR (38.1±0.6 cm) than in RX and XX (39.1±0.3 cm), but the differences were not significant (P=0.114). Analysis in pooled subjects indicated that RR was associated with significantly lower flexibility than RX and XX (P=0.009). The RR genotype of ACTN3 R577X in the general Japanese population showed lower flexibility compared to the RX and XX genotypes. © Georg Thieme Verlag KG Stuttgart · New York.

  9. Immunosuppression for acquired hemophilia A: results from the European Acquired Haemophilia Registry (EACH2)

    PubMed Central

    Baudo, Francesco; Knoebl, Paul; Lévesque, Hervé; Nemes, László; Pellegrini, Fabio; Marco, Pascual; Tengborn, Lilian; Huth-Kühne, Angela

    2012-01-01

    Acquired hemophilia A (AHA) is an autoimmune disease caused by an autoantibody to factor VIII. Patients are at risk of severe and fatal hemorrhage until the inhibitor is eradicated, and guidelines recommend immunosuppression as soon as the diagnosis has been made. The optimal immunosuppressive regimen is unclear; therefore, data from 331 patients entered into the prospective EACH2 registry were analyzed. Steroids combined with cyclophosphamide resulted in more stable complete remission (70%), defined as inhibitor undetectable, factor VIII more than 70 IU/dL and immunosuppression stopped, than steroids alone (48%) or rituximab-based regimens (59%). Propensity score-matched analysis controlling for age, sex, factor VIII level, inhibitor titer, and underlying etiology confirmed that stable remission was more likely with steroids and cyclophosphamide than steroids alone (odds ratio = 3.25; 95% CI, 1.51-6.96; P < .003). The median time to complete remission was approximately 5 weeks for steroids with or without cyclophosphamide; rituximab-based regimens required approximately twice as long. Immunoglobulin administration did not improve outcome. Second-line therapy was successful in approximately 60% of cases that failed first-line therapy. Outcome was not affected by the choice of first-line therapy. The likelihood of achieving stable remission was not affected by underlying etiology but was influenced by the presenting inhibitor titer and FVIII level. PMID:22517903

  10. Immunosuppression for acquired hemophilia A: results from the European Acquired Haemophilia Registry (EACH2).

    PubMed

    Collins, Peter; Baudo, Francesco; Knoebl, Paul; Lévesque, Hervé; Nemes, László; Pellegrini, Fabio; Marco, Pascual; Tengborn, Lilian; Huth-Kühne, Angela

    2012-07-05

    Acquired hemophilia A (AHA) is an autoimmune disease caused by an autoantibody to factor VIII. Patients are at risk of severe and fatal hemorrhage until the inhibitor is eradicated, and guidelines recommend immunosuppression as soon as the diagnosis has been made. The optimal immunosuppressive regimen is unclear; therefore, data from 331 patients entered into the prospective EACH2 registry were analyzed. Steroids combined with cyclophosphamide resulted in more stable complete remission (70%), defined as inhibitor undetectable, factor VIII more than 70 IU/dL and immunosuppression stopped, than steroids alone (48%) or rituximab-based regimens (59%). Propensity score-matched analysis controlling for age, sex, factor VIII level, inhibitor titer, and underlying etiology confirmed that stable remission was more likely with steroids and cyclophosphamide than steroids alone (odds ratio = 3.25; 95% CI, 1.51-6.96; P < .003). The median time to complete remission was approximately 5 weeks for steroids with or without cyclophosphamide; rituximab-based regimens required approximately twice as long. Immunoglobulin administration did not improve outcome. Second-line therapy was successful in approximately 60% of cases that failed first-line therapy. Outcome was not affected by the choice of first-line therapy. The likelihood of achieving stable remission was not affected by underlying etiology but was influenced by the presenting inhibitor titer and FVIII level.

  11. Accurate, simple, and inexpensive assays to diagnose F8 gene inversion mutations in hemophilia A patients and carriers.

    PubMed

    Dutta, Debargh; Gunasekera, Devi; Ragni, Margaret V; Pratt, Kathleen P

    2016-12-27

    The most frequent mutations resulting in hemophilia A are an intron 22 or intron 1 gene inversion, which together cause ∼50% of severe hemophilia A cases. We report a simple and accurate RNA-based assay to detect these mutations in patients and heterozygous carriers. The assays do not require specialized equipment or expensive reagents; therefore, they may provide useful and economic protocols that could be standardized for central laboratory testing. RNA is purified from a blood sample, and reverse transcription nested polymerase chain reaction (RT-NPCR) reactions amplify DNA fragments with the F8 sequence spanning the exon 22 to 23 splice site (intron 22 inversion test) or the exon 1 to 2 splice site (intron 1 inversion test). These sequences will be amplified only from F8 RNA without an intron 22 or intron 1 inversion mutation, respectively. Additional RT-NPCR reactions are then carried out to amplify the inverted sequences extending from F8 exon 19 to the first in-frame stop codon within intron 22 or a chimeric transcript containing F8 exon 1 and the VBP1 gene. These latter 2 products are produced only by individuals with an intron 22 or intron 1 inversion mutation, respectively. The intron 22 inversion mutations may be further classified (eg, as type 1 or type 2, reflecting the specific homologous recombination sites) by the standard DNA-based "inverse-shifting" PCR assay if desired. Efficient Bcl I and T4 DNA ligase enzymes that cleave and ligate DNA in minutes were used, which is a substantial improvement over previous protocols that required overnight incubations. These protocols can accurately detect F8 inversion mutations via same-day testing of patient samples.

  12. Constructing Alternate Assessment Cohorts: An Oregon Perspective. Research Brief 3

    ERIC Educational Resources Information Center

    Saven, Jessica L.; Farley, Dan; Tindal, Gerald

    2013-01-01

    Longitudinally modeling the growth of students with significant cognitive disabilities (SWSCDs) on alternate assessments based on alternate achievement standards (AA-AAS) presents many challenges for states. The number of students in Grades 3-8 who remain in a cohort group varies over time, depending on the methods used to construct the…

  13. Association of autoimmune Addison's disease with alleles of STAT4 and GATA3 in European cohorts.

    PubMed

    Mitchell, Anna L; Macarthur, Katie D R; Gan, Earn H; Baggott, Lucy E; Wolff, Anette S B; Skinningsrud, Beate; Platt, Hazel; Short, Andrea; Lobell, Anna; Kämpe, Olle; Bensing, Sophie; Betterle, Corrado; Kasperlik-Zaluska, Anna; Zurawek, Magdalena; Fichna, Marta; Kockum, Ingrid; Nordling Eriksson, Gabriel; Ekwall, Olov; Wahlberg, Jeanette; Dahlqvist, Per; Hulting, Anna-Lena; Penna-Martinez, Marissa; Meyer, Gesine; Kahles, Heinrich; Badenhoop, Klaus; Hahner, Stephanie; Quinkler, Marcus; Falorni, Alberto; Phipps-Green, Amanda; Merriman, Tony R; Ollier, William; Cordell, Heather J; Undlien, Dag; Czarnocka, Barbara; Husebye, Eystein; Pearce, Simon H S

    2014-01-01

    Gene variants known to contribute to Autoimmune Addison's disease (AAD) susceptibility include those at the MHC, MICA, CIITA, CTLA4, PTPN22, CYP27B1, NLRP-1 and CD274 loci. The majority of the genetic component to disease susceptibility has yet to be accounted for. To investigate the role of 19 candidate genes in AAD susceptibility in six European case-control cohorts. A sequential association study design was employed with genotyping using Sequenom iPlex technology. In phase one, 85 SNPs in 19 genes were genotyped in UK and Norwegian AAD cohorts (691 AAD, 715 controls). In phase two, 21 SNPs in 11 genes were genotyped in German, Swedish, Italian and Polish cohorts (1264 AAD, 1221 controls). In phase three, to explore association of GATA3 polymorphisms with AAD and to determine if this association extended to other autoimmune conditions, 15 SNPs in GATA3 were studied in UK and Norwegian AAD cohorts, 1195 type 1 diabetes patients from Norway, 650 rheumatoid arthritis patients from New Zealand and in 283 UK Graves' disease patients. Meta-analysis was used to compare genotype frequencies between the participating centres, allowing for heterogeneity. We report significant association with alleles of two STAT4 markers in AAD cohorts (rs4274624: P = 0.00016; rs10931481: P = 0.0007). In addition, nominal association of AAD with alleles at GATA3 was found in 3 patient cohorts and supported by meta-analysis. Association of AAD with CYP27B1 alleles was also confirmed, which replicates previous published data. Finally, nominal association was found at SNPs in both the NF-κB1 and IL23A genes in the UK and Italian cohorts respectively. Variants in the STAT4 gene, previously associated with other autoimmune conditions, confer susceptibility to AAD. Additionally, we report association of GATA3 variants with AAD: this adds to the recent report of association of GATA3 variants with rheumatoid arthritis.

  14. Clinical utility and patient perspectives on the use of extended half-life rFIXFc in the management of hemophilia B

    PubMed Central

    Miguelino, Maricel G; Powell, Jerry S

    2014-01-01

    Hemophilia B is an X-linked genetic disease caused by mutation of the gene for coagulation protein factor IX (FIX), with an incidence of approximately once every 30,000 male births in all populations and ethnic groups. When severe, the disease leads to spontaneous life threatening bleeding episodes. When untreated, most patients die from bleeding complications before 25 years of age. Current therapy requires frequent intravenous infusions of therapeutic recombinant or plasma-derived protein concentrates containing FIX. Most patients administer the infusions at home every few days, and must limit their physical activities to avoid abnormal bleeding when the FIX activity levels are below normal. After completing the pivotal Phase III clinical trial, a new therapeutic FIX preparation that has been engineered for an extended half-life in circulation, received regulatory approval in March 2014 in Canada and the US. This new FIX represents a major therapeutic advance for patients with hemophilia B. The half-life is prolonged due to fusion of the native FIX molecule with the normal constant region of immunoglobulin G. This fusion molecule then follows the normal immunoglobulin recirculation pathways through endothelial cells, resulting in prolonged times in circulation. In the clinical trials, over 150 patients successfully used eftrenonacog alfa regularly for more than 1 year to prevent spontaneous bleeding, to successfully treat any bleeding episodes, and to provide effective coagulation for major surgery. All infusions were well tolerated and effective, with no inhibitors detected and no safety concerns. This promising therapy should allow patients to use fewer infusions to maintain appropriate FIX activity levels in all clinical settings. PMID:25143713

  15. Effect of Biophysical Properties of Phosphatidylserine Particle on Immune Tolerance Induction Toward Factor VIII in a Hemophilia A Mouse Model.

    PubMed

    Ramakrishnan, Radha; Balu-Iyer, Sathy V

    2016-10-01

    A major complication in the replacement therapy of Factor VIII (FVIII) for Hemophilia A is the development of unwanted immune responses. Previous studies from our laboratory have shown that pretreatment of FVIII in the presence of phosphatidylserine (PS) resulted in hyporesponsiveness to subsequent administration of FVIII alone, due to the ability of PS to convert an immunogen to a tolerogen. We investigated the importance of biophysical properties of PS liposomes on its ability to convert an immunogen to a tolerogen. PS particles were prepared differing in size, protein-lipid topology, lamellarity, and % association to FVIII keeping the composition of the particle same. PS particles were prepared in 2 different sizes with differing biophysical properties: smaller particles in the nanometer range (200 nm) and larger size particles in the micron range (2 μm). Hemophilia A animals treated with both the nanometer and micron size PS particles showed a significant reduction in anti-FVIII antibody titers when compared to animals receiving free FVIII alone. Upon rechallenge with free FVIII animals that received FVIII along with the nanometer size particle continued to show reduced antibody responses. Animals receiving the micron size particle showed a slight increase in titers although they remained significantly lower than the free FVIII treated group. Upon culture with bone marrow derived dendritic cells, the nanometer size particle showed a reduction in CD40 expression and an increase in transforming growth factor-β cytokine production, which was not observed with the micron size particle. These results show that biophysical properties of PS play an important role in tolerance. Copyright © 2016 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

  16. Neonatal circumcision in severe haemophilia: a survey of paediatric haematologists at United States Hemophilia Treatment Centers.

    PubMed

    Kearney, S; Sharathkumar, A; Rodriguez, V; Chitlur, M; Valentino, L; Boggio, L; Gill, J

    2015-01-01

    Neonatal circumcision in patients with severe haemophilia has not been well studied. We performed a survey of paediatric haematologists from Hemophilia Treatment Centers (HTC) across the United States to better understand the attitudes toward and management of neonatal circumcision in haemophilia patients. Response rate to our survey was 40% (n = 64/159). Thirty-eight percent of respondents (n = 24) said that they would allow this procedure in the newborn period but in many cases this was against medical advice. The most reported concern regarding neonatal circumcision in haemophilia patients was the risk of development of an inhibitor (n = 25; 39%) followed by the concern for bleeding (n = 22; 34%) and issues related to vascular access in the neonate (n = 11; 17%). All respondents recommended at least one preprocedure dose of factor replacement. Twenty-two percent (n = 14) of respondents did not use more than one dose of factor replacement but 32% (n = 21) used 1-2 postoperative doses. The remainder of paediatric haematologists surveyed recommended between 3-5 (16%; n = 10) and 6-10 (3%, n = 2) additional days postoperatively. There was wide variation in both techniques of circumcision as well as adjuvant haemostatic agents used. Only 22% of respondents said that they had an established protocol for management of circumcision in the newborn haemophilia patient. These survey results highlight the need for evidence-based guidelines regarding the optimal management of circumcision in neonates with severe haemophilia. © 2014 John Wiley & Sons Ltd.

  17. Acquired hemophilia in the patient suffering from rheumatoid arthritis: case report.

    PubMed

    Drobiecki, Arkadiusz; Pasiarski, Marcin; Hus, Iwona; Sokołowska, Bożena; Wątek, Marzena

    2013-12-01

    Acquired hemophilia is a severe bleeding diathesis caused by autoantibodies against a coagulation factor VIII (FVIII inhibitor). Massive bleeding diathesis, often life threatening are observed in almost 90% of patients. In 50-60% of cases, inhibitor emerges spontaneously. However, there are some conditions like pregnancy, puerperium, autoimmune disorders or cancers that seem to induce acquired hemophilia. We report a case of a 49-year-old woman suffering from rheumatoid arthritis (RA) for several years, who was diagnosed with acquired hemophilia in September 2011. The patient had been treated by steroids and leflunomide during the last few months. At the time of diagnosis, diffuse bruising of the forearms and the trunk was observed. The patient was treated with recombinant activated factor VII, and the first-line immunosuppressive therapy was introduced (cyclophosphamide and prednisone). We observed the elimination of symptoms and the disappearance of diathesis. Significant reduction of the titer of inhibitor was achieved, but only partial remission was obtained. It lasted until the beginning of December 2011, when the titer of the inhibitor increased again and massive bleeding to the left lower limb occurred. It was necessary to administer recombinant factor VIIa together with the second-line immunosuppressive therapy based on the Budapest protocol. The rapid reduction of the diathesis and improvement of the patient's general condition was achieved as previously. However, still there was no complete remission. After 2 weeks of treatment, the titer of inhibitor diminished, and factor VIII activity increased slightly. Because of RA, the patient was treated with methylprednisolone in maintenance doses during the next few weeks. Unfortunately, after over a month, the increase of inhibitor titer and the decrease of FVIII level were observed again. Some bruises appeared. It was necessary to increase doses of corticosteroids to therapeutic levels and add cyclophosphamide

  18. Omega-3 Fatty Acids and Incident Ischemic Stroke and Its Atherothrombotic and Cardioembolic Subtypes in 3 US Cohorts.

    PubMed

    Saber, Hamidreza; Yakoob, Mohammad Yawar; Shi, Peilin; Longstreth, W T; Lemaitre, Rozenn N; Siscovick, David; Rexrode, Kathryn M; Willett, Walter C; Mozaffarian, Dariush

    2017-10-01

    The associations of individual long-chain n-3 polyunsaturated fatty acids with incident ischemic stroke and its main subtypes are not well established. We aimed to investigate prospectively the relationship of circulating eicosapentaenoic acid, docosapentaenoic acid (DPA), and docosahexaenoic acid (DHA) with risk of total ischemic, atherothrombotic, and cardioembolic stroke. We measured circulating phospholipid fatty acids at baseline in 3 separate US cohorts: CHS (Cardiovascular Health Study), NHS (Nurses' Health Study), and HPFS (Health Professionals Follow-Up Study). Ischemic strokes were prospectively adjudicated and classified into atherothrombotic (large- and small-vessel infarctions) or cardioembolic by imaging studies and medical records. Risk according to fatty acid levels was assessed using Cox proportional hazards (CHS) or conditional logistic regression (NHS, HPFS) according to study design. Cohort findings were pooled using fixed-effects meta-analysis. A total of 953 incident ischemic strokes were identified (408 atherothrombotic, 256 cardioembolic, and 289 undetermined subtypes) during median follow-up of 11.2 years (CHS) and 8.3 years (pooled, NHS and HPFS). After multivariable adjustment, lower risk of total ischemic stroke was seen with higher DPA (highest versus lowest quartiles; pooled hazard ratio [HR], 0.74; 95% confidence interval [CI], 0.58-0.92) and DHA (HR, 0.80; 95% CI, 0.64-1.00) but not eicosapentaenoic acid (HR, 0.94; 95% CI, 0.77-1.19). DHA was associated with lower risk of atherothrombotic stroke (HR, 0.53; 95% CI, 0.34-0.83) and DPA with lower risk of cardioembolic stroke (HR, 0.58; 95% CI, 0.37-0.92). Findings in each individual cohort were consistent with pooled results. In 3 large US cohorts, higher circulating levels of DHA were inversely associated with incident atherothrombotic stroke and DPA with cardioembolic stroke. These novel findings suggest differential pathways of benefit for DHA, DPA, and eicosapentaenoic acid. © 2017

  19. First analysis of 10-year trends in national factor concentrates usage in haemophilia: data from CHARMS, the Canadian Hemophilia Assessment and Resource Management System

    PubMed Central

    Traore, A N; Chan, A K C; Webert, K E; Heddle, N; Ritchie, B; St-Louis, J; Teitel, J; Lillicrap, D; Iorio, A; Walker, I

    2014-01-01

    The Canadian Hemophilia Assessment and Resource Management System (CHARMS) tracks factor concentrates (FC) from the sole suppliers, Canadian Blood Services (CBS) and Hema-Quebec (HQ), to hospitals and to patients’ homes. Patients FC infusion data are entered into CHARMS at Canadian Hemophilia Treatment Centres (HTCs) then exported to the national database (CentrePoint). From 2000 to 2009, 2260 registered haemophilia A or B patients received FVIII (1 009 097 765 IU) and FIX (272 406 859 IU). Over 91% of FVIII and over 84% of FIX was infused at home. Utilization of FVIII progressively increased; this was accounted for by an increase in the number of patients treated (r = 0.97; P < 0.001), there being a linear relationship between the increase in utilization and the increase in number of patients treated (P < 0.001). There was also a correlation with the annual amount used per patient (r = 0.95; P < 0.001). Utilization of FIX did not increase over time. The highest proportional utilization of both FVIII and FIX was for prophylaxis, and this proportion progressively increased being, in year 10 (2009), 77% and 66% for FVIII and FIX respectively. The proportion used for bleeding remained steady; in year 10 that proportion was 14% for FVIII and 26% for FIX, the use per patient for bleeding decreasing. The HTC-based CHARMS tracking system is essential, in Canada, for analysing indications for infusion, for predicting utilization and planning for future needs. PMID:24948405

  20. Remarkable variation in the informativeness of RFLP markers linked to hemophilia B locus in Indian population groups: implication in the strategy for carrier detection.

    PubMed

    Mukherjee, S; Saha, A; Kumar P, Senthil; Chandak, G R; Majumder, P P; Ray, K

    2006-01-01

    Hemophilia B, an X-linked recessive bleeding disorder, is caused by heterogeneous mutations in the factor IX (F9) gene. Hence, carriers of the disease are usually detected by F9 gene linked RFLP analysis. We aimed to test a set of RFLP markers (DdeI, XmnI, MnlI, TaqI & HhaI), used worldwide for carrier detection, to estimate its heterozygosity in different population groups of India, and identify additional single nucleotide polymorphisms (SNPs) if necessary. A total of 8 population groups encompassing different regions of India, consisting of 107 unrelated normal females without any history of hemophilia B in the family and 13 unrelated obligate carriers were recruited in the study. Regions of F9 gene were amplified by PCR from genomic DNA of the donors followed by restriction enzyme digestion and/or sequencing as appropriate. Combined informativeness for the markers varied between 52-86% among normal females belonging to different geographical locations of India. Haplotype analysis revealed that the most prevalent haplotype lacked the restriction sites for all five RFLP markers. Screening regions of F9 gene that harbor 10 SNPs reported in dbSNP yielded only two SNPs, which increased the overall informativeness in each population group and heterozygosity in the obligate carriers for the disease from 38% to 69%. Our data show that heterozygosity of commonly used RFLP markers is remarkably variable across different regions of India. Thus prudent selection of the markers based on specific population groups including usage of additional markers is recommended for efficient carrier detection.

  1. Remarkable Variation in the Informativeness of RFLP Markers Linked to Hemophilia B Locus in Indian Population Groups: Implication in the Strategy for Carrier Detection

    PubMed Central

    Mukherjee, S.; Saha, A.; Kumar P., Senthil; Chandak, G. R.; Majumder, P. P.; Ray, K.

    2006-01-01

    Hemophilia B, an X-linked recessive bleeding disorder, is caused by heterogeneous mutations in the factor IX (F9) gene. Hence, carriers of the disease are usually detected by F9 gene linked RFLP analysis. We aimed to test a set of RFLP markers (DdeI, XmnI, MnlI, TaqI & HhaI), used worldwide for carrier detection, to estimate its heterozygosity in different population groups of India, and identify additional single nucleotide polymorphisms (SNPs) if necessary. A total of 8 population groups encompassing different regions of India, consisting of 107 unrelated normal females without any history of hemophilia B in the family and 13 unrelated obligate carriers were recruited in the study. Regions of F9 gene were amplified by PCR from genomic DNA of the donors followed by restriction enzyme digestion and/or sequencing as appropriate. Combined informativeness for the markers varied between 52–86% among normal females belonging to different geographical locations of India. Haplotype analysis revealed that the most prevalent haplotype lacked the restriction sites for all five RFLP markers. Screening regions of F9 gene that harbor 10 SNPs reported in dbSNP yielded only two SNPs, which increased the overall informativeness in each population group and heterozygosity in the obligate carriers for the disease from 38% to 69%. Our data show that heterozygosity of commonly used RFLP markers is remarkably variable across different regions of India. Thus prudent selection of the markers based on specific population groups including usage of additional markers is recommended for efficient carrier detection. PMID:17264403

  2. First analysis of 10-year trends in national factor concentrates usage in haemophilia: data from CHARMS, the Canadian Hemophilia Assessment and Resource Management System.

    PubMed

    Traore, A N; Chan, A K C; Webert, K E; Heddle, N; Ritchie, B; St-Louis, J; Teitel, J; Lillicrap, D; Iorio, A; Walker, I

    2014-07-01

    The Canadian Hemophilia Assessment and Resource Management System (CHARMS) tracks factor concentrates (FC) from the sole suppliers, Canadian Blood Services (CBS) and Hema-Quebec (HQ), to hospitals and to patients' homes. Patients FC infusion data are entered into CHARMS at Canadian Hemophilia Treatment Centres (HTCs) then exported to the national database (CentrePoint). From 2000 to 2009, 2260 registered haemophilia A or B patients received FVIII (1,009,097,765 IU) and FIX (272,406,859 IU). Over 91% of FVIII and over 84% of FIX was infused at home. Utilization of FVIII progressively increased; this was accounted for by an increase in the number of patients treated (r = 0.97; P < 0.001), there being a linear relationship between the increase in utilization and the increase in number of patients treated (P < 0.001). There was also a correlation with the annual amount used per patient (r = 0.95; P < 0.001). Utilization of FIX did not increase over time. The highest proportional utilization of both FVIII and FIX was for prophylaxis, and this proportion progressively increased being, in year 10 (2009), 77% and 66% for FVIII and FIX respectively. The proportion used for bleeding remained steady; in year 10 that proportion was 14% for FVIII and 26% for FIX, the use per patient for bleeding decreasing. The HTC-based CHARMS tracking system is essential, in Canada, for analysing indications for infusion, for predicting utilization and planning for future needs. © 2014 The Authors. Haemophilia Published by John Wiley & Sons Ltd.

  3. Recombinant factor concentrates may increase inhibitor development: a single centre cohort study.

    PubMed

    Strauss, T; Lubetsky, A; Ravid, B; Bashari, D; Luboshitz, J; Lalezari, S; Misgav, M; Martinowitz, U; Kenet, G

    2011-07-01

    Recent reports have raised concerns regarding potential risk factors for inhibitor development. In Israel, all haemophilia patients (n = 479) are followed by the National Hemophilia Center. Most children are neonatally exposed to factor concentrate (due to circumcision performed at the age of 8 days). The impact of early exposure and recombinant FVIII products (rFVIII) administration (approved in Israel since 1996) upon inhibitor occurrence in our cohort of haemophilia A (HA) patients was analysed. Two hundred ninety-two consecutive paediatric cases with a first symptomatic onset of HA were enrolled and followed over a median time of 7 years [min-max: 9 months to 17 years]. Study endpoint was inhibitor development against factor VIII. In addition, the treatment regimens applied, i.e. bolus administration or 'continuous infusion' and the family history of inhibitor development were investigated. During the follow-up period 31/292 children (10.6%) developed high titre inhibitors. Inhibitors occurred in 14/43 (32.5%) HA patients neonatally exposed to rFVIII, as compared to 22/249 previously treated with Plasma Derived (PD) products (8.8%). The odds ratio for inhibitor formation in rFVIII treated HA patients was 3.43 (95% CI: 1.36-8.65). Transient inhibitor evolved among 2/43 paediatric HA patients, only among those treated with rFVIII. The risk of inhibitor detection significantly increased among HA children treated by continuous infusion (P = 0.025). Our experience shows that the risk of inhibitor formation may be increased by early exposure to recombinant concentrates. The multiple variables affecting inhibitor incidence deserve further attention by larger prospective studies. © 2011 Blackwell Publishing Ltd.

  4. Cohort fertility in Western Europe: comparing fertility trends in recent birth cohorts.

    PubMed

    Hopflinger, F

    1984-01-01

    A comparative study of fertility levels among cohorts of women born in 1940, 1945, 1950, 1955, and 1960 in 16 European countries was undertaken using vital statistics data. The average number of live birth/woman for each of the 5 cohorts by age 20, 25, 30, and 35 was computed by cumulating age-specific fertility rates of women born in specific years. Median age at childbirth and completed fertility were estimated for the 3 oldest cohorts (1940, 1945, and 1950). 2 estimations of completed fertility were made. 1 was based on the assumption of a constant age-specific fertility rate, and the other was based on a relational Gompertz model. Where possible cohort fertility was disaggregated by birth order. Since the data for the countries was not fully comparable, it was not possible to use sophisticated analytical techniques. Other limits of the study were that fertility, especially for the more recent cohorts was incomplete, parity specific data was not available for all the countries, and open cohorts rather than closed cohorts were used. The analysis indicated that completed cohort fertility was lower for the 1950 cohort than for the 1940 cohort in all 16 countries. For the 1940 cohort, only Germany's estimated completed fertility was less than 2.00. For the other 15 countries, estimated completed fertility ranged from 2.04 (Finland) to 3.36 (Ireland). For the 1950 cohort, estimated completed fertility was less than 2.00 in 8 of the countries. Estimated completed fertility was lowest in Finland and Switzerland (1.82) and highest in Ireland (3.33). No marked increase in childlessness was observed, and for the 1940 and 1950 cohorts, childlessness did not exceed 20% in any of the countries and was considerably less than 20% in most of the countries. There was a trend toward delayed childbearing in most of the countries. An examination of available parity data for the 1940 and 1950 cohorts lead to the conclusion that the major factor contributing toward the decline in

  5. Single nucleotide primer extension to detect genetic diseases: Experimental application to hemophilia B (factor IX) and cystic fibrosis genes

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

    Kuppuswamy, M.N.; Hoffmann, J.W.; Spitzer, S.G.

    1991-02-15

    In this report, the authors describe an approach to detect the presence of abnormal alleles in those genetic diseases in which frequency of occurrence of the same mutation is high (e.g., hemophilia B). Initially, from each subject, the DNA fragment containing the putative mutation site is amplified by the polymerase chain reaction. For each fragment two reaction mixtures are then prepared. Each contains the amplified fragment, a primer (18-mer or longer) whose sequence is identical to the coding sequence of the normal gene immediately flanking the 5{prime} end of the mutation site, and either an {alpha}-{sup 32}P-labeled nucleotide corresponding tomore » the normal coding sequence at the mutation site or an {alpha}-{sup 32}P-labeled nucleotide corresponding to the mutant sequence. An essential feature of the present methodology is that the base immediately 3{prime} to the template-bound primer is one of those altered in the mutant, since in this way an extension of the primer by a single base will give an extended molecule characteristic of either the mutant or the wild type. The method is rapid and should be useful in carrier detection and prenatal diagnosis of every genetic disease with a known sequence variation.« less

  6. 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.

  7. X-chromosome Forkhead Box P3 polymorphisms associate with atopy in girls in three Dutch birth cohorts.

    PubMed

    Bottema, R W B; Kerkhof, M; Reijmerink, N E; Koppelman, G H; Thijs, C; Stelma, F F; Smit, H A; Brunekreef, B; van Schayck, C P; Postma, D S

    2010-07-01

    The Forkhead Box P3 (FOXP3) gene, located on the X-chromosome, encodes a transcription factor that directs T cells toward a regulatory phenotype. Regulatory T cells may suppress development of atopy. We evaluated whether single-nucleotide polymorphisms (SNPs) of FOXP3 are associated with atopy development in childhood. Seven SNPs in FOXP3 were genotyped in 3062 children (51% boys) participating in the Allergenic study, which consists of three Dutch birth cohorts (PIAMA, PREVASC and KOALA). Association of FOXP3 SNPs with total serum IgE and sensitisation (presence of specific serum IgE to egg, milk, and indoor, i.e. house-dust mite, cat, and/or dog allergens) was investigated at ages 1, 2, 4, and 8. Analysis of variance and logistic regression were performed, stratified for gender. Our most consistent finding was observed for sensitisation to egg and indoor allergens. In girls, five FOXP3 SNPs (rs5906761, rs2294021, rs2294019, rs6609857 and rs3761548) were significantly associated with sensitisation to egg at ages 1 and 2 and with sensitisation to indoor allergens at age 2 (P < 0.05), but not at 4 and 8, a finding that was observed across the three cohorts. Rs5906761 and rs2294021 were associated with remission of sensitisation to food allergens in boys, as tested in the PIAMA cohort. This is the first study showing across three cohorts that X-chromosomal FOXP3 genotypes may contribute to development of sensitisation against egg and indoor allergens in girls in early childhood. In addition, an association with remission of sensitisation to food allergens existed in boys only.

  8. Novel Anthropometry Based on 3D-Bodyscans Applied to a Large Population Based Cohort

    PubMed Central

    Löffler-Wirth, Henry; Willscher, Edith; Ahnert, Peter; Wirkner, Kerstin; Engel, Christoph; Loeffler, Markus; Binder, Hans

    2016-01-01

    Three-dimensional (3D) whole body scanners are increasingly used as precise measuring tools for the rapid quantification of anthropometric measures in epidemiological studies. We analyzed 3D whole body scanning data of nearly 10,000 participants of a cohort collected from the adult population of Leipzig, one of the largest cities in Eastern Germany. We present a novel approach for the systematic analysis of this data which aims at identifying distinguishable clusters of body shapes called body types. In the first step, our method aggregates body measures provided by the scanner into meta-measures, each representing one relevant dimension of the body shape. In a next step, we stratified the cohort into body types and assessed their stability and dependence on the size of the underlying cohort. Using self-organizing maps (SOM) we identified thirteen robust meta-measures and fifteen body types comprising between 1 and 18 percent of the total cohort size. Thirteen of them are virtually gender specific (six for women and seven for men) and thus reflect most abundant body shapes of women and men. Two body types include both women and men, and describe androgynous body shapes that lack typical gender specific features. The body types disentangle a large variability of body shapes enabling distinctions which go beyond the traditional indices such as body mass index, the waist-to-height ratio, the waist-to-hip ratio and the mortality-hazard ABSI-index. In a next step, we will link the identified body types with disease predispositions to study how size and shape of the human body impact health and disease. PMID:27467550

  9. Novel Anthropometry Based on 3D-Bodyscans Applied to a Large Population Based Cohort.

    PubMed

    Löffler-Wirth, Henry; Willscher, Edith; Ahnert, Peter; Wirkner, Kerstin; Engel, Christoph; Loeffler, Markus; Binder, Hans

    2016-01-01

    Three-dimensional (3D) whole body scanners are increasingly used as precise measuring tools for the rapid quantification of anthropometric measures in epidemiological studies. We analyzed 3D whole body scanning data of nearly 10,000 participants of a cohort collected from the adult population of Leipzig, one of the largest cities in Eastern Germany. We present a novel approach for the systematic analysis of this data which aims at identifying distinguishable clusters of body shapes called body types. In the first step, our method aggregates body measures provided by the scanner into meta-measures, each representing one relevant dimension of the body shape. In a next step, we stratified the cohort into body types and assessed their stability and dependence on the size of the underlying cohort. Using self-organizing maps (SOM) we identified thirteen robust meta-measures and fifteen body types comprising between 1 and 18 percent of the total cohort size. Thirteen of them are virtually gender specific (six for women and seven for men) and thus reflect most abundant body shapes of women and men. Two body types include both women and men, and describe androgynous body shapes that lack typical gender specific features. The body types disentangle a large variability of body shapes enabling distinctions which go beyond the traditional indices such as body mass index, the waist-to-height ratio, the waist-to-hip ratio and the mortality-hazard ABSI-index. In a next step, we will link the identified body types with disease predispositions to study how size and shape of the human body impact health and disease.

  10. 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.

  11. Impact of aging on host immune response and survival in melanoma: an analysis of 3 patient cohorts.

    PubMed

    Weiss, Sarah A; Han, Joseph; Darvishian, Farbod; Tchack, Jeremy; Han, Sung Won; Malecek, Karolina; Krogsgaard, Michelle; Osman, Iman; Zhong, Judy

    2016-10-19

    Age has been reported as an independent prognostic factor for melanoma-specific survival (MSS). We tested the hypothesis that age impacts the host anti-tumor immune response, accounting for age-specific survival outcomes in three unique melanoma patient cohorts. We queried the U.S. population-based Surveillance, Epidemiology, and End Results Program (SEER), the prospective tertiary care hospital-based Interdisciplinary Melanoma Cooperative Group (IMCG) biorepository, and the Cancer Genome Atlas (TCGA) biospecimen database to test the association of patient age at time of melanoma diagnosis with clinicopathologic features and survival outcomes. Age groups were defined as ≤45 (young), 46-65 (intermediate), and >65 (older). Each age group in the IMCG and TCGA cohorts was stratified by tumor infiltrating lymphocyte (TIL) measurements and tested for association with MSS. Differential expression of 594 immunoregulatory genes was assessed in a subset of primary melanomas in the IMCG and TCGA cohorts using an integrative pathway analysis. We analyzed 304, 476 (SEER), 1241 (IMCG), and 292 (TCGA) patients. Increasing age at melanoma diagnosis in both the SEER and IMCG cohorts demonstrated a positive correlation with tumor thickness, ulceration, stage, and mortality, however age in the TCGA cohort did not correlate with mortality. Older age was associated with shorter MSS in all three cohorts. When the young age group in both the IMCG and TCGA cohorts was stratified by TIL status, there were no differences in MSS. However, older IMCG patients with brisk TILs and intermediate aged TCGA patients with high lymphocyte scores (3-6) had improved MSS. Gene expression analysis revealed top pathways (T cell trafficking, communication, and differentiation) and top upstream regulators (CD3, CD28, IFNG, and STAT3) that significantly changed with age in 84 IMCG and 43 TCGA primary melanomas. Older age at time of melanoma diagnosis is associated with shorter MSS, however age

  12. Management of HCV-Related Liver Disease in Hemophilia and Thalassemia.

    PubMed

    Rumi, Maria Grazia; Di Marco, Vito; Colombo, Massimo

    2018-05-01

    Chronic infection with the hepatitis C virus (HCV) has long been the dominant complication of substitution therapy in patients with inherited blood disorders and the cause of anticipated death due to end-stage liver disease. In hemophilia, transmission of HCV with clotting factors concentrates started to be curbed in the mid-1980s following the adoption of procedures of virus inactivation of concentrates based on heat, whereas in the 1990s treatment of HCV infection with interferon monotherapy was attempted, however, with little success. The advent of combination therapy of interferon with ribavirin led to a substantial improvement of treatment outcome (40% rate of cure), that however was still of limited efficacy in patients with advanced liver disease, those with high load of HCV genotype 1, and patients coinfected with the human immunodeficiency virus. In this latter population, while the course of hepatitis C was accelerated as a consequence of immunodeficiency, the advent of highly active antiretroviral therapy led acquired immunodeficiency syndrome (AIDS) to decline and hepatitis C to progressively emerge as a dominant cause of mortality, in parallel. In patients with thalassemia, transfusion-related transmission of HCV was efficiently interrupted in 1992 with the advent of sensitive screening tests for testing donors for HCV, whereas treatment with interferon and ribavirin of infected thalassemics was constrained by an increased risk of anemia due to the hemolytic properties of ribavirin coupled with interferon-induced bone marrow suppression. The advent of safe and potent regimens based on the oral administration of direct antiviral agents has revolutionized therapy of HCV in patients with congenital blood diseases, providing substantial clinical benefits and making elimination of infection in these populations, possible. Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

  13. Breast and Prostate Cancer Cohort Consortium (BPC3)

    Cancer.gov

    Breast and Prostate Cancer Cohort Consortium collaborates with three genomic facilities, epidemiologists, population geneticists, and biostatisticians from multiple institutions to study hormone-related gene variants and environmental factors in breast and prostate cancers.

  14. Omega 3:6 ratio intake and incidence of glaucoma: the SUN cohort.

    PubMed

    Pérez de Arcelus, Mónica; Toledo, Estefanía; Martínez-González, Miguel Á; Sayón-Orea, Carmen; Gea, Alfredo; Moreno-Montañés, Javier

    2014-12-01

    Omega 3 and omega 6 polyunsaturated fatty acids have been related to many diseases, especially to cardiovascular diseases. We aimed to assess the association between the intake of omega 3, omega 6 fatty acids and their ratio and the incidence of glaucoma in this prospective cohort study. We followed-up 17,128 participants initially free of glaucoma for a median time of 8.2 years. Validated data of diet were collected at baseline with a 136-item semi-quantitative food-frequency questionnaire and information of new diagnosis of glaucoma in biennial follow-up questionnaires. Multivariable Cox regression models were fit to assess the relationship between omega 3, omega 6 and their ratio and the incidence of glaucoma in the total sample and in participants aged ≥40 years at baseline. During a median follow-up time of 8.2 years, 156 new cases of glaucoma were identified. No significant association was observed for the omega 3 or the omega 6 intake and the risk of glaucoma. Participants in the highest quintile of omega 3:6 ratio intake had a significantly higher risk of glaucoma than participants in the lowest quintile (hazard ratio (HR): 1.91 [95%CI: 1.05-3.46], p for trend 0.03). The association became stronger (HR for the comparison of the 5th versus the 1st quintile: 2.43 [95%CI: 1.17-5.03], p for trend 0.02) when we considered only those participants who were ≥40 years old. Our data suggest an association between omega 3:6 ratio intake and incident glaucoma in our cohort, especially among older participants. Copyright © 2013 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.

  15. 34 CFR 668.204 - Draft cohort default rates and your ability to challenge before official cohort default rates are...

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 34 Education 3 2011-07-01 2011-07-01 false Draft cohort default rates and your ability to... OF EDUCATION STUDENT ASSISTANCE GENERAL PROVISIONS Cohort Default Rates § 668.204 Draft cohort.... (1) We notify you of your draft cohort default rate before your official cohort default rate is...

  16. 34 CFR 668.204 - Draft cohort default rates and your ability to challenge before official cohort default rates are...

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 34 Education 3 2012-07-01 2012-07-01 false Draft cohort default rates and your ability to... OF EDUCATION STUDENT ASSISTANCE GENERAL PROVISIONS Cohort Default Rates § 668.204 Draft cohort.... (1) We notify you of your draft cohort default rate before your official cohort default rate is...

  17. 34 CFR 668.204 - Draft cohort default rates and your ability to challenge before official cohort default rates are...

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 34 Education 3 2014-07-01 2014-07-01 false Draft cohort default rates and your ability to... OF EDUCATION STUDENT ASSISTANCE GENERAL PROVISIONS Cohort Default Rates § 668.204 Draft cohort.... (1) We notify you of your draft cohort default rate before your official cohort default rate is...

  18. 34 CFR 668.204 - Draft cohort default rates and your ability to challenge before official cohort default rates are...

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 34 Education 3 2013-07-01 2013-07-01 false Draft cohort default rates and your ability to... OF EDUCATION STUDENT ASSISTANCE GENERAL PROVISIONS Cohort Default Rates § 668.204 Draft cohort.... (1) We notify you of your draft cohort default rate before your official cohort default rate is...

  19. The Omega-3 Index and relative risk for coronary heart disease mortality: Estimation from 10 cohort studies.

    PubMed

    Harris, William S; Del Gobbo, Liana; Tintle, Nathan L

    2017-07-01

    A recent 19-cohort meta-analysis examined the relationships between biomarkers of omega-3 fatty acids and risk for coronary heart disease (CHD). That study did not, however, report hazard ratios (HRs) specifically as a function of erythrocyte eicosapentaenoic (EPA) plus docosahexaenoic (DHA) levels, a metric called the Omega-3 Index in which EPA + DHA content is expressed as a percent of total fatty acids. The Omega-3 Index has been used in several recent studies and is a validated biomarker of omega-3 fatty acid tissue levels, but additional data are needed to confirm (or refute) the originally-proposed clinical cut-points of <4% (higher risk) and 8%-12% (lower risk). The present study was therefore undertaken using published data from this meta-analysis to estimate HRs per 1-SD increase in the Omega-3 Index and median quintile values for this metric across 10 of the cohorts for which the needed data were available. The overall mean (SD) for the Omega-3 Index in these 10 cohort studies was 6.1% (2.1%), and the HR for a 1-SD increase was 0.85 (95% confidence interval, 0.80-0.91). Median quintile 1 and 5 levels were 4.2% vs. 8.3%, respectively. Based on these values, we estimate that risk for fatal CHD would have been reduced by about 30% moving from an Omega-3 Index of 4%-8%. These findings support the use of <4% and >8% as reasonable therapeutic targets for the Omega-3 Index. Copyright © 2017 Elsevier B.V. All rights reserved.

  20. Factor IX expression in skeletal muscle of a severe hemophilia B patient 10 years after AAV-mediated gene transfer.

    PubMed

    Buchlis, George; Podsakoff, Gregory M; Radu, Antonetta; Hawk, Sarah M; Flake, Alan W; Mingozzi, Federico; High, Katherine A

    2012-03-29

    In previous work we transferred a human factor IX-encoding adeno-associated viral vector (AAV) into skeletal muscle of men with severe hemophilia B. Biopsy of injected muscle up to 1 year after vector injection showed evidence of gene transfer by Southern blot and of protein expression by IHC and immunofluorescent staining. Although the procedure appeared safe, circulating F.IX levels remained subtherapeutic (< 1%). Recently, we obtained muscle tissue from a subject injected 10 years earlier who died of causes unrelated to gene transfer. Using Western blot, IHC, and immunofluorescent staining, we show persistent factor IX expression in injected muscle tissue. F.IX transcripts were detected in injected skeletal muscle using RT-PCR, and isolated whole genomic DNA tested positive for the presence of the transferred AAV vector sequence. This is the longest reported transgene expression to date from a parenterally administered AAV vector, with broad implications for the future of muscle-directed gene transfer.

  1. Factor IX expression in skeletal muscle of a severe hemophilia B patient 10 years after AAV-mediated gene transfer

    PubMed Central

    Buchlis, George; Podsakoff, Gregory M.; Radu, Antonetta; Hawk, Sarah M.; Flake, Alan W.; Mingozzi, Federico

    2012-01-01

    In previous work we transferred a human factor IX–encoding adeno-associated viral vector (AAV) into skeletal muscle of men with severe hemophilia B. Biopsy of injected muscle up to 1 year after vector injection showed evidence of gene transfer by Southern blot and of protein expression by IHC and immunofluorescent staining. Although the procedure appeared safe, circulating F.IX levels remained subtherapeutic (< 1%). Recently, we obtained muscle tissue from a subject injected 10 years earlier who died of causes unrelated to gene transfer. Using Western blot, IHC, and immunofluorescent staining, we show persistent factor IX expression in injected muscle tissue. F.IX transcripts were detected in injected skeletal muscle using RT-PCR, and isolated whole genomic DNA tested positive for the presence of the transferred AAV vector sequence. This is the longest reported transgene expression to date from a parenterally administered AAV vector, with broad implications for the future of muscle-directed gene transfer. PMID:22271447

  2. Clinical characteristics and outcomes of acquired hemophilia A: experience at a single center in Japan.

    PubMed

    Ogawa, Yoshiyuki; Yanagisawa, Kunio; Uchiumi, Hideki; Ishizaki, Takuma; Mitsui, Takeki; Gouda, Fumito; Ieko, Masahiro; Ichinose, Akitada; Nojima, Yoshihisa; Handa, Hiroshi

    2017-07-01

    Acquired hemophilia A (AHA), which is caused by autoantibodies against coagulation factor VIII (FVIII) is a rare, life-threatening bleeding disorder, the incidence of which appears to be increasing in Japan as the population ages. However, the clinical characteristics, treatment, and outcomes of AHA remain difficult to establish due to the rarity of this disease. We retrospectively analyzed data from 25 patients (median age 73 years; range 24-92 years; male n = 15) diagnosed with AHA between 1999 and 2015 at Gunma University Hospital. We identified autoimmune diseases and malignancy as underlying conditions in four and three patients, respectively. Factor VIII activity was significantly decreased in all patients (median 2.0%; range <1.0-8.0) by FVIII inhibitor (median 47.0 BU/mL; range 2.0-1010). Among 71 bleeding events, subcutaneous or intramuscular hemorrhage was the most prevalent. Seventeen patients required bypassing agents. Twenty-two (91.7%) of 24 patients treated with immunosuppressive agents achieved complete response (CR) during a median of 57.5 days (range 19-714 days). Although three patients (12%) relapsed and seven (28%) died of infection, none of the deaths were related to bleeding. Although most of our patients achieved CR after immunosuppressive therapy, the rate of infection-related mortality was unsatisfactorily high.

  3. Phenotypic Correction of Hemophilia A in Sheep by Postnatal Intraperitoneal Transplantation of FVIII-Expressing MSC

    PubMed Central

    Porada, Christopher D.; Sanada, Chad; Kuo, Chung-Jung; Colletti, Evan; Mandeville, Walter; Hasenau, John; Zanjani, Esmail D.; Moot, Robert; Doering, Christopher; Spencer, H. Trent; Almeida-Porada, Graça

    2011-01-01

    We recently re-established a line of sheep that accurately mimics the clinical symptoms and genetics of severe hemophilia A (HA). Herein, we tested a novel, non-ablative transplant therapy in 2 pediatric HA animals. Paternal mesenchymal stem cells (MSC) were transduced with a porcine FVIII-encoding lentivector, and transplanted via the intraperitoneal route, without preconditioning. At the time of transplantation, these animals had received multiple hFVIII treatments for various spontaneous bleeds, and had developed debilitating hemarthroses which produced severe defects in posture and gait. Transplantation of transduced MSC resolved all existent hemarthroses, and spontaneous bleeds ceased. Damaged joints recovered fully; the animals regained normal posture and gait and resumed normal activity. Despite achieving factor-independence, a sharp rise in pre-existent Bethesda titers occurred following transplantation, decreasing the effectiveness and duration of therapy. Post-mortem examination revealed widespread engraftment, with MSC present within the lung, liver, intestine, and thymus, but particularly within joints affected at the time of transplantation, suggesting MSC homed to sites of ongoing injury/inflammation to release FVIII, explaining the dramatic improvement in hemarthrotic joints. In summary, this novel, non-ablative MSC transplantation was straightforward, safe, and converted life-threatening, debilitating HA to a moderate phenotype in a large animal model. PMID:21906573

  4. AAV liver expression of FIX-Padua prevents and eradicates FIX inhibitor without increasing thrombogenicity in hemophilia B dogs and mice.

    PubMed

    Crudele, Julie M; Finn, Jonathan D; Siner, Joshua I; Martin, Nicholas B; Niemeyer, Glenn P; Zhou, Shangzhen; Mingozzi, Federico; Lothrop, Clinton D; Arruda, Valder R

    2015-03-05

    Emerging successful clinical data on gene therapy using adeno-associated viral (AAV) vector for hemophilia B (HB) showed that the risk of cellular immune response to vector capsid is clearly dose dependent. To decrease the vector dose, we explored AAV-8 (1-3 × 10(12) vg/kg) encoding a hyperfunctional factor IX (FIX-Padua, arginine 338 to leucine) in FIX inhibitor-prone HB dogs. Two naïve HB dogs showed sustained expression of FIX-Padua with an 8- to 12-fold increased specific activity reaching 25% to 40% activity without antibody formation to FIX. A third dog with preexisting FIX inhibitors exhibited a transient anamnestic response (5 Bethesda units) at 2 weeks after vector delivery following by spontaneous eradication of the antibody to FIX by day 70. In this dog, sustained FIX expression reached ∼200% and 30% of activity and antigen levels, respectively. Immune tolerance was confirmed in all dogs after challenges with plasma-derived FIX concentrate. Shortening of the clotting times and lack of bleeding episodes support the phenotypic correction of the severe phenotype, with no clinical or laboratory evidence of risk of thrombosis. Provocative studies in mice showed that FIX-Padua exhibits similar immunogenicity and thrombogenicity compared with FIX wild type. Collectively, these data support the potential translation of gene-based strategies using FIX-Padua for HB. © 2015 by The American Society of Hematology.

  5. Cesarean section and risk of obesity in childhood, adolescence, and early adulthood: evidence from 3 Brazilian birth cohorts123

    PubMed Central

    Matijasevich, Alicia; Hallal, Pedro C; Horta, Bernardo L; Barros, Aluísio J; Menezes, Ana B; Santos, Iná S; Gigante, Denise P; Victora, Cesar G

    2012-01-01

    Background: The number of cesarean sections (CSs) is increasing in many countries, and there are concerns about their short- and long-term effects. A recent Brazilian study showed a 58% higher prevalence of obesity in young adults born by CS than in young adults born vaginally. Because CS-born individuals do not make contact at birth with maternal vaginal and intestinal bacteria, the authors proposed that this could lead to long-term changes in the gut microbiota that could contribute to obesity. Objective: We assessed whether CS births lead to increased obesity during childhood, adolescence, and early adulthood in 3 birth cohorts. Design: We analyzed data from 3 birth-cohort studies started in 1982, 1993, and 2004 in Southern Brazil. Subjects were assessed at different ages until 23 y of age. Poisson regression was used to estimate prevalence ratios with adjustment for ≤15 socioeconomic, demographic, maternal, anthropometric, and behavioral covariates. Results: In the crude analyses, subjects born by CS had ∼50% higher prevalence of obesity at 4, 11, and 15 y of age but not at 23 y of age. After adjustment for covariates, prevalence ratios were markedly reduced and no longer significant for men or women. The only exception was an association for 4-y-old boys in the 1993 cohort, which was not observed in the other 2 cohorts or for girls. Conclusion: In these 3 birth cohorts, CSs do not seem to lead to an important increased risk of obesity during childhood, adolescence, or early adulthood. PMID:22237058

  6. Prevalence, Incidence, and Factor Concentrate Usage Trends of Hemophiliacs in Taiwan

    PubMed Central

    Tu, Tsu-Chiang; Liou, Wen-Shyong; Chou, Tsui-Yun; Lin, Tsung-Kun; Lee, Chuan-Fang; Chen, Jye-Daa; Cham, Thau-Ming

    2013-01-01

    Purpose Hemophilia A and B (HA, HB) are the most common X-linked inherited bleeding disorders. The introduction of factor concentrates has allowed for control of the lifelong chronic disease. However, no studies have been published regarding the epidemiology of hemophilia in Taiwan. Our aim was to determine the prevalence, incidence, and mortality rate, as well as trends in the use of factor concentrates, in individuals with hemophilia in Taiwan. Materials and Methods A retrospective study was conducted using the National Health Insurance Research Database between 1997 and 2007. Results We identified 988 males with hemophilia (HA : HB ratio=5.4 : 1). The mean prevalence per 100000 males was 6.7±0.1 for HA and 1.2±0.1 for HB. The estimated mean annual incidence per live male birth was 1 in 10752 for HA and 1 in 47619 for HB. Standardized mortality ratios for males with hemophilia (all severities) or severe hemophilia were 1.3- and 2.1-fold higher than that of the general male population, respectively. Mean factor VIII (FVIII) and factor IX (FIX) usage was 1.5003±0.4029 and 0.3126±0.0904 international units (IUs) per capita, respectively. Mean FVIII and FIX usage per patient with hemophilia (all severities) or severe hemophilia was 44027±11532 and 72341±17298, respectively, and 49407±13015 and 74369±18411 IUs per person with HA or HB, respectively. Conclusion Our data revealed epidemiologic and factor concentrate usage trends in males with hemophilia in Taiwan, highlighting a need for improvements in the mandatory National Health Insurance registry. A better-designed, patient-centered registry system would enable more detailed patient information collection and analysis, improving subsequent care. PMID:23225801

  7. [Successful management of neurosurgical procedures with continuous infusion of recombinant factor IX in a child with hemophilia B].

    PubMed

    Yamamoto, Mariko; Nakadate, Hisaya; Iguchi, Umefumi; Masuda, Hiroshi; Sakai, Hirokazu; Ishiguro, Akira

    2013-03-01

    This report describes the successful management of neurosurgical procedures with continuous infusion of recombinant factor IX (rFIX). A 1-year-old boy with severe hemophilia B was administered prophylactic therapy with rFIX after intracranial bleeding. We found the enlargement of an arachnoid cyst in a follow-up CT scan. He underwent marsupialization of the cyst under the continuous infusion of rFIX. FIX levels were examined in our hospital and the rFIX infusion rate was adjusted in an attempt to keep FIX levels above 90% intraoperatively, and 70% until his 7th post-operative day. We studied the pharmacokinetic profile of rFIX and found a half-time of 25 hours and mean in vivo recovery of 0.69 IU/dl/IU/kg. Reconstituted rFIX also retained at least 95% activity after 72 hours at room temperature. This is the first report of the perioperative management of a child undergoing a neurosurgical procedure under the continuous infusion of rFIX in Japan. Further studies are required before the routine use of this product for continuous infusion.

  8. Assessment of Relative Bioavailability of Moroctocog Alfa and Moroctocog Alfa (AF-CC) in Subjects With Severe Hemophilia A.

    PubMed

    Korth-Bradley, Joan; Rupon, Jeremy; Plotka, Anna; Charnigo, Robert; Rendo, Pablo

    2018-05-01

    An open-label, single-dose, randomized, two-period, crossover study comparing the pharmacokinetics of factor VIII activity in plasma (FVIII:C) after administration of an albumin-free presentation of moroctocog alfa (test) and moroctocog alfa manufactured using the previous technique (reference) was conducted in 30 (25 evaluable) male subjects who had severe hemophilia A (FVIII:C < 1 IU/dL). Blood samples were collected for 48 h after administration of each dose. C was assayed using a chromogenic substrate assay. The FVIII:C pharmacokinetic parameters were calculated using noncompartmental analysis. The presentations would be bioequivalent if the 90% confidence limits of the ratio of the geometric mean values of AUC inf and recovery fell within the interval of 80-125%. The bioequivalence criteria were met. A total of 10 treatment-related adverse events were observed in a total of nine subjects. All were mild and none was determined to be related to administration of study medication. © 2018 The Authors. Clinical and Translational Science published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.

  9. Rare Variants in PLD3 Do Not Affect Risk for Early-Onset Alzheimer Disease in a European Consortium Cohort.

    PubMed

    Cacace, Rita; Van den Bossche, Tobi; Engelborghs, Sebastiaan; Geerts, Nathalie; Laureys, Annelies; Dillen, Lubina; Graff, Caroline; Thonberg, Håkan; Chiang, Huei-Hsin; Pastor, Pau; Ortega-Cubero, Sara; Pastor, Maria A; Diehl-Schmid, Janine; Alexopoulos, Panagiotis; Benussi, Luisa; Ghidoni, Roberta; Binetti, Giuliano; Nacmias, Benedetta; Sorbi, Sandro; Sanchez-Valle, Raquel; Lladó, Albert; Gelpi, Ellen; Almeida, Maria Rosário; Santana, Isabel; Tsolaki, Magda; Koutroumani, Maria; Clarimon, Jordi; Lleó, Alberto; Fortea, Juan; de Mendonça, Alexandre; Martins, Madalena; Borroni, Barbara; Padovani, Alessandro; Matej, Radoslav; Rohan, Zdenek; Vandenbulcke, Mathieu; Vandenberghe, Rik; De Deyn, Peter P; Cras, Patrick; van der Zee, Julie; Sleegers, Kristel; Van Broeckhoven, Christine

    2015-12-01

    Rare variants in the phospholipase D3 gene (PLD3) were associated with increased risk for late-onset Alzheimer disease (LOAD). We identified a missense mutation in PLD3 in whole-genome sequence data of a patient with autopsy confirmed Alzheimer disease (AD) and onset age of 50 years. Subsequently, we sequenced PLD3 in a Belgian early-onset Alzheimer disease (EOAD) patient (N = 261) and control (N = 319) cohort, as well as in European EOAD patients (N = 946) and control individuals (N = 1,209) ascertained in different European countries. Overall, we identified 22 rare variants with a minor allele frequency <1%, 20 missense and two splicing mutations. Burden analysis did not provide significant evidence for an enrichment of rare PLD3 variants in EOAD patients in any of the patient/control cohorts. Also, meta-analysis of the PLD3 data, including a published dataset of a German EOAD cohort, was not significant (P = 0.43; OR = 1.53, 95% CI 0.60-3.31). Consequently, our data do not support a role for PLD3 rare variants in the genetic etiology of EOAD in European EOAD patients. Our data corroborate the negative replication data obtained in LOAD studies and therefore a genetic role of PLD3 in AD remains to be demonstrated. © 2015 The Authors. **Human Mutation published by Wiley Periodicals, Inc.

  10. Rare Variants in PLD3 Do Not Affect Risk for Early‐Onset Alzheimer Disease in a European Consortium Cohort

    PubMed Central

    Cacace, Rita; Van den Bossche, Tobi; Engelborghs, Sebastiaan; Geerts, Nathalie; Laureys, Annelies; Dillen, Lubina; Graff, Caroline; Thonberg, Håkan; Chiang, Huei‐Hsin; Pastor, Pau; Ortega‐Cubero, Sara; Pastor, Maria A.; Diehl‐Schmid, Janine; Alexopoulos, Panagiotis; Benussi, Luisa; Ghidoni, Roberta; Binetti, Giuliano; Nacmias, Benedetta; Sorbi, Sandro; Sanchez‐Valle, Raquel; Lladó, Albert; Gelpi, Ellen; Almeida, Maria Rosário; Santana, Isabel; Tsolaki, Magda; Koutroumani, Maria; Clarimon, Jordi; Lleó, Alberto; Fortea, Juan; de Mendonça, Alexandre; Martins, Madalena; Borroni, Barbara; Padovani, Alessandro; Matej, Radoslav; Rohan, Zdenek; Vandenbulcke, Mathieu; Vandenberghe, Rik; De Deyn, Peter P.; Cras, Patrick; van der Zee, Julie; Sleegers, Kristel

    2015-01-01

    ABSTRACT Rare variants in the phospholipase D3 gene (PLD3) were associated with increased risk for late‐onset Alzheimer disease (LOAD). We identified a missense mutation in PLD3 in whole‐genome sequence data of a patient with autopsy confirmed Alzheimer disease (AD) and onset age of 50 years. Subsequently, we sequenced PLD3 in a Belgian early‐onset Alzheimer disease (EOAD) patient (N = 261) and control (N = 319) cohort, as well as in European EOAD patients (N = 946) and control individuals (N = 1,209) ascertained in different European countries. Overall, we identified 22 rare variants with a minor allele frequency <1%, 20 missense and two splicing mutations. Burden analysis did not provide significant evidence for an enrichment of rare PLD3 variants in EOAD patients in any of the patient/control cohorts. Also, meta‐analysis of the PLD3 data, including a published dataset of a German EOAD cohort, was not significant (P = 0.43; OR = 1.53, 95% CI 0.60–3.31). Consequently, our data do not support a role for PLD3 rare variants in the genetic etiology of EOAD in European EOAD patients. Our data corroborate the negative replication data obtained in LOAD studies and therefore a genetic role of PLD3 in AD remains to be demonstrated. PMID:26411346

  11. 34 CFR 668.185 - Draft cohort default rates and your ability to challenge before official cohort default rates are...

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 34 Education 3 2014-07-01 2014-07-01 false Draft cohort default rates and your ability to... OF EDUCATION STUDENT ASSISTANCE GENERAL PROVISIONS Two Year Cohort Default Rates § 668.185 Draft...) General. (1) We notify you of your draft cohort default rate before your official cohort default rate is...

  12. 34 CFR 668.185 - Draft cohort default rates and your ability to challenge before official cohort default rates are...

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 34 Education 3 2011-07-01 2011-07-01 false Draft cohort default rates and your ability to... OF EDUCATION STUDENT ASSISTANCE GENERAL PROVISIONS Two Year Cohort Default Rates § 668.185 Draft...) General. (1) We notify you of your draft cohort default rate before your official cohort default rate is...

  13. 34 CFR 668.185 - Draft cohort default rates and your ability to challenge before official cohort default rates are...

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 34 Education 3 2013-07-01 2013-07-01 false Draft cohort default rates and your ability to... OF EDUCATION STUDENT ASSISTANCE GENERAL PROVISIONS Two Year Cohort Default Rates § 668.185 Draft...) General. (1) We notify you of your draft cohort default rate before your official cohort default rate is...

  14. 34 CFR 668.185 - Draft cohort default rates and your ability to challenge before official cohort default rates are...

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 34 Education 3 2012-07-01 2012-07-01 false Draft cohort default rates and your ability to... OF EDUCATION STUDENT ASSISTANCE GENERAL PROVISIONS Two Year Cohort Default Rates § 668.185 Draft...) General. (1) We notify you of your draft cohort default rate before your official cohort default rate is...

  15. Association analysis of ACE, ACTN3 and PPARGC1A gene polymorphisms in two cohorts of European strength and power athletes

    PubMed Central

    Jakaitiene, A; Aksenov, MO; Aksenova, AV; Druzhevskaya, AM; Astratenkova, IV; Egorova, ES; Gabdrakhmanova, LJ; Tubelis, L; Kucinskas, V; Utkus, A

    2016-01-01

    The performance of professional strength and power athletes is influenced, at least partly, by genetic components. The main aim of this study was to investigate individually and in combination the association of ACE (I/D), ACTN3 (R577X) and PPARGC1A (Gly482Ser) gene polymorphisms with strength/power-oriented athletes’ status in two cohorts of European athletes. A cohort of European Caucasians from Russia and Lithuania (161 athletes: by groups – weightlifters (87), powerlifters (60), throwers (14); by elite status – ‘elite’ (104), ‘sub-elite’ (57); and 1,202 controls) were genotyped for ACE, ACTN3 and PPARGC1A polymorphisms. Genotyping was performed by polymerase chain reaction and/or restriction fragment length polymorphism analysis. Statistically significant differences in ACTN3 (R577X) allele/genotype distribution were not observed in the whole cohort of athletes or between analysed groups separately when compared with controls. The odds ratio for athletes compared to controls of the ACE I/I genotype was 1.71 (95% CI 1.01-2.92) in the Russian cohort and for the ACE I/D genotype it was 2.35 (95% CI 1.10-5.06) in the Lithuanian cohort. The odds ratio of being a powerlifter in PPARGC1A Ser/Ser genotype carriers was 2.11 (95% CI: 1.09-4.09, P = 0.026). The ACTN3 (R577X) polymorphism is not associated with strength/power athletic status in two cohorts of European athletes. The ACE I/I genotype is probably the ‘preferable genotype’ for Russian athletes and the ACE I/D genotype for Lithuanian strength/power athletes. We found that the PPARGC1A (Gly482Ser) polymorphism is associated with strength/power athlete status. Specifically, the PPARGC1A Ser/Ser genotype is more favourable for powerlifters compared to controls. PMID:27601773

  16. Bernard-Soulier Syndrome

    MedlinePlus

    ... and Women with Hemophilia Inheritance of Hemophilia Definitions & Terminology Bleeding Symptoms Carrier Diagnosis When to Test for ... and Women with Hemophilia Inheritance of Hemophilia Definitions & Terminology Bleeding Symptoms Carrier Diagnosis When to Test for ...

  17. Glanzmann Thrombasthenia

    MedlinePlus

    ... and Women with Hemophilia Inheritance of Hemophilia Definitions & Terminology Bleeding Symptoms Carrier Diagnosis When to Test for ... and Women with Hemophilia Inheritance of Hemophilia Definitions & Terminology Bleeding Symptoms Carrier Diagnosis When to Test for ...

  18. Storage Pool Deficiencies

    MedlinePlus

    ... and Women with Hemophilia Inheritance of Hemophilia Definitions & Terminology Bleeding Symptoms Carrier Diagnosis When to Test for ... and Women with Hemophilia Inheritance of Hemophilia Definitions & Terminology Bleeding Symptoms Carrier Diagnosis When to Test for ...

  19. 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

  20. 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.

  1. Identification of FVIII gene mutations in patients with hemophilia A using new combinatorial sequencing by hybridization

    PubMed Central

    Chetta, M.; Drmanac, A.; Santacroce, R.; Grandone, E.; Surrey, S.; Fortina, P.; Margaglione, M.

    2008-01-01

    BACKGROUND: Standard methods of mutation detection are time consuming in Hemophilia A (HA) rendering their application unavailable in some analysis such as prenatal diagnosis. OBJECTIVES: To evaluate the feasibility of combinatorial sequencing-by-hybridization (cSBH) as an alternative and reliable tool for mutation detection in FVIII gene. PATIENTS/METHODS: We have applied a new method of cSBH that uses two different colors for detection of multiple point mutations in the FVIII gene. The 26 exons encompassing the HA gene were analyzed in 7 newly diagnosed Italian patients and in 19 previously characterized individuals with FVIII deficiency. RESULTS: Data show that, when solution-phase TAMRA and QUASAR labeled 5-mer oligonucleotide sets mixed with unlabeled target PCR templates are co-hybridized in the presence of DNA ligase to universal 6-mer oligonucleotide probe-based arrays, a number of mutations can be successfully detected. The technique was reliable also in identifying a mutant FVIII allele in an obligate heterozygote. A novel missense mutation (Leu1843Thr) in exon 16 and three novel neutral polymorphisms are presented with an updated protocol for 2-color cSBH. CONCLUSIONS: cSBH is a reliable tool for mutation detection in FVIII gene and may represent a complementary method for the genetic screening of HA patients. PMID:20300295

  2. How are European birth-cohort studies engaging and consulting with young cohort members?

    PubMed

    Lucas, Patricia J; Allnock, Debra; Jessiman, Tricia

    2013-04-11

    Birth cohort studies, where parents consent for their child to be enrolled in a longitudinal study prior to or soon after birth, are a powerful study design in epidemiology and developmental research. Participation often continues into adulthood. Where participants are enrolled as infants, provision should be made for consent, consultation and involvement in study design as they age. This study aims to audit and describe the extent and types of consultation and engagement currently used in birth cohorts in Europe. Seventy study groups (representing 84 cohorts) were contacted to ask about their practice in engaging and involving study members. Information was gathered from study websites and publications, 15 cohorts provided additional information via email and 17 cohorts were interviewed over the phone. The cohorts identified confirm the growth of this study design, with more than half beginning since 1990, and 4 since 2011. Most studies maintain a website open to the general public, although many are written for the scientific community only. Five studies have web pages specifically for young cohort members and one study provides a dedicated page for fathers. Cohorts send newsletters, cards, and summaries of findings to participants to stay in touch. Six cohorts use Facebook for this purpose. Five cohorts provide feedback opportunities for participants after completing a round of data collection. We know of just 8 cohorts who have a mechanism for consulting with parents and 3 a mechanism for consulting with young people themselves, although these were 'one off' consultations for some groups. Barriers to further consultation with cohort members were: concerns about impact on quality of research, ethical constraints, resource limitations, lack of importance, and previous adverse experiences. Although the children in some of the cohorts are still young (born in the last 10 years) many are old enough to include some element of consultation. Barriers to greater

  3. User-centered requirements engineering in health information systems: a study in the hemophilia field.

    PubMed

    Teixeira, Leonor; Ferreira, Carlos; Santos, Beatriz Sousa

    2012-06-01

    The use of sophisticated information and communication technologies (ICTs) in the health care domain is a way to improve the quality of services. However, there are also hazards associated with the introduction of ICTs in this domain and a great number of projects have failed due to the lack of systematic consideration of human and other non-technology issues throughout the design or implementation process, particularly in the requirements engineering process. This paper presents the methodological approach followed in the design process of a web-based information system (WbIS) for managing the clinical information in hemophilia care, which integrates the values and practices of user-centered design (UCD) activities into the principles of software engineering, particularly in the phase of requirements engineering (RE). This process followed a paradigm that combines a grounded theory for data collection with an evolutionary design based on constant development and refinement of the generic domain model using three well-known methodological approaches: (a) object-oriented system analysis; (b) task analysis; and, (c) prototyping, in a triangulation work. This approach seems to be a good solution for the requirements engineering process in this particular case of the health care domain, since the inherent weaknesses of individual methods are reduced, and emergent requirements are easier to elicit. Moreover, the requirements triangulation matrix gives the opportunity to look across the results of all used methods and decide what requirements are critical for the system success. Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

  4. 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

  5. Longitudinal Surveys of Australian Youth (LSAY) 2009 Cohort: Wave 3 (2011)--Questionnaire. Technical Report 72A

    ERIC Educational Resources Information Center

    National Centre for Vocational Education Research (NCVER), 2012

    2012-01-01

    The Longitudinal Surveys of Australian Youth (LSAY) program studies the progress of several groups of young Australians as they move from school into post-secondary education and work. This technical paper contains the questionnaire for the LSAY 2009 cohort Wave 3 (2011) data set.

  6. Cohort profile: the Geoscience and Health Cohort Consortium (GECCO) in the Netherlands

    PubMed Central

    Timmermans, Erik J; Lakerveld, Jeroen; Beulens, Joline W J; Boomsma, Dorret I; Kramer, Sophia E; Oosterman, Mirjam; Willemsen, Gonneke; Stam, Mariska; Nijpels, Giel; Schuengel, Carlo; Smit, Jan H; Brunekreef, Bert; Dekkers, Jasper E C; Deeg, Dorly J H; Penninx, Brenda W J H; Huisman, Martijn

    2018-01-01

    Purpose In the Netherlands, a great variety of objectively measured geo-data is available, but these data are scattered and measured at varying spatial and temporal scales. The centralisation of these geo-data and the linkage of these data to individual-level data from longitudinal cohort studies enable large-scale epidemiological research on the impact of the environment on public health in the Netherlands. In the Geoscience and Health Cohort Consortium (GECCO), six large-scale and ongoing cohort studies have been enriched with a variety of existing geo-data. Here, we introduce GECCO by describing: (1) the phenotypes of the involved cohort studies, (2) the collected geo-data and their sources, (3) the methodology that was used to link the collected geo-data to individual cohort studies, (4) the similarity of commonly used geo-data between our consortium and the nationwide situation in the Netherlands and (5) the distribution of geo-data within our consortium. Participants GECCO includes participants from six prospective cohort studies (eg, 44 657 respondents (18–100 years) in 2006) and it covers all municipalities in the Netherlands. Using postal code information of the participants, geo-data on the address-level, postal code-level as well as neighbourhood-level could be linked to individual-level cohort data. Findings to date The geo-data could be successfully linked to almost all respondents of all cohort studies, with successful data-linkage rates ranging from 97.1% to 100.0% between cohort studies. The results show variability in geo-data within and across cohorts. GECCO increases power of analyses, provides opportunities for cross-checking and replication, ensures sufficient geographical variation in environmental determinants and allows for nuanced analyses on specific subgroups. Future plans GECCO offers unique opportunities for (longitudinal) studies on the complex relationships between the environment and health outcomes. For example, GECCO will be

  7. Cohort profile: the Geoscience and Health Cohort Consortium (GECCO) in the Netherlands.

    PubMed

    Timmermans, Erik J; Lakerveld, Jeroen; Beulens, Joline W J; Boomsma, Dorret I; Kramer, Sophia E; Oosterman, Mirjam; Willemsen, Gonneke; Stam, Mariska; Nijpels, Giel; Schuengel, Carlo; Smit, Jan H; Brunekreef, Bert; Dekkers, Jasper E C; Deeg, Dorly J H; Penninx, Brenda W J H; Huisman, Martijn

    2018-06-09

    In the Netherlands, a great variety of objectively measured geo-data is available, but these data are scattered and measured at varying spatial and temporal scales. The centralisation of these geo-data and the linkage of these data to individual-level data from longitudinal cohort studies enable large-scale epidemiological research on the impact of the environment on public health in the Netherlands. In the Geoscience and Health Cohort Consortium (GECCO), six large-scale and ongoing cohort studies have been enriched with a variety of existing geo-data. Here, we introduce GECCO by describing: (1) the phenotypes of the involved cohort studies, (2) the collected geo-data and their sources, (3) the methodology that was used to link the collected geo-data to individual cohort studies, (4) the similarity of commonly used geo-data between our consortium and the nationwide situation in the Netherlands and (5) the distribution of geo-data within our consortium. GECCO includes participants from six prospective cohort studies (eg, 44 657 respondents (18-100 years) in 2006) and it covers all municipalities in the Netherlands. Using postal code information of the participants, geo-data on the address-level, postal code-level as well as neighbourhood-level could be linked to individual-level cohort data. The geo-data could be successfully linked to almost all respondents of all cohort studies, with successful data-linkage rates ranging from 97.1% to 100.0% between cohort studies. The results show variability in geo-data within and across cohorts. GECCO increases power of analyses, provides opportunities for cross-checking and replication, ensures sufficient geographical variation in environmental determinants and allows for nuanced analyses on specific subgroups. GECCO offers unique opportunities for (longitudinal) studies on the complex relationships between the environment and health outcomes. For example, GECCO will be used for further research on environmental determinants

  8. Analysis of risk factors for infant mortality in the 1992-3 and 2002-3 birth cohorts in rural Guinea-Bissau.

    PubMed

    Byberg, Stine; Østergaard, Marie D; Rodrigues, Amabelia; Martins, Cesario; Benn, Christine S; Aaby, Peter; Fisker, Ane B

    2017-01-01

    Though still high, the infant mortality rate in Guinea-Bissau has declined. We aimed to identify risk factors including vaccination coverage, for infant mortality in the rural population of Guinea-Bissau and assess whether these risk factors changed from 1992-3 to 2002-3. The Bandim Health Project (BHP) continuously surveys children in rural Guinea-Bissau. We investigated the association between maternal and infant factors (especially DTP and measles coverage) and infant mortality. Hazard ratios (HR) were calculated using Cox regression. We tested for interactions with sex, age groups (defined by current vaccination schedule) and cohort to assess whether the risk factors were the same for boys and girls, in different age groups in 1992-3 and in 2002-3. The infant mortality rate declined from 148/1000 person years (PYRS) in 1992-3 to 124/1000 PYRS in 2002-3 (HR = 0.88;95%CI:0.77-0.99); this decline was significant for girls (0.77;0.64-0.94) but not for boys (0.97;0.82-1.15) (p = 0.10 for interaction). Risk factors did not differ significantly by cohort in either distribution or effect. Mortality decline was most marked among girls aged 9-11 months (0.56;0.37-0.83). There was no significant mortality decline for girls 1.5-8 months of age (0.93;0.68-1.28) (p = 0.05 for interaction). DTP and measles coverage increased from 1992-3 to 2002-3. Risk factors did not change with the decline in mortality. Due to beneficial non-specific effects for girls, the increased coverage of measles vaccination may have contributed to the disproportional decline in mortality by sex and age group.

  9. 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

  10. Methodology Series Module 1: Cohort Studies

    PubMed Central

    Setia, Maninder Singh

    2016-01-01

    Cohort design is a type of nonexperimental or observational study design. In a cohort study, the participants do not have the outcome of interest to begin with. They are selected based on the exposure status of the individual. They are then followed over time to evaluate for the occurrence of the outcome of interest. Some examples of cohort studies are (1) Framingham Cohort study, (2) Swiss HIV Cohort study, and (3) The Danish Cohort study of psoriasis and depression. These studies may be prospective, retrospective, or a combination of both of these types. Since at the time of entry into the cohort study, the individuals do not have outcome, the temporality between exposure and outcome is well defined in a cohort design. If the exposure is rare, then a cohort design is an efficient method to study the relation between exposure and outcomes. A retrospective cohort study can be completed fast and is relatively inexpensive compared with a prospective cohort study. Follow-up of the study participants is very important in a cohort study, and losses are an important source of bias in these types of studies. These studies are used to estimate the cumulative incidence and incidence rate. One of the main strengths of a cohort study is the longitudinal nature of the data. Some of the variables in the data will be time-varying and some may be time independent. Thus, advanced modeling techniques (such as fixed and random effects models) are useful in analysis of these studies. PMID:26955090

  11. Methodology Series Module 1: Cohort Studies.

    PubMed

    Setia, Maninder Singh

    2016-01-01

    Cohort design is a type of nonexperimental or observational study design. In a cohort study, the participants do not have the outcome of interest to begin with. They are selected based on the exposure status of the individual. They are then followed over time to evaluate for the occurrence of the outcome of interest. Some examples of cohort studies are (1) Framingham Cohort study, (2) Swiss HIV Cohort study, and (3) The Danish Cohort study of psoriasis and depression. These studies may be prospective, retrospective, or a combination of both of these types. Since at the time of entry into the cohort study, the individuals do not have outcome, the temporality between exposure and outcome is well defined in a cohort design. If the exposure is rare, then a cohort design is an efficient method to study the relation between exposure and outcomes. A retrospective cohort study can be completed fast and is relatively inexpensive compared with a prospective cohort study. Follow-up of the study participants is very important in a cohort study, and losses are an important source of bias in these types of studies. These studies are used to estimate the cumulative incidence and incidence rate. One of the main strengths of a cohort study is the longitudinal nature of the data. Some of the variables in the data will be time-varying and some may be time independent. Thus, advanced modeling techniques (such as fixed and random effects models) are useful in analysis of these studies.

  12. Clinical and molecular characterization of a re-established line of sheep exhibiting hemophilia A

    PubMed Central

    PORADA, C. D.; SANADA, C.; LONG, C. R.; WOOD, J. A.; DESAI, J.; FREDERICK, N.; MILLSAP, L.; BORMANN, C.; MENGES, S. L.; HANNA, C.; FLORES-FOXWORTH, G.; SHIN, T.; WESTHUSIN, M. E.; LIU, W.; GLIMP, H.; ZANJANI, E. D.; LOZIER, J. N.; PLISKA, V.; STRANZINGER, G.; JOERG, H.; KRAEMER, D. C.; ALMEIDA-PORADA, G.

    2010-01-01

    Summary Background Large animal models that accurately mimic human hemophilia A (HA) are in great demand for developing and testing novel therapies to treat HA. Objectives To re-establish a line of sheep exhibiting a spontaneous bleeding disorder closely mimicking severe human HA, fully characterize their clinical presentation, and define the molecular basis for disease. Patients/methods Sequential reproductive manipulations were performed with cryopreserved semen from a deceased affected ram. The resultant animals were examined for hematologic parameters, clinical symptoms, and responsiveness to human FVIII (hFVIII). The full coding region of sheep FVIII mRNA was sequenced to identify the genetic lesion. Results and conclusions The combined reproductive technologies yielded 36 carriers and 8 affected animals. The latter had almost non-existent levels of FVIII:C and extremely prolonged aPTT, with otherwise normal hematologic parameters. These animals exhibited bleeding from the umbilical cord, prolonged tail and nail cuticle bleeding time, and multiple episodes of severe spontaneous bleeding, including hemarthroses, muscle hematomas and hematuria, all of which responded to hFVIII. Inhibitors of hFVIII were detected in four treated animals, further establishing the preclinical value of this model. Sequencing identified a premature stop codon and frame-shift in exon 14, providing a molecular explanation for HA. Given the decades of experience using sheep to study both normal physiology and a wide array of diseases and the high homology between human and sheep FVIII, this new model will enable a better understanding of HA and facilitate the development and testing of novel treatments that can directly translate to HA patients. PMID:19943872

  13. Preclinical safety and efficacy of a new recombinant FIX drug product for treatment of hemophilia B.

    PubMed

    Dietrich, Barbara; Schiviz, Alexandra; Hoellriegl, Werner; Horling, Frank; Benamara, Karima; Rottensteiner, Hanspeter; Turecek, Peter L; Schwarz, Hans Peter; Scheiflinger, Friedrich; Muchitsch, Eva-Maria

    2013-11-01

    Baxter has developed a new recombinant factor IX (rFIX) drug product (BAX326) for treating patients with hemophilia B, or congenital FIX deficiency. An extensive preclinical program evaluated the pharmacokinetics, efficacy, and safety of BAX326 in different species. The efficacy of BAX326 was tested in three mouse models of primary pharmacodynamics: tail-tip bleeding, carotid occlusion, and thrombelastography. The pharmacokinetics was evaluated after a single intravenous bolus injection in mice, rats, and macaques. Toxicity was assessed in rats and macaques, safety pharmacology in rabbits and macaques, and immunogenicity in mice. BAX326 was shown to be efficacious in all three primary pharmacodynamic studies (P ≤ 0.0076). Hemostatic efficacy was dose related and similar for the three lots tested. Pharmacokinetic results showed that rFIX activity and rFIX antigen concentrations declined in a bi-phasic manner, similar to a previously licensed rFIX product. BAX326 was well tolerated in rabbits and macaques at all dose levels; no thrombogenic events and no adverse clinical, respiratory, or cardiovascular effects occurred. BAX326 was also shown to have a similar immunogenicity profile to the comparator rFIX product in mice. These results demonstrate that BAX326 has a favorable preclinical safety and efficacy profile, predictive of a comparable effect to that of the previously licensed rFIX in humans.

  14. 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

  15. Evaluation of the rheumatoid arthritis susceptibility loci HLA-DRB1, PTPN22, OLIG3/TNFAIP3, STAT4 and TRAF1/C5 in an inception cohort

    PubMed Central

    2010-01-01

    Introduction This study investigated five confirmed rheumatoid arthritis (RA) susceptibility genes/loci (HLA-DRB1, PTPN22, STAT4, OLIG3/TNFAIP3 and TRAF1/C5) for association with susceptibility and severity in an inception cohort. Methods The magnitude of association for each genotype was assessed in 1,046 RA subjects from the Yorkshire Early RA cohort and in 5,968 healthy UK controls. Additional exploratory subanalyses were undertaken in subgroups defined by autoantibody status (rheumatoid factor and anti-cyclic citrullinated peptide) or disease severity (baseline articular erosions, Health Assessment Questionnaire (HAQ) score and swollen joint count (SJC)). Results In the total RA inception cohort, the HLA-DRB1 shared epitope (per-allele odds ratio (OR) = 2.1, trend P < 0.0001), PTPN22 (per-allele OR = 1.5, trend P < 0.0001), OLIG3/TNFAIP3 locus (per-allele OR = 1.2, trend P = 0.009) and TRAF1/C5 locus (per-allele OR = 1.1, trend P = 0.04) were associated with RA. The magnitude of association for these loci was increased in those patients who were autoantibody-positive. PTPN22 was associated with autoantibody-negative RA (per-allele OR = 1.3, trend P = 0.04). There was no evidence of association between these five genetic loci and baseline erosions or SJC in the total RA cohort, after adjustment for symptom duration. TRAF1/C5 was significantly associated with baseline HAQ, however, following adjustment for symptom duration (P trend = 0.03). Conclusions These findings support the mounting evidence that different genetic loci are associated with autoantibody-positive and autoantibody-negative RA, possibly suggesting that many of the genes identified to date are associated with autoantibody production. Additional studies with a specific focus on autoantibody-negative RA will be needed to identify the genes predisposing to this RA subgroup. The TRAF1/C5 locus in particular warrants further investigation in RA as a potential disease severity locus. PMID:20353580

  16. PNPLA3 Association with Alcoholic Liver Disease in a Cohort of Heavy Drinkers.

    PubMed

    Kolla, Bhanu Prakash; Schneekloth, Terry D; Biernacka, Joanna; Shah, Vijay; Lazaridis, Konstantinos N; Geske, Jennifer; Karpyak, Victor

    2018-02-21

    Prior studies have established variation at the PNPLA3gene to be associated with a risk of developing alcoholic liver disease (ALD). We attempt to replicate this finding and other potential genetic variations previously associated with ALD utilizing a case-control design in a cohort of subjects with alcohol use disorders. This case-control study performed in a US clinical sample of heavy drinkers, replicates the previously reported association between ALD and rs738409 polymorphism in the PNPLA3gene in heavy drinkers. This association persisted after accounting for the subject's diabetes status. Patients of European ancestry with a history of ALD were identified (n = 169). Controls consisted of patients without ALD who were from the same cohorts and were ≥ 30 years of age, had lifetime total years drinking ≥20 and lifetime maximum drinks per day ≥12 (n = 259). Patients were genotyped for 40 candidate single nucleotide polymorphisms (SNPs) selected for the purpose of testing their association with ALD. The association of each SNP with ALD was tested using a logistic regression model, assuming log-additive allele effects. Bonferroni correction was applied and multivariable logistic regression models were used to account for relevant covariates. Age, sex, and body mass index (BMI) distributions were similar between cases and controls. Diabetes was more prevalent in the ALD cases. Three SNPs were associated with ALD at the nominal significance level (rs738409 in PNPLA3, P = 0.00029; rs3741559 in AQP2, P = 0.0185; rs4290029 in NVL, P = 0.0192); only PNPLA3rs738409 SNP was significant at the Bonferroni-corrected P-value threshold of 0.00125. Association results remained significant after adjustment for diabetes status. Our case-control study confirmed that PNPLA3 rs738409 SNP is associated with ALD. This is an important replication in a US clinical sample with control subjects who had long histories of alcohol consumption.

  17. Cohort profile: The lidA Cohort Study—a German Cohort Study on Work, Age, Health and Work Participation

    PubMed Central

    Hasselhorn, Hans Martin; Peter, Richard; Rauch, Angela; Schröder, Helmut; Swart, Enno; Bender, Stefan; du Prel, Jean-Baptist; Ebener, Melanie; March, Stefanie; Trappmann, Mark; Steinwede, Jacob; Müller, Bernd Hans

    2014-01-01

    The lidA Cohort Study (German Cohort Study on Work, Age, Health and Work Participation) was set up to investigate and follow the effects of work and work context on the physical and psychological health of the ageing workforce in Germany and subsequently on work participation. Cohort participants are initially employed people subject to social security contributions and born in either 1959 (n = 2909) or 1965 (n = 3676). They were personally interviewed in their homes in 2011 and will be visited every 3 years. Data collection comprises socio-demographic data, work and private exposures, work ability, work and work participation attitudes, health, health-related behaviour, personality and attitudinal indicators. Employment biographies are assessed using register data. Subjective health reports and physical strength measures are complemented by health insurance claims data, where permission was given. A conceptual framework has been developed for the lidA Cohort Study within which three confirmatory sub-models assess the interdependencies of work and health considering age, gender and socioeconomic status. The first set of the data will be available to the scientific community by 2015. Access will be given by the Research Data Centre of the German Federal Employment Agency at the Institute for Employment Research (http://fdz.iab.de/en.aspx). PMID:24618186

  18. Consumption of fruit and vegetables and risk of frailty: a dose-response analysis of 3 prospective cohorts of community-dwelling older adults.

    PubMed

    García-Esquinas, Esther; Rahi, Berna; Peres, Karine; Colpo, Marco; Dartigues, Jean-François; Bandinelli, Stefania; Feart, Catherine; Rodríguez-Artalejo, Fernando

    2016-07-01

    Consuming fruit and vegetables (FVs) may protect against frailty, but to our knowledge no study has yet assessed their prospective dose-response relation. We sought to examine the dose-response association between FV consumption and the risk of frailty in older adults. Data were taken from 3 independent cohorts of community-dwelling older adults: the Seniors-ENRICA (Study on Nutrition and Cardiovascular Risk Factors in Spain) cohort (n = 1872), Three-City (3C) Bordeaux cohort (n = 581), and integrated multidisciplinary approach cohort (n = 473). Baseline food consumption was assessed with a validated computerized diet history (Seniors-ENRICA) or with a food-frequency questionnaire (3C Bordeaux and AMI). In all cohorts, incident frailty was assessed with the use of the Fried criteria. Results across cohorts were pooled with the use of a random-effects model. During a mean 2.5-y follow-up, 300 incident frailty cases occurred. Fully adjusted models showed that the pooled ORs (95% CIs) of incident frailty comparing participants who consumed 1, 2, or ≥3 portions of fruit/d to those with no consumption were, respectively, 0.59 (0.27, 0.90), 0.58 (0.29, 0.86), and 0.48 (0.20, 0.75), with a P-trend of 0.04. The corresponding values for vegetables were 0.69 (0.42, 0.97), 0.56 (0.35, 0.77), and 0.52 (0.13, 0.92), with a P-trend < 0.01. When FVs were analyzed together, the pooled ORs (95% CIs) of incident frailty were 0.41 (0.21, 0.60), 0.47 (0.25, 0.68), 0.36 (0.18, 0.53), and 0.31 (0.13, 0.48), with a P-trend < 0.01 for participants who consumed 2, 3, 4, or ≥5 portions/d, respectively, compared with those who consumed ≤1 portion/d. An inverse dose-response relation was also found between the baseline consumption of fruit and risk of exhaustion, low physical activity, and slow walking speed, whereas the consumption of vegetables was associated with a decreased risk of exhaustion and unintentional weight loss. Among community-dwelling older adults, FV consumption was

  19. Ischemic heart disease mortality and PM(3.5) in a cohort of autoworkers.

    PubMed

    Costello, Sadie; Garcia, Erika; Hammond, S Katharine; Eisen, Ellen A

    2013-03-01

    Increased risk of ischemic heart disease (IHD) has been associated with particulate matter (PM) from air pollution. Yet evidence of increased risk associated with higher workplace exposures is scant. We examined the exposure-response relationship between IHD mortality and PM(3.5) (<3.5 µm diameter) from current and cumulative exposure to straight metalworking fluid in a cohort of 39,412 autoworkers followed from 1941 to 1995. Age, calendar year of follow up, sex, race, and plant were included in each model. To address the decrease in polycyclic-aromatic hydrocarbon (PAH) content in the straight metalworking fluid over time, analyses were stratified by calendar time. Increased risk of IHD mortality was associated with current exposure to PM(3.5) before 1971 and with cumulative exposure to PM(3.5) after 1971. Results provide modest evidence that occupational exposure to fine PM from straight fluids, especially fluid with higher PAH, may increase the risk of IHD mortality. Copyright © 2012 Wiley Periodicals, Inc.

  20. [Frequency of intron 1 inversion of factor VIII gene in Chinese hemophilia A patients with case report of a female patient with heterozygous intron 1 inversion].

    PubMed

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

    2008-10-21

    To investigate the frequency of intron 1 inversion (inv1) in FVIII gene in Chinese hemophilia A (HA) patients and to investigate the mechanism of pathogenesis. Peripheral blood samples were collected from 158 unrelated HA patients, aged 20 (1 - 73), including one female HA patient, aged 5, and several family members of a patient positive in inv1. One-stage method was used to assay the FVIII activity (FVIII:C). Long distance PCR and multiple PCR in duplex reactions were used to screen for the intron 22 inversion (inv22) and inv1 of the FVIII coding gene (F8). The F8 coding sequence was amplified with PCR and sequenced with an automatic sequencer. Two unrelated patients (pedigrees) were detected as inv1 positive with a positive rate of 1.26%. A rare female HA patient with inv1 was also discovered in a positive family (3 HA cases were found in this family and regarded as one case in calculating the total detection rate). The full length of FVIII was sequenced, and no other mutation was detected. There frequency of FVIII inv1 is low in Chinese HA patients compared with other populations. Female HA patients are heterozygous for FVIII inv1 and that may be resulted from nonrandom inactivation of X chromosome.

  1. In situ genetic correction of F8 intron 22 inversion in hemophilia A patient-specific iPSCs

    PubMed Central

    Wu, Yong; Hu, Zhiqing; Li, Zhuo; Pang, Jialun; Feng, Mai; Hu, Xuyun; Wang, Xiaolin; Lin-Peng, Siyuan; Liu, Bo; Chen, Fangping; Wu, Lingqian; Liang, Desheng

    2016-01-01

    Nearly half of severe Hemophilia A (HA) cases are caused by F8 intron 22 inversion (Inv22). This 0.6-Mb inversion splits the 186-kb F8 into two parts with opposite transcription directions. The inverted 5′ part (141 kb) preserves the first 22 exons that are driven by the intrinsic F8 promoter, leading to a truncated F8 transcript due to the lack of the last 627 bp coding sequence of exons 23–26. Here we describe an in situ genetic correction of Inv22 in patient-specific induced pluripotent stem cells (iPSCs). By using TALENs, the 627 bp sequence plus a polyA signal was precisely targeted at the junction of exon 22 and intron 22 via homologous recombination (HR) with high targeting efficiencies of 62.5% and 52.9%. The gene-corrected iPSCs retained a normal karyotype following removal of drug selection cassette using a Cre-LoxP system. Importantly, both F8 transcription and FVIII secretion were rescued in the candidate cell types for HA gene therapy including endothelial cells (ECs) and mesenchymal stem cells (MSCs) derived from the gene-corrected iPSCs. This is the first report of an efficient in situ genetic correction of the large inversion mutation using a strategy of targeted gene addition. PMID:26743572

  2. In situ genetic correction of F8 intron 22 inversion in hemophilia A patient-specific iPSCs.

    PubMed

    Wu, Yong; Hu, Zhiqing; Li, Zhuo; Pang, Jialun; Feng, Mai; Hu, Xuyun; Wang, Xiaolin; Lin-Peng, Siyuan; Liu, Bo; Chen, Fangping; Wu, Lingqian; Liang, Desheng

    2016-01-08

    Nearly half of severe Hemophilia A (HA) cases are caused by F8 intron 22 inversion (Inv22). This 0.6-Mb inversion splits the 186-kb F8 into two parts with opposite transcription directions. The inverted 5' part (141 kb) preserves the first 22 exons that are driven by the intrinsic F8 promoter, leading to a truncated F8 transcript due to the lack of the last 627 bp coding sequence of exons 23-26. Here we describe an in situ genetic correction of Inv22 in patient-specific induced pluripotent stem cells (iPSCs). By using TALENs, the 627 bp sequence plus a polyA signal was precisely targeted at the junction of exon 22 and intron 22 via homologous recombination (HR) with high targeting efficiencies of 62.5% and 52.9%. The gene-corrected iPSCs retained a normal karyotype following removal of drug selection cassette using a Cre-LoxP system. Importantly, both F8 transcription and FVIII secretion were rescued in the candidate cell types for HA gene therapy including endothelial cells (ECs) and mesenchymal stem cells (MSCs) derived from the gene-corrected iPSCs. This is the first report of an efficient in situ genetic correction of the large inversion mutation using a strategy of targeted gene addition.

  3. Establishing a comprehensive genetic diagnosis strategy for hemophilia B and its application in Chinese population.

    PubMed

    Lin, X Y; Wang, J; Xiao, X; Xu, Y W; Yan, Q J; Jiang, W Y

    2018-04-01

    To reduce the incidence of hemophilia B (HB) which with no complete cure currently, prenatal diagnosis and preimplantation genetic diagnosis (PGD) are effective and feasible means. However, previous studies about genetic diagnosis in HB mostly just focused on the detection of patients and carriers. Here, we established a comprehensive genetic diagnosis strategy for HB and worked it out in Chinese population. The strategy includes the detection of patients and carriers, prenatal diagnosis, and PGD. Seven unrelated HB families from Chinese population involved in this study. Firstly, probands and available members were carried out coagulation laboratory assays, and the clinical information has been recorded. Secondly, we used DNA direct sequencing to screen the whole FIX gene of them. The pathogenicity of novel mutations was verified according to 2015 ACMG-AM guidelines. For prenatal diagnosis, a mix of DNA direct sequencing and STR linkage analysis was employed. To explore a better PGD protocol, Karyomapping was first applied in PGD of HB, comparing with conventional PCR-based methods. Six different pathogenic mutations including 1 novel duplication (c.660_661dup ATCA) were identified. The results of prenatal diagnosis were consistent with birth outcomes. In the PGD case, 4 of 11 embryos were confirmed to be normal and one of them was transferred and led to a healthy birth. The established genetic diagnosis strategy for HB in our study was comprehensive and well applied in clinic practice. Besides, we recommended that DNA direct sequencing combined with Karyomapping was a better PGD protocol. © 2017 John Wiley & Sons Ltd.

  4. Overrepresentation of missense mutations in mild hemophilia A patients from Belgium: founder effect or independent occurrence?

    PubMed

    Lannoy, N; Lambert, C; Vikkula, M; Hermans, C

    2015-06-01

    Roughly 40% of observed mutations responsible for hemophilia A (HA) are novel and present in either a single family or a limited number of unrelated families. During routine diagnostic analysis of 73 unrelated Belgian patients with mild HA, 4 out of 43 different mutations (p.Ser2030Asn, p.Arg2178Cys, p.Arg2178His, and p.Pro2311His) were detected in more than one family, representing 35% of total identified mutations. To discriminate between an independent recurrence or a founder effect, an analysis of intra- and -extragenic single nucleotide polymorphisms (SNPs) and short tandem repeats (STRs) flanking the F8 gene was conducted. SNP haplotype and microsatellite analysis revealed strong evidence that p.Ser2030Asn and p.Pro2311His mutations were probably associated with a founder effect. The two other mutations localized in an F8 cytosine-phosphate-guanine (CpG) site likely resulted from recurrent de novo events. This study suggests that missense mutations producing C-to-T or G-to-A substitutions in CpG dinucleotide can occur de novo with more repetition than other causal substitutions that do not affect the CpG site. Analysis of F8 database implied that CpG sites throughout the F8 gene are not all mutated with the same frequency. Causes are still unknown and remain to be identified. Copyright © 2015 Elsevier Ltd. All rights reserved.

  5. Longitudinal Surveys of Australian Youth (LSAY) 2009 Cohort: Wave 3 (2011)--Frequency Tables. Technical Report 72B

    ERIC Educational Resources Information Center

    National Centre for Vocational Education Research (NCVER), 2012

    2012-01-01

    The Longitudinal Surveys of Australian Youth (LSAY) program studies the progress of several groups of young Australians as they move from school into post-secondary education and work. This technical paper contains the frequency tables for the LSAY 2009 cohort Wave 3 (2011) data set. [For the related questionnaire, see ED536306.

  6. Coffee, caffeine, and risk of completed suicide: results from 3 prospective cohorts of American adults

    PubMed Central

    Lucas, Michel; O’Reilly, Eilis J.; Pan, An; Mirzaei, Fariba; Willett, Walter C.; Okereke, Olivia I.; Ascherio, Alberto

    2014-01-01

    Objective To evaluate the association between coffee and caffeine consumption and suicide risk in three large-scale cohorts of U.S. men and women. Methods We accessed data of 43,599 men enrolled in the Health Professionals Follow-up Study (HPFS, 1988–2008), 73,820 women in the Nurses’ Health Study (NHS, 1992–2008), and 91,005 women in the NHS II (1993–2007). Consumption of caffeine, coffee, and decaffeinated coffee, was assessed every four years by validated food-frequency questionnaires. Deaths from suicide were determined by physician review of death certificates. Multivariate adjusted relative risks (RRs) were estimated with Cox proportional hazard models. Cohort specific RRs were pooled using random-effect models. Results We documented 277 deaths from suicide. Compared to those consuming ≤1 cup/week of caffeinated coffee (≤8 oz/237 ml), the pooled multivariate RR (95% confidence interval [CI]) of suicide was 0.55 (0.38–0.78) for those consuming 2–3 cups/day and 0.47 (0.27–0.81) for those consuming ≥4 cups/day (P trend <0.001). The pooled multivariate RR (95% CI) for suicide was 0.75 (0.63–0.90) for each increment of 2 cups/day of caffeinated coffee and 0.77 (0.63–0.93) for each increment of 300 mg/day of caffeine. Conclusions These results from three large cohorts support an association between caffeine consumption and lower risk of suicide. PMID:23819683

  7. Clinical spectrum and features of activated phosphoinositide 3-kinase δ syndrome: A large patient cohort study.

    PubMed

    Coulter, Tanya I; Chandra, Anita; Bacon, Chris M; Babar, Judith; Curtis, James; Screaton, Nick; Goodlad, John R; Farmer, George; Steele, Cathal Laurence; Leahy, Timothy Ronan; Doffinger, Rainer; Baxendale, Helen; Bernatoniene, Jolanta; Edgar, J David M; Longhurst, Hilary J; Ehl, Stephan; Speckmann, Carsten; Grimbacher, Bodo; Sediva, Anna; Milota, Tomas; Faust, Saul N; Williams, Anthony P; Hayman, Grant; Kucuk, Zeynep Yesim; Hague, Rosie; French, Paul; Brooker, Richard; Forsyth, Peter; Herriot, Richard; Cancrini, Caterina; Palma, Paolo; Ariganello, Paola; Conlon, Niall; Feighery, Conleth; Gavin, Patrick J; Jones, Alison; Imai, Kohsuke; Ibrahim, Mohammad A A; Markelj, Gašper; Abinun, Mario; Rieux-Laucat, Frédéric; Latour, Sylvain; Pellier, Isabelle; Fischer, Alain; Touzot, Fabien; Casanova, Jean-Laurent; Durandy, Anne; Burns, Siobhan O; Savic, Sinisa; Kumararatne, D S; Moshous, Despina; Kracker, Sven; Vanhaesebroeck, Bart; Okkenhaug, Klaus; Picard, Capucine; Nejentsev, Sergey; Condliffe, Alison M; Cant, Andrew James

    2017-02-01

    Activated phosphoinositide 3-kinase δ syndrome (APDS) is a recently described combined immunodeficiency resulting from gain-of-function mutations in PIK3CD, the gene encoding the catalytic subunit of phosphoinositide 3-kinase δ (PI3Kδ). We sought to review the clinical, immunologic, histopathologic, and radiologic features of APDS in a large genetically defined international cohort. We applied a clinical questionnaire and performed review of medical notes, radiology, histopathology, and laboratory investigations of 53 patients with APDS. Recurrent sinopulmonary infections (98%) and nonneoplastic lymphoproliferation (75%) were common, often from childhood. Other significant complications included herpesvirus infections (49%), autoinflammatory disease (34%), and lymphoma (13%). Unexpectedly, neurodevelopmental delay occurred in 19% of the cohort, suggesting a role for PI3Kδ in the central nervous system; consistent with this, PI3Kδ is broadly expressed in the developing murine central nervous system. Thoracic imaging revealed high rates of mosaic attenuation (90%) and bronchiectasis (60%). Increased IgM levels (78%), IgG deficiency (43%), and CD4 lymphopenia (84%) were significant immunologic features. No immunologic marker reliably predicted clinical severity, which ranged from asymptomatic to death in early childhood. The majority of patients received immunoglobulin replacement and antibiotic prophylaxis, and 5 patients underwent hematopoietic stem cell transplantation. Five patients died from complications of APDS. APDS is a combined immunodeficiency with multiple clinical manifestations, many with incomplete penetrance and others with variable expressivity. The severity of complications in some patients supports consideration of hematopoietic stem cell transplantation for severe childhood disease. Clinical trials of selective PI3Kδ inhibitors offer new prospects for APDS treatment. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights

  8. Impact of 5-HT3 receptor antagonists on chemotherapy-induced nausea and vomiting: a retrospective cohort study

    PubMed Central

    2012-01-01

    Background 1st generation 5-hydroxytryptamine receptor antagonists (5-HT3 RAs), and palonosetron, a 2nd generation 5-HT3 RA, are indicated for the prevention of chemotherapy (CT)-induced nausea and vomiting (CINV) associated with moderately (MEC) and highly emetogenic CT agents (HEC). This study explores the impact of step therapy policies requiring use of an older 5-HT3 RA before palonosetron on risk of CINV associated with hospital or emergency department (ED) admissions. Methods Patients who received cyclophosphamide post breast cancer (BC) surgery or who were diagnosed with lung cancer on carboplatin (LC-carboplatin) or cisplatin (LC-cisplatin) were selected from PharMetrics’ (IMS LifeLink) claims dataset (2005-2008). Patients were followed for 6 months from initial CT administration for CINV events identified through ICD-9-CM codes. Patients were grouped into those initiated with older, generic 5-HT3 RAs (ondansetron, granisetron, and dolasetron) and those initiated and maintained on palonosetron throughout study follow-up. CINV events and CINV days were analyzed using multivariate regressions controlling for demographic and clinical variables. Results Eligible patients numbered 3,606 in BC, 4,497 in LC-carboplatin and 1,154 in LC-cisplatin cohorts, with 52%, 40%, and 34% in the palonosetron group, respectively. There was no significant difference between the two 5-HT3 RA groups in age or Charlson Comorbidity Index among the two MEC cohorts (BC and LC-carboplatin). Among the LC-cisplatin cohort, palonosetron users were older with more males than the older 5-HT3 RA group (age: 60.1 vs. 61.3; males, 66.9% vs. 56.9%). Compared to the older 5-HT3 RAs, the palonosetron groups incurred 22%-51% fewer 5-HT3 RA pharmacy claims, had fewer patients with CINV events (3.5% vs. 5.5% in BC, 9.5% vs. 12.8% in LC-carboplatin, 16.4% vs. 21.7% in LC-cisplatin), and had lower risk for CINV events (odds ratios 0.62, 0.71, or 0.71, respectively; p < 0.05). The BC and LC

  9. Impact of 5-HT3 receptor antagonists on chemotherapy-induced nausea and vomiting: a retrospective cohort study.

    PubMed

    Lin, Swu-Jane; Hatoum, Hind T; Buchner, Deborah; Cox, David; Balu, Sanjeev

    2012-07-23

    1st generation 5-hydroxytryptamine receptor antagonists (5-HT3 RAs), and palonosetron, a 2nd generation 5-HT3 RA, are indicated for the prevention of chemotherapy (CT)-induced nausea and vomiting (CINV) associated with moderately (MEC) and highly emetogenic CT agents (HEC). This study explores the impact of step therapy policies requiring use of an older 5-HT3 RA before palonosetron on risk of CINV associated with hospital or emergency department (ED) admissions. Patients who received cyclophosphamide post breast cancer (BC) surgery or who were diagnosed with lung cancer on carboplatin (LC-carboplatin) or cisplatin (LC-cisplatin) were selected from PharMetrics' (IMS LifeLink) claims dataset (2005-2008). Patients were followed for 6 months from initial CT administration for CINV events identified through ICD-9-CM codes. Patients were grouped into those initiated with older, generic 5-HT3 RAs (ondansetron, granisetron, and dolasetron) and those initiated and maintained on palonosetron throughout study follow-up. CINV events and CINV days were analyzed using multivariate regressions controlling for demographic and clinical variables. Eligible patients numbered 3,606 in BC, 4,497 in LC-carboplatin and 1,154 in LC-cisplatin cohorts, with 52%, 40%, and 34% in the palonosetron group, respectively. There was no significant difference between the two 5-HT3 RA groups in age or Charlson Comorbidity Index among the two MEC cohorts (BC and LC-carboplatin). Among the LC-cisplatin cohort, palonosetron users were older with more males than the older 5-HT3 RA group (age: 60.1 vs. 61.3; males, 66.9% vs. 56.9%). Compared to the older 5-HT3 RAs, the palonosetron groups incurred 22%-51% fewer 5-HT3 RA pharmacy claims, had fewer patients with CINV events (3.5% vs. 5.5% in BC, 9.5% vs. 12.8% in LC-carboplatin, 16.4% vs. 21.7% in LC-cisplatin), and had lower risk for CINV events (odds ratios 0.62, 0.71, or 0.71, respectively; p<0.05). The BC and LC-carboplatin palonosetron groups

  10. A Cohort, Is a Cohort, Is a Cohort...or Is It?

    ERIC Educational Resources Information Center

    Pemberton, Cynthia Lee A.; Akkary, Rima Karami

    2010-01-01

    This paper presents findings from a multi-year qualitative study based upon life-history narratives of women pursuing doctoral degrees in Educational Leadership. This paper focuses on findings specific to educational cohort models, and suggests that perhaps, at least for women, naturally emergent cohorts--born of relationships of choice--may be…

  11. Validation of the pooled cohort risk score in an Asian population - a retrospective cohort study.

    PubMed

    Chia, Yook Chin; Lim, Hooi Min; Ching, Siew Mooi

    2014-11-20

    The Pooled Cohort Risk Equation was introduced by the American College of Cardiology (ACC) and American Heart Association (AHA) 2013 in their Blood Cholesterol Guideline to estimate the 10-year atherosclerotic cardiovascular disease (ASCVD) risk. However, absence of Asian ethnicity in the contemporary cohorts and limited studies to examine the use of the risk score limit the applicability of the equation in an Asian population. This study examines the validity of the pooled cohort risk score in a primary care setting and compares the cardiovascular risk using both the pooled cohort risk score and the Framingham General Cardiovascular Disease (CVD) risk score. This is a 10-year retrospective cohort study of randomly selected patients aged 40-79 years. Baseline demographic data, co-morbidities and cardiovascular (CV) risk parameters were captured from patient records in 1998. Pooled cohort risk score and Framingham General CVD risk score for each patient were computed. All ASCVD events (nonfatal myocardial infarction, coronary heart disease (CHD) death, fatal and nonfatal stroke) occurring from 1998-2007 were recorded. A total of 922 patients were studied. In 1998, mean age was 57.5 ± 8.8 years with 66.7% female. There were 47% diabetic patients and 59.9% patients receiving anti-hypertensive treatment. More than 98% of patients with pooled cohort risk score ≥7.5% had FRS >10%. A total of 45 CVD events occurred, 22 (7.2%) in males and 23 (3.7%) in females. The median pooled cohort risk score for the population was 10.1 (IQR 4.7-20.6) while the actual ASCVD events that occurred was 4.9% (45/922). Our study showed moderate discrimination with AUC of 0.63. There was good calibration with Hosmer-Lemeshow test χ2 = 12.6, P = 0.12. The pooled cohort risk score appears to overestimate CV risk but this apparent over-prediction could be a result of treatment. In the absence of a validated score in an untreated population, the pooled cohort risk score appears to be

  12. 34 CFR 668.204 - Draft cohort default rates and your ability to challenge before official cohort default rates are...

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 34 Education 3 2010-07-01 2010-07-01 false Draft cohort default rates and your ability to challenge before official cohort default rates are issued. 668.204 Section 668.204 Education Regulations of the Offices of the Department of Education (Continued) OFFICE OF POSTSECONDARY EDUCATION, DEPARTMENT...

  13. 34 CFR 668.185 - Draft cohort default rates and your ability to challenge before official cohort default rates are...

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 34 Education 3 2010-07-01 2010-07-01 false Draft cohort default rates and your ability to challenge before official cohort default rates are issued. 668.185 Section 668.185 Education Regulations of the Offices of the Department of Education (Continued) OFFICE OF POSTSECONDARY EDUCATION, DEPARTMENT...

  14. Cohort Differences in Cognitive Aging in the Longitudinal Aging Study Amsterdam.

    PubMed

    Brailean, Anamaria; Huisman, Martijn; Prince, Martin; Prina, A Matthew; Deeg, Dorly J H; Comijs, Hannie

    2016-09-30

    This study aims to examine cohort differences in cognitive performance and rates of change in episodic memory, processing speed, inductive reasoning, and general cognitive performance and to investigate whether these cohort effects may be accounted for by education attainment. The first cohort (N = 705) was born between 1920 and 1930, whereas the second cohort (N = 646) was born between 1931 and 1941. Both birth cohorts were aged 65 to 75 years at baseline and were followed up 3 and 6 years later. Data were analyzed using linear mixed models. The later born cohort had better general cognitive performance, inductive reasoning, and processing speed at baseline, but cohort differences in inductive reasoning and general cognitive performance disappeared after adjusting for education. The later born cohort showed steeper decline in processing speed. Memory decline was steeper in the earlier born cohort but only from Time 1 to Time 3 when the same memory test was administered. Education did not account for cohort differences in cognitive decline. The later born cohort showed better initial performance in certain cognitive abilities, but no better preservation of cognitive abilities overtime compared with the earlier born cohort. These findings carry implications for healthy cognitive aging. © The Author 2016. Published by Oxford University Press on behalf of The Gerontological Society of America.

  15. The Swiss Cystic Fibrosis Infant Lung Development (SCILD) cohort.

    PubMed

    Korten, Insa; Kieninger, Elisabeth; Yammine, Sophie; Regamey, Nicolas; Nyilas, Sylvia; Ramsey, Kathryn; Casaulta, Carmen; Latzin, Philipp; For The Scild Study Group

    2018-04-26

    The Swiss Cystic Fibrosis Infant Lung Development (SCILD) cohort is a prospective birth cohort study investigating the initiating events of cystic fibrosis lung disease during infancy, and their influence on the trajectory of disease progression throughout early childhood. Infants with cystic fibrosis are recruited throughout Switzerland after diagnosis by new-born screening. It is the first European population-based prospective cohort study of infants with cystic fibrosis taking advantage of a nationwide new-born screening programme. The study was established in 2011 and recruitment is ongoing. The cohort study is currently divided into three study phases (phase 1: diagnosis to age 1 year; phase 2: age 1 to 3 years; and phase 3: age 3 to 6 years). Study participants have weekly telephone interviews, weekly anterior nasal swab collection and two study visits in the first year of life. They also complete follow-up study visits at 3 and 6 years of age. Data for this study are derived from questionnaires, lung function measurements, telephone interviews, nasal swab material and magnetic resonance imaging. To date, 70 infants have been recruited into the study and 56 have completed phase 1, including a baseline study visit at 6 weeks of age, weekly surveillance and a study visit at one year of age. More than 2500 data points on respiratory health and almost 2000 nasal samples have been collected. Phases 2 and 3 will commence in 2018. The dataset of the SCILD cohort combines lung function data, the collection of environmental and sociodemographic factors, documentation of respiratory symptoms, and microbiological analyses. The design not only allows tracking of the cystic fibrosis lung disease independent of clinical status, but also surveillance of early disease prior to severe clinical symptoms. This cohort profile provides details on the study design and summarizes the first published results of the SCILD cohort.

  16. Japanese Legacy Cohorts: The Life Span Study Atomic Bomb Survivor Cohort and Survivors’ Offspring

    PubMed Central

    Grant, Eric J; Kodama, Kazunori

    2018-01-01

    Cohorts of atomic bomb survivors—including those exposed in utero—and children conceived after parental exposure were established to investigate late health effects of atomic bomb radiation and its transgenerational effects by the Atomic Bomb Casualty Commission (ABCC) in the 1950s. ABCC was reorganized to the Radiation Effects Research Foundation (RERF) in 1975, and all work has been continued at RERF. The Life Span Study, the cohort of survivors, consists of about 120,000 subjects and has been followed since 1950. Cohorts of in utero survivors and the survivors’ children include about 3,600 and 77,000 subjects, respectively, and have been followed since 1945. Atomic bomb radiation dose was estimated for each subject based on location at the time of the bombing and shielding conditions from exposure, which were obtained through enormous efforts of investigators and cooperation of subjects. Outcomes include vital status, cause of death, and cancer incidence. In addition, sub-cohorts of these three cohorts were constructed to examine clinical features of late health effects, and the subjects have been invited to periodic health examinations at clinics of ABCC and RERF. They were also asked to donate biosamples for biomedical investigations. Epidemiological studies have observed increased radiation risks for malignant diseases among survivors, including those exposed in utero, and possible risks for some non-cancer diseases. In children of survivors, no increased risks due to parental exposure to radiation have been observed for malignancies or other diseases, but investigations are continuing, as these cohorts are still relatively young. PMID:29553058

  17. Japanese Legacy Cohorts: The Life Span Study Atomic Bomb Survivor Cohort and Survivors' Offspring.

    PubMed

    Ozasa, Kotaro; Grant, Eric J; Kodama, Kazunori

    2018-04-05

    Cohorts of atomic bomb survivors-including those exposed in utero-and children conceived after parental exposure were established to investigate late health effects of atomic bomb radiation and its transgenerational effects by the Atomic Bomb Casualty Commission (ABCC) in the 1950s. ABCC was reorganized to the Radiation Effects Research Foundation (RERF) in 1975, and all work has been continued at RERF. The Life Span Study, the cohort of survivors, consists of about 120,000 subjects and has been followed since 1950. Cohorts of in utero survivors and the survivors' children include about 3,600 and 77,000 subjects, respectively, and have been followed since 1945. Atomic bomb radiation dose was estimated for each subject based on location at the time of the bombing and shielding conditions from exposure, which were obtained through enormous efforts of investigators and cooperation of subjects. Outcomes include vital status, cause of death, and cancer incidence. In addition, sub-cohorts of these three cohorts were constructed to examine clinical features of late health effects, and the subjects have been invited to periodic health examinations at clinics of ABCC and RERF. They were also asked to donate biosamples for biomedical investigations. Epidemiological studies have observed increased radiation risks for malignant diseases among survivors, including those exposed in utero, and possible risks for some non-cancer diseases. In children of survivors, no increased risks due to parental exposure to radiation have been observed for malignancies or other diseases, but investigations are continuing, as these cohorts are still relatively young.

  18. Maternal Malaria and Malnutrition (M3) initiative, a pooled birth cohort of 13 pregnancy studies in Africa and the Western Pacific

    PubMed Central

    Unger, Holger W; Gutman, Julie; Briand, Valerie; Fievet, Nadine; Valea, Innocent; Tinto, Halidou; d'Alessandro, Umberto; Landis, Sarah H; Adu-Afarwuah, Seth; Dewey, Kathryn G; Ter Kuile, Feiko; Dellicour, Stephanie; Ouma, Peter; Slutsker, Laurence; Terlouw, Dianne J; Kariuki, Simon; Ayisi, John; Nahlen, Bernard; Desai, Meghna; Madanitsa, Mwayi; Kalilani-Phiri, Linda; Ashorn, Per; Maleta, Kenneth; Mueller, Ivo; Stanisic, Danielle; Schmiegelow, Christentze; Lusingu, John; Westreich, Daniel; van Eijk, Anna Maria; Meshnick, Steven; Rogerson, Stephen

    2016-01-01

    Purpose The Maternal Malaria and Malnutrition (M3) initiative has pooled together 13 studies with the hope of improving understanding of malaria–nutrition interactions during pregnancy and to foster collaboration between nutritionists and malariologists. Participants Data were pooled on 14 635 singleton, live birth pregnancies from women who had participated in 1 of 13 pregnancy studies. The 13 studies cover 8 countries in Africa and Papua New Guinea in the Western Pacific conducted from 1996 to 2015. Findings to date Data are available at the time of antenatal enrolment of women into their respective parent study and at delivery. The data set comprises essential data such as malaria infection status, anthropometric assessments of maternal nutritional status, presence of anaemia and birth weight, as well as additional variables such gestational age at delivery for a subset of women. Participating studies are described in detail with regard to setting and primary outcome measures, and summarised data are available from each contributing cohort. Future plans This pooled birth cohort is the largest pregnancy data set to date to permit a more definite evaluation of the impact of plausible interactions between poor nutritional status and malaria infection in pregnant women on fetal growth and gestational length. Given the current comparative lack of large pregnancy cohorts in malaria-endemic settings, compilation of suitable pregnancy cohorts is likely to provide adequate statistical power to assess malaria–nutrition interactions, and could point towards settings where such interactions are most relevant. The M3 cohort may thus help to identify pregnant women at high risk of adverse outcomes who may benefit from tailored intensive antenatal care including nutritional supplements and alternative or intensified malaria prevention regimens, and the settings in which these interventions would be most effective. PMID:28003287

  19. Paediatric Crohn Disease: Disease Activity and Growth in the BELCRO Cohort After 3 Years Follow-up.

    PubMed

    De Greef, Elisabeth; Hoffman, Ilse; Smets, Francoise; Van Biervliet, Stephanie; Bontems, Patrick; Hauser, Bruno; Paquot, Isabelle; Alliet, Philippe; Arts, Wim; Dewit, Olivier; De Vos, Martine; Baert, Filip; Bossuyt, Peter; Rahier, Jean-Francois; Franchimont, Denis; Vermeire, Severine; Fontaine, Fernand; Louis, Edouard; Coche, J C; Veereman, Gigi

    2016-08-01

    The Belgian registry for paediatric Crohn disease (BELCRO) cohort is a prospective, multicentre registry for newly diagnosed paediatric patients with Crohn disease (CD) (<18 years) recruited from 2008 to 2010 to identify predictive factors for disease activity and growth. Data from the BELCRO database were evaluated at diagnosis, 24 and 36 months follow-up. At month 36 (M36), data were available on 84 of the 98 patients included at diagnosis. Disease activity evolved as follows: inactive 5% to 70%, mild 19% to 24%, and moderate to severe 76% to 6%. None of the variables such as age, sex, diagnostic delay, type of treatment, disease location, disease activity at diagnosis, and growth were associated with disease activity at M36. Paediatricians studied significantly less patients with active disease at M36 compared with adult physicians. Sixty percent of the patients had biologicals as part of their treatment at M36. Adult gastroenterologists initiated biologicals significantly earlier. They were the only factor determining biologicals' initiation, not disease location or disease severity at diagnosis. Median body mass index (BMI) z score evolved from -0.97 (range -5.5-2.1) to 0.11 (range -3.4-2) and median height z score from -0.15 (range -3.4-1.6) to 0.12 (range -2.3-2.3) at M36. None of the variables mentioned above influenced growth over time. Present treatment strategies lead to good disease control in the BELCRO cohort after 3 years. Logistic regression analysis did not show any influence of disease location or present treatment strategy on disease activity and growth, but patients under paediatric care had significantly less severe disease at M36.

  20. ACTN3 R577X genotype and athletic performance in a large cohort of Japanese athletes.

    PubMed

    Kikuchi, Naoki; Miyamoto-Mikami, Eri; Murakami, Haruka; Nakamura, Tomohiro; Min, Seok-Ki; Mizuno, Masuhiko; Naito, Hisashi; Miyachi, Motohiko; Nakazato, Koichi; Fuku, Noriyuki

    2016-09-01

    Recent meta-analyses of the literature confirmed the association between the RR+RX genotype of the ACTN3 R577X polymorphism and elite sprint/power athletic status in Europeans but not in Asians and Africans, while the association between the R577X genotype and elite endurance athlete status is less convincing. The aim of the present study was to investigate the association between the ACTN3 R577X genotype and elite athlete status in a large Asian (Japanese) cohort of track and field athletes. One-thousand fifty-seven Japanese track and field athletes (627 sprint/power athletes and 430 endurance athletes) and 810 Japanese controls were genotyped for the ACTN3 R577X polymorphism (rs1815739) by using the TaqMan® SNP Genotyping Assay. Elite sprint/power athletes had a higher frequency of the RR+RX genotype than the controls (OR: 1.59, 95% CI: 1.16-2.18; P = .003). A significant linear correlation was found between the RR + RX genotype and athlete status (i.e. regional < national < international) in sprint/power athletes (regional: 71%, national: 81%, international: 84%; P = .001 for trend) and long-distance runners (regional: 65%, national: 72%, international: 82%; P = .030 for trend). The data obtained for this large Asian (Japanese) cohort of track and field athletes served to confirm the association between the RR + RX genotype of the ACTN3 R577X polymorphism and elite sprint/power athlete status and also the association between the ACTN3 RR + RX genotype and long-distance running athletic status.

  1. Cohort profile: the National Health Insurance Service-National Health Screening Cohort (NHIS-HEALS) in Korea

    PubMed Central

    Seong, Sang Cheol; Kim, Yeon-Yong; Park, Sue K; Khang, Young Ho; Kim, Hyeon Chang; Park, Jong Heon; Kang, Hee-Jin; Do, Cheol-Ho; Song, Jong-Sun; Lee, Eun-Joo; Ha, Seongjun; Shin, Soon Ae; Jeong, Seung-Lyeal

    2017-01-01

    Purpose The National Health Insurance Service-Health Screening Cohort (NHIS-HEALS) is a cohort of participants who participated in health screening programmes provided by the NHIS in the Republic of Korea. The NHIS constructed the NHIS-HEALS cohort database in 2015. The purpose of this cohort is to offer relevant and useful data for health researchers, especially in the field of non-communicable diseases and health risk factors, and policy-maker. Participants To construct the NHIS-HEALS database, a sample cohort was first selected from the 2002 and 2003 health screening participants, who were aged between 40 and 79 in 2002 and followed up through 2013. This cohort included 514 866 health screening participants who comprised a random selection of 10% of all health screening participants in 2002 and 2003. Findings to date The age-standardised prevalence of anaemia, diabetes mellitus, hypertension, obesity, hypercholesterolaemia and abnormal urine protein were 9.8%, 8.2%, 35.6%, 2.7%, 14.2% and 2.0%, respectively. The age-standardised mortality rate for the first 2 years (through 2004) was 442.0 per 100 000 person-years, while the rate for 10 years (through 2012) was 865.9 per 100 000 person-years. The most common cause of death was malignant neoplasm in both sexes (364.1 per 100 000 person-years for men, 128.3 per 100 000 person-years for women). Future plans This database can be used to study the risk factors of non-communicable diseases and dental health problems, which are important health issues that have not yet been fully investigated. The cohort will be maintained and continuously updated by the NHIS. PMID:28947447

  2. Cohort Profile: Antiretroviral Therapy Cohort Collaboration (ART-CC)

    PubMed Central

    May, Margaret T; Ingle, Suzanne M; Costagliola, Dominique; Justice, Amy C; de Wolf, Frank; Cavassini, Matthias; D’Arminio Monforte, Antonella; Casabona, Jordi; Hogg, Robert S; Mocroft, Amanda; Lampe, Fiona C; Dabis, François; Fätkenheuer, Gerd; Sterling, Timothy R; del Amo, Julia; Gill, M John; Crane, Heidi M; Saag, Michael S; Guest, Jodie; Brodt, Hans-Reinhard; Sterne, Jonathan AC

    2014-01-01

    The advent of effective combination antiretroviral therapy (ART) in 1996 resulted in fewer patients experiencing clinical events, so that some prognostic analyses of individual cohort studies of human immunodeficiency virus-infected individuals had low statistical power. Because of this, the Antiretroviral Therapy Cohort Collaboration (ART-CC) of HIV cohort studies in Europe and North America was established in 2000, with the aim of studying the prognosis for clinical events in acquired immune deficiency syndrome (AIDS) and the mortality of adult patients treated for HIV-1 infection. In 2002, the ART-CC collected data on more than 12,000 patients in 13 cohorts who had begun combination ART between 1995 and 2001. Subsequent updates took place in 2004, 2006, 2008, and 2010. The ART-CC data base now includes data on more than 70 000 patients participating in 19 cohorts who began treatment before the end of 2009. Data are collected on patient demographics (e.g. sex, age, assumed transmission group, race/ethnicity, geographical origin), HIV biomarkers (e.g. CD4 cell count, plasma viral load of HIV-1), ART regimen, dates and types of AIDS events, and dates and causes of death. In recent years, additional data on co-infections such as hepatitis C; risk factors such as smoking, alcohol and drug use; non-HIV biomarkers such as haemoglobin and liver enzymes; and adherence to ART have been collected whenever available. The data remain the property of the contributing cohorts, whose representatives manage the ART-CC via the steering committee of the Collaboration. External collaboration is welcomed. Details of contacts are given on the ART-CC website (www.art-cohort-collaboration.org). PMID:23599235

  3. Physical activity during pregnancy and infant's birth weight: results from the 3D Birth Cohort.

    PubMed

    Bisson, Michèle; Croteau, Jordie; Guinhouya, Benjamin C; Bujold, Emmanuel; Audibert, François; Fraser, William D; Marc, Isabelle

    2017-01-01

    To evaluate the association between maternal physical activity and infant's birth weight or risk of inappropriate weight for gestational age (GA), and whether this association differs by infant's sex, maternal body mass index (BMI) or pregnancy complications in a prospective cohort study. 1913 pregnant women from the 3D Birth Cohort (Québec, Canada) completed the Pregnancy Physical Activity Questionnaire at each trimester. Energy expenditure (metabolic equivalent of task (MET)*hours/week) for total activity, sports and exercise and vigorous intensity activities was calculated. The associations with birth weight and risk of inappropriate weight for GA were evaluated by regression modelling. Interactions were tested with infant's sex, maternal prepregnancy BMI, gestational diabetes, hypertensive disorders and prematurity. Each 1 MET/hours/week increase in sports and exercise in the first trimester was associated with a 2.5 g reduction in infant's birth weight (95% CI -4.8 to -0.3) but was not associated with the risk of small weight for GA. In contrast, although not significant, a 17% reduction in the risk of large weight for GA was observed with increasing sports and exercise. Furthermore, in women with subsequent pre-eclampsia (but not normotensive or hypertensive women), each 1 MET/hours/week increment spent in any vigorous exercise in the first trimester reduced the infant's birth weight by 19.8 g (95% CI -35.2 to -4.3). Pregnant women with higher sports and exercise levels in the first trimester delivered infants with a lower birth weight. The risk of reducing infant's birth weight with vigorous exercise in women who develop pre-eclampsia later in pregnancy requires evaluation.

  4. Cohort profile: the National Health Insurance Service-National Health Screening Cohort (NHIS-HEALS) in Korea.

    PubMed

    Seong, Sang Cheol; Kim, Yeon-Yong; Park, Sue K; Khang, Young Ho; Kim, Hyeon Chang; Park, Jong Heon; Kang, Hee-Jin; Do, Cheol-Ho; Song, Jong-Sun; Lee, Eun-Joo; Ha, Seongjun; Shin, Soon Ae; Jeong, Seung-Lyeal

    2017-09-24

    The National Health Insurance Service-Health Screening Cohort (NHIS-HEALS) is a cohort of participants who participated in health screening programmes provided by the NHIS in the Republic of Korea. The NHIS constructed the NHIS-HEALS cohort database in 2015. The purpose of this cohort is to offer relevant and useful data for health researchers, especially in the field of non-communicable diseases and health risk factors, and policy-maker. To construct the NHIS-HEALS database, a sample cohort was first selected from the 2002 and 2003 health screening participants, who were aged between 40 and 79 in 2002 and followed up through 2013. This cohort included 514 866 health screening participants who comprised a random selection of 10% of all health screening participants in 2002 and 2003. The age-standardised prevalence of anaemia, diabetes mellitus, hypertension, obesity, hypercholesterolaemia and abnormal urine protein were 9.8%, 8.2%, 35.6%, 2.7%, 14.2% and 2.0%, respectively. The age-standardised mortality rate for the first 2 years (through 2004) was 442.0 per 100 000 person-years, while the rate for 10 years (through 2012) was 865.9 per 100 000 person-years. The most common cause of death was malignant neoplasm in both sexes (364.1 per 100 000 person-years for men, 128.3 per 100 000 person-years for women). This database can be used to study the risk factors of non-communicable diseases and dental health problems, which are important health issues that have not yet been fully investigated. The cohort will be maintained and continuously updated by the NHIS. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

  5. Cohort profile: Antiretroviral Therapy Cohort Collaboration (ART-CC).

    PubMed

    May, Margaret T; Ingle, Suzanne M; Costagliola, Dominique; Justice, Amy C; de Wolf, Frank; Cavassini, Matthias; D'Arminio Monforte, Antonella; Casabona, Jordi; Hogg, Robert S; Mocroft, Amanda; Lampe, Fiona C; Dabis, François; Fätkenheuer, Gerd; Sterling, Timothy R; del Amo, Julia; Gill, M John; Crane, Heidi M; Saag, Michael S; Guest, Jodie; Brodt, Hans-Reinhard; Sterne, Jonathan A C

    2014-06-01

    The advent of effective combination antiretroviral therapy (ART) in 1996 resulted in fewer patients experiencing clinical events, so that some prognostic analyses of individual cohort studies of human immunodeficiency virus-infected individuals had low statistical power. Because of this, the Antiretroviral Therapy Cohort Collaboration (ART-CC) of HIV cohort studies in Europe and North America was established in 2000, with the aim of studying the prognosis for clinical events in acquired immune deficiency syndrome (AIDS) and the mortality of adult patients treated for HIV-1 infection. In 2002, the ART-CC collected data on more than 12,000 patients in 13 cohorts who had begun combination ART between 1995 and 2001. Subsequent updates took place in 2004, 2006, 2008, and 2010. The ART-CC data base now includes data on more than 70,000 patients participating in 19 cohorts who began treatment before the end of 2009. Data are collected on patient demographics (e.g. sex, age, assumed transmission group, race/ethnicity, geographical origin), HIV biomarkers (e.g. CD4 cell count, plasma viral load of HIV-1), ART regimen, dates and types of AIDS events, and dates and causes of death. In recent years, additional data on co-infections such as hepatitis C; risk factors such as smoking, alcohol and drug use; non-HIV biomarkers such as haemoglobin and liver enzymes; and adherence to ART have been collected whenever available. The data remain the property of the contributing cohorts, whose representatives manage the ART-CC via the steering committee of the Collaboration. External collaboration is welcomed. Details of contacts are given on the ART-CC website (www.art-cohort-collaboration.org). Published by Oxford University Press on behalf of the International Epidemiological Association © The Author 2013; all rights reserved.

  6. A Comparison of Different Methods for Evaluating Diet, Physical Activity, and Long-Term Weight Gain in 3 Prospective Cohort Studies.

    PubMed

    Smith, Jessica D; Hou, Tao; Hu, Frank B; Rimm, Eric B; Spiegelman, Donna; Willett, Walter C; Mozaffarian, Dariush

    2015-11-01

    The insidious pace of long-term weight gain (∼ 1 lb/y or 0.45 kg/y) makes it difficult to study in trials; long-term prospective cohorts provide crucial evidence on its key contributors. Most previous studies have evaluated how prevalent lifestyle habits relate to future weight gain rather than to lifestyle changes, which may be more temporally and physiologically relevant. Our objective was to evaluate and compare different methodological approaches for investigating diet, physical activity (PA), and long-term weight gain. In 3 prospective cohorts (total n = 117,992), we assessed how lifestyle relates to long-term weight change (up to 24 y of follow-up) in 4-y periods by comparing 3 analytic approaches: 1) prevalent diet and PA and 4-y weight change (prevalent analysis); 2) 4-y changes in diet and PA with a 4-y weight change (change analysis); and 3) 4-y change in diet and PA with weight change in the subsequent 4 y (lagged-change analysis). We compared these approaches and evaluated the consistency across cohorts, magnitudes of associations, and biological plausibility of findings. Across the 3 methods, consistent, robust, and biologically plausible associations were seen only for the change analysis. Results for prevalent or lagged-change analyses were less consistent across cohorts, smaller in magnitude, and biologically implausible. For example, for each serving of a sugar-sweetened beverage, the observed weight gain was 0.01 lb (95% CI: -0.08, 0.10) [0.005 kg (95% CI: -0.04, 0.05)] based on prevalent analysis; 0.99 lb (95% CI: 0.83, 1.16) [0.45 kg (95% CI: 0.38, 0.53)] based on change analysis; and 0.05 lb (95% CI: -0.10, 0.21) [0.02 kg (95% CI: -0.05, 0.10)] based on lagged-change analysis. Findings were similar for other foods and PA. Robust, consistent, and biologically plausible relations between lifestyle and long-term weight gain are seen when evaluating lifestyle changes and weight changes in discrete periods rather than in prevalent lifestyle or

  7. The Netherlands Cohort Study−Meat Investigation Cohort; a population-based cohort over-represented with vegetarians, pescetarians and low meat consumers.

    PubMed

    Gilsing, Anne M J; Weijenberg, Matty P; Goldbohm, R Alexandra; Dagnelie, Pieter C; van den Brandt, Piet A; Schouten, Leo J

    2013-11-29

    Vegetarian diets have been associated with lower risk of chronic disease, but little is known about the health effects of low meat diets and the reliability of self-reported vegetarian status. We aimed to establish an analytical cohort over-represented with vegetarians, pescetarians and 1 day/week meat consumers, and to describe their lifestyle and dietary characteristics. In addition, we were able to compare self-reported vegetarians with vegetarians whose status has been confirmed by their response on the extensive food frequency questionnaire (FFQ). Embedded within the Netherlands Cohort Study (n = 120,852; including 1150 self-reported vegetarians), the NLCS-Meat Investigation Cohort (NLCS-MIC) was defined by combining all FFQ-confirmed-vegetarians (n = 702), pescetarians (n = 394), and 1 day/week meat consumers (n = 1,396) from the total cohort with a random sample of 2-5 days/week- and 6-7 days/week meat consumers (n = 2,965 and 5,648, respectively). Vegetarians, pescetarians, and 1 day/week meat consumers had more favorable dietary intakes (e.g., higher fiber/vegetables) and lifestyle characteristics (e.g. lower smoking rates) compared to regular meat consumers in both sexes. Vegetarians adhered to their diet longer than pescetarians and 1 day/week meat consumers. 75% of vegetarians with a prevalent cancer at baseline had changed to this diet after diagnosis. 50% of self-reported vegetarians reported meat or fish consumption on the FFQ. Although the misclassification that occurred in terms of diet and lifestyle when merely relying on self-reporting was relatively small, the impact on associations with disease risk remains to be studied. We established an analytical cohort over-represented with persons at the lower end of the meat consumption spectrum which should facilitate prospective studies of major cancers and causes of death using ≥20.3 years of follow-up.

  8. A Population-Based Cohort Study Evaluating Outcomes and Costs for Syncope Presentations to the Emergency Department.

    PubMed

    Sandhu, Roopinder K; Tran, Dat T; Sheldon, Robert S; Kaul, Padma

    2018-02-01

    This study sought to examine outcomes and costs of patients with syncope admitted and discharged from the emergency department (ED). ED visits for syncope are common, yet the impact on health care utilization is relatively unknown. A total of 51,831 consecutive patients presented to the ED with a primary diagnosis of syncope (International Classification of Diseases-9 code 780.2 and International Classification of Diseases-10 code R55) in Alberta, Canada from 2006 to 2014. Outcomes included 30-day syncope ED and hospital readmissions; 30-day and 1-year mortality; and annual inpatient, outpatient, physician, and drug costs, cumulative. Of adults presenting to the ED, 6.6% were hospitalized and discharged with a primary diagnosis of syncope (Cohort 1), 8.7% were hospitalized and discharged with a primary diagnosis other than syncope (Cohort 2), and 84.7% were discharged home with a syncope diagnosis (Cohort 3). The 30-day ED revisits for syncope varied from 1.2% (Cohort 2) to 2.4% (Cohort 1) (p < 0.001), and readmission rates were <1% among cohorts. Short- and long-term mortality rates were highest for Cohort 2 and lowest for Cohort 3 (30-day mortality: Cohort 1 of 1.2%, Cohort 2 of 5.2%, Cohort 3 of 0.4%; p < 0.001) (1-year mortality: Cohort 1 of 9.2%, Cohort 2 of 17.7%, Cohort 3 of 3.0%; p < 0.001). Total cost of syncope presentations was $530.6 million (Cohort 1: $75.3 million; $29,519/patient, Cohort 2: $138.1 million; $42,042/patient, Cohort 3: $317.3 million; $9,963/patient; p<0.001). Most patients with syncope presenting to the ED were discharged and had a favorable prognosis but overall costs were high compared with patients hospitalized. Further research is needed for cost-saving strategies across all cohorts. Copyright © 2018 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

  9. The Hokkaido Birth Cohort Study on Environment and Children's Health: cohort profile-updated 2017.

    PubMed

    Kishi, Reiko; Araki, Atsuko; Minatoya, Machiko; Hanaoka, Tomoyuki; Miyashita, Chihiro; Itoh, Sachiko; Kobayashi, Sumitaka; Ait Bamai, Yu; Yamazaki, Keiko; Miura, Ryu; Tamura, Naomi; Ito, Kumiko; Goudarzi, Houman

    2017-05-18

    The Hokkaido Study on Environment and Children's Health is an ongoing study consisting of two birth cohorts of different population sizes: the Sapporo cohort and the Hokkaido cohort. Our primary study goals are (1) to examine the effects of low-level environmental chemical exposures on birth outcomes, including birth defects and growth retardation; (2) to follow the development of allergies, infectious diseases, and neurobehavioral developmental disorders and perform a longitudinal observation of child development; (3) to identify high-risk groups based on genetic susceptibility to environmental chemicals; and (4) to identify the additive effects of various chemicals, including tobacco smoking. The purpose of this report is to update the progress of the Hokkaido Study, to summarize the recent results, and to suggest future directions. In particular, this report provides the basic characteristics of the cohort populations, discusses the population remaining in the cohorts and those who were lost to follow-up at birth, and introduces the newly added follow-up studies and case-cohort study design. In the Sapporo cohort of 514 enrolled pregnant women, various specimens, including maternal and cord blood, maternal hair, and breast milk, were collected for the assessment of exposures to dioxins, polychlorinated biphenyls, organochlorine pesticides, perfluoroalkyl substances, phthalates, bisphenol A, and methylmercury. As follow-ups, face-to-face neurobehavioral developmental tests were conducted at several different ages. In the Hokkaido cohort of 20,926 enrolled pregnant women, the prevalence of complicated pregnancies and birth outcomes, such as miscarriage, stillbirth, low birth weight, preterm birth, and small for gestational age were examined. The levels of exposure to environmental chemicals were relatively low in these study populations compared to those reported previously. We also studied environmental chemical exposure in association with health outcomes

  10. Expanding on #YouDoYou: Reflections from the 2015 Cohort of 3M National Student Fellows on Exploring Authenticity in Education

    ERIC Educational Resources Information Center

    Baek, Justine; Shah, Wali; Spencer, Vrindy; Thompson, Piper Riley; Young, Karen; Zowmi, Aniqah

    2016-01-01

    The fourth cohort of 3M National Student Fellows explores the current state of our post-secondary education system across Canada and opportunities to further tune into practice in order to pursue an authentic and meaningful academic life. Six of the 2015 3M National Student Fellows propose recommendations for decision-makers at post-secondary…

  11. Sex Differences in Faculty Salaries: A Cohort Analysis.

    ERIC Educational Resources Information Center

    Perna, Laura Walter

    This study examined sex differences in faculty salaries, exploring how lower salaries for women varied across different rank/experience cohorts. Data came from the 1993 National Study of Postsecondary Faculty. Six cohorts were defined: assistant professors with 1-2 years experience, 3-6 years experience, 7-12 years experience, or 13-20 years…

  12. The effect of platelets on fibrin gel structure formed in the presence of recombinant factor VIIa in hemophilia plasma and in plasma from a patient with Glanzmann thrombasthenia.

    PubMed

    He, S; Ekman, G Jacobsson; Hedner, U

    2005-02-01

    Fibrin gel structure has been shown to be dependent on the thrombin concentration as well as the rate of thrombin generation. Accordingly, factor VIII (FVIII)- and FIX-deficient plasma (hemophilia A and B) form loose fibrin clots with high permeability constants. By adding rFVIIa in vitro to FVIII-deficient plasma containing platelets (frozen and thawed), the fibrin gel permeability constant normalized, indicating that extra rFVIIa (1.2 microg mL(-1) or higher) induced a tight fibrin structure. Thrombin generation is highly dependent on the number of platelets, and in this study it was demonstrated that the addition of rFVIIa (5 microg mL(-1)) normalizes the fibrin gel permeability in samples containing platelets (frozen-thawed) in numbers of at least down to 20 x 10(6) mL(-1). The effect of rFVIIa was not observed when unfrozen platelets instead of frozen-thawed platelets were added. Neither was any effect on the fibrin permeability seen, in the presence of annexin V, known to block the effect of phospholipids on the platelet surface. This indicates an important role of platelet phospholipids for the effect of rFVIIa. A similar effect on the fibrin permeability of rFVIIa was observed when added to platelet-rich plasma from a patient with Glanzmann thrombasthenia. Recombinant FVIIa has been found to induce hemostasis in patients with hemophilia and inhibitors against FVIII/FIX as well as in patients with Glanzmann thrombasthenia, indicating the importance of the formation of a tight fibrin gel structure, more resistant against premature proteolysis, for maintaining hemostasis. In conclusion, the addition of rFVIIa (5 microg mL(-1)) also substantially decreased the permeability constant of fibrin gels formed in FVIII-deficient plasma in the presence of low numbers of frozen-thawed platelets (down to 20 x 10(6) mL(-1)). A similar pattern was obtained in plasma from a Glanzmann patient. No effect was found in the presence of unfrozen instead of frozen-thawed platelets

  13. The Hemophiliac and His World.

    ERIC Educational Resources Information Center

    Gourdeau, R., Ed.

    The document contains the papers presented at the 5th Congress of the World Federation of Hemophilia in Montreal in 1968. Seven papers concern specific therapy of hemophilia, five papers treat nonspecific forms of therapy, seven papers deal with prophylaxis and complications in hemophilia, seven others deal with orthopedic and other surgical…

  14. Impact of mild versus moderate intensity aerobic walking exercise training on markers of bone metabolism and hand grip strength in moderate hemophilic A patients.

    PubMed

    Al-Sharif, Fadwa Al-Ghalib; Al-Jiffri, Osama Hussien; El-Kader, Shehab Mahmoud Abd; Ashmawy, Eman Mohamed

    2014-03-01

    Patients with hemophilia A have low bone density than healthy controls. It is now widely recognized that physical activity and sports are beneficial for patients with hemophilia. To compare the effects of mild and moderate intensity treadmill walking exercises on markers of bone metabolism and hand grip strength in male patients with moderate hemophilia A. Fifty male patients with moderate hemophilia, and age range from 25 to 45 years. The subjects were randomly assigned into 2 equal groups; the first group (A) received moderate intensity aerobic exercise training. The second group (B) received mild intensity aerobic exercise training. There was a 32.1% and 24.8% increase in mean values of serum calcium and hand grip strength respectively and 22.7 % reduction in mean values of parathyroid hormone in moderate exercise training group (A). While there was a 15.1 % and 15 % increase in mean values of Serum Calcium and Hand grip strength respectively and 10.3 % reduction in mean values of parathyroid hormone in mild exercise training group(B). The mean values of serum calcium and hand grip strength were significantly increased, while the mean values of parathyroid hormone were significantly decreased in both groups . There were significant differences between mean levels of the investigated parameters in group (A) and group (B) after treatment. Moderate intensity aerobic exercise training on treadmill is appropriate to improve markers of bone metabolism and hand grip strength in male patients with hemophilia A.

  15. Maternal Malaria and Malnutrition (M3) initiative, a pooled birth cohort of 13 pregnancy studies in Africa and the Western Pacific.

    PubMed

    Unger, Holger W; Cates, Jordan E; Gutman, Julie; Briand, Valerie; Fievet, Nadine; Valea, Innocent; Tinto, Halidou; d'Alessandro, Umberto; Landis, Sarah H; Adu-Afarwuah, Seth; Dewey, Kathryn G; Ter Kuile, Feiko; Dellicour, Stephanie; Ouma, Peter; Slutsker, Laurence; Terlouw, Dianne J; Kariuki, Simon; Ayisi, John; Nahlen, Bernard; Desai, Meghna; Madanitsa, Mwayi; Kalilani-Phiri, Linda; Ashorn, Per; Maleta, Kenneth; Mueller, Ivo; Stanisic, Danielle; Schmiegelow, Christentze; Lusingu, John; Westreich, Daniel; van Eijk, Anna Maria; Meshnick, Steven; Rogerson, Stephen

    2016-12-21

    The Maternal Malaria and Malnutrition (M3) initiative has pooled together 13 studies with the hope of improving understanding of malaria-nutrition interactions during pregnancy and to foster collaboration between nutritionists and malariologists. Data were pooled on 14 635 singleton, live birth pregnancies from women who had participated in 1 of 13 pregnancy studies. The 13 studies cover 8 countries in Africa and Papua New Guinea in the Western Pacific conducted from 1996 to 2015. Data are available at the time of antenatal enrolment of women into their respective parent study and at delivery. The data set comprises essential data such as malaria infection status, anthropometric assessments of maternal nutritional status, presence of anaemia and birth weight, as well as additional variables such gestational age at delivery for a subset of women. Participating studies are described in detail with regard to setting and primary outcome measures, and summarised data are available from each contributing cohort. This pooled birth cohort is the largest pregnancy data set to date to permit a more definite evaluation of the impact of plausible interactions between poor nutritional status and malaria infection in pregnant women on fetal growth and gestational length. Given the current comparative lack of large pregnancy cohorts in malaria-endemic settings, compilation of suitable pregnancy cohorts is likely to provide adequate statistical power to assess malaria-nutrition interactions, and could point towards settings where such interactions are most relevant. The M3 cohort may thus help to identify pregnant women at high risk of adverse outcomes who may benefit from tailored intensive antenatal care including nutritional supplements and alternative or intensified malaria prevention regimens, and the settings in which these interventions would be most effective. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence

  16. Clinical importance of the drug interaction between statins and CYP3A4 inhibitors: a retrospective cohort study in The Health Improvement Network

    PubMed Central

    Rowan, Christopher G.; Brunelli, Steven M.; Munson, Jeffrey; Flory, James; Reese, Peter P.; Hennessy, Sean; Lewis, James; Mines, Daniel; Barrett, Jeffrey S.; Bilker, Warren; Strom, Brian L.

    2014-01-01

    Objective To compare the relative hazard of muscle toxicity, renal dysfunction, and hepatic dysfunction associated with the drug interaction between statins and concomitant medications that inhibit the CYP3A4 isoenzyme. Background Although statins provide important clinical benefits related to mitigating the risk of cardiovascular events, this class of medications also has the potential for severe adverse reactions. The risk for adverse events may be potentiated by concomitant use of medications that interfere with statin metabolism. Methods Data from The Health Improvement Network (THIN) from 1990 to 2008 were used to conduct a retrospective cohort study. Cohorts were created to evaluate each outcome (muscle toxicity, renal dysfunction, and hepatic dysfunction) independently. Each cohort included new statin initiators and compared the relative hazard of the outcome. The interaction ratio (I*R) was the primary contrast of interest. The I*R represents the relative effect of each statin type (statin 3A4 substrate vs. statin non-3A4 substrate) with a CYP3A4 inhibitor, independent of the effect of the statin type without a CYP3A4 inhibitor. We adjusted for confounding variables using the multinomial propensity score. Results The median follow-up time per cohort was 1.5 years. There were 7889 muscle toxicity events among 362 809 patients and 792 665 person-years. The adjusted muscle toxicity I*R was 1.22 (95% confidence interval [CI] = 0.90–1.66). There were 1449 renal dysfunction events among 272,099 patients and 574 584 person-years. The adjusted renal dysfunction I*R was 0.91 (95%CI = 0.58–1.44). There were 1434 hepatic dysfunction events among 367 612 patients and 815 945 person-years. The adjusted hepatic dysfunction I*R was 0.78 (95%CI = 0.45–1.31). Conclusions Overall, this study found no difference in the relative hazard of muscle toxicity, renal dysfunction, or hepatic dysfunction for patients prescribed a statin 3A4 substrate versus a statin non-3A4

  17. The MANGUA Project: A Population-Based HIV Cohort in Guatemala

    PubMed Central

    García, Juan Ignacio; Samayoa, Blanca; Sabidó, Meritxell; Prieto, Luis Alberto; Nikiforov, Mikhail; Pinzón, Rodolfo; Santa Marina de León, Luis Roberto; Ortiz, José Fernando; Ponce, Ernesto; Mejía, Carlos Rodolfo; Arathoon, Eduardo; Casabona, Jordi; Study Group, The Mangua Cohort

    2015-01-01

    Introduction. The MANGUA cohort is an ongoing multicenter, observational study of people living with HIV/AIDS in Guatemala. The cohort is based on the MANGUA application which is an electronic database to capture essential data from the medical records of HIV patients in care. Methods. The cohort enrolls HIV-positive adults ≥16 years of age. A predefined set of sociodemographic, behavioral, clinical, and laboratory data are registered at entry to the cohort study. Results. As of October 1st, 2012, 21 697 patients had been included in the MANGUA cohort (median age: 33 years, 40.3% female). At enrollment 74.1% had signs of advanced HIV infection and only 56.3% had baseline CD4 cell counts. In the first 12 months after starting antiretroviral treatment 26.9% (n = 3938) of the patients were lost to the program. Conclusions. The implementation of a cohort of HIV-positive patients in care in Guatemala is feasible and has provided national HIV indicators to monitor and evaluate the HIV epidemic. The identified percentages of late presenters and high rates of LTFU will help the Ministry to target their current efforts in improving access to diagnosis and care. PMID:26425365

  18. The MANGUA Project: A Population-Based HIV Cohort in Guatemala.

    PubMed

    García, Juan Ignacio; Samayoa, Blanca; Sabidó, Meritxell; Prieto, Luis Alberto; Nikiforov, Mikhail; Pinzón, Rodolfo; Santa Marina de León, Luis Roberto; Ortiz, José Fernando; Ponce, Ernesto; Mejía, Carlos Rodolfo; Arathoon, Eduardo; Casabona, Jordi; Study Group, The Mangua Cohort

    2015-01-01

    Introduction. The MANGUA cohort is an ongoing multicenter, observational study of people living with HIV/AIDS in Guatemala. The cohort is based on the MANGUA application which is an electronic database to capture essential data from the medical records of HIV patients in care. Methods. The cohort enrolls HIV-positive adults ≥16 years of age. A predefined set of sociodemographic, behavioral, clinical, and laboratory data are registered at entry to the cohort study. Results. As of October 1st, 2012, 21 697 patients had been included in the MANGUA cohort (median age: 33 years, 40.3% female). At enrollment 74.1% had signs of advanced HIV infection and only 56.3% had baseline CD4 cell counts. In the first 12 months after starting antiretroviral treatment 26.9% (n = 3938) of the patients were lost to the program. Conclusions. The implementation of a cohort of HIV-positive patients in care in Guatemala is feasible and has provided national HIV indicators to monitor and evaluate the HIV epidemic. The identified percentages of late presenters and high rates of LTFU will help the Ministry to target their current efforts in improving access to diagnosis and care.

  19. A prospective randomized cohort study evaluating 3 weeks vs 6 weeks of oral antibiotic treatment in the setting of "maximal medical therapy" for chronic rhinosinusitis.

    PubMed

    Sreenath, Satyan B; Taylor, Robert J; Miller, Justin D; Ambrose, Emily C; Rawal, Rounak B; Ebert, Charles S; Senior, Brent A; Zanation, Adam M

    2015-09-01

    Surprisingly, little literature exists evaluating the optimal duration of antibiotic treatment in "maximal medical therapy" for chronic rhinosinusitis (CRS). As such, we investigated whether 3 weeks vs 6 weeks of antibiotic therapy resulted in significant differences in clinical response. A prospective, randomized cohort study was performed with patients assigned to 3-week or 6-week cohorts. Our primary outcome was failure of "maximal medical therapy" and surgical recommendation. Secondary outcomes included changes in pretherapy and posttherapy scores for the Rhinosinusitis Disability Index (RSDI), Chronic Sinusitis Survey (CSS), and computed tomography (CT)-based Lund-Mackay (LM) evaluation. Analyses were substratified based on presence of nasal polyps. Forty patients were randomized to the 3-week or 6-week treatment cohorts, with near-complete clinical follow-up achieved. No significant difference was found between the proportion of patients who failed medical therapy and were deemed surgical candidates between the 2 cohorts (71% vs 68%, p = 1.000). No significant difference was found in the change of RSDI or CSS scores in the 3 vs 6 weeks of treatment groups (mean ± standard error of the mean [SEM]; RSDI: 9.62 ± 4.14 vs 1.53 ± 4.01, p = 0.868; CSS: 5.75 ± 4.36 vs 9.65 ± 5.34, p = 0.573). Last, no significant difference was found in the change of LM scores (3.35 ± 1.11 vs 1.53 ± 0.81, p = 0.829). Based on this data, there is little difference in clinical outcomes between 3 weeks vs 6 weeks of antibiotic treatment as part of "maximal medical therapy" for CRS. Increased duration of antibiotic treatment theoretically may increase risk from side effects and creates higher healthcare costs. © 2015 ARS-AAOA, LLC.

  20. The International Childhood Cardiovascular Cohort (i3C) consortium outcomes study of childhood cardiovascular risk factors and adult cardiovascular morbidity and mortality: Design and recruitment.

    PubMed

    Sinaiko, Alan R; Jacobs, David R; Woo, Jessica G; Bazzano, Lydia; Burns, Trudy; Hu, Tian; Juonala, Markus; Prineas, Ronald; Raitakari, Olli; Steinberger, Julia; Urbina, Elaine; Venn, Alison; Jaquish, Cashell; Dwyer, Terry

    2018-04-22

    Although it is widely thought that childhood levels of cardiovascular (CV) risk factors are related to adult CV disease, longitudinal data directly linking the two are lacking. This paper describes the design and organization of the International Childhood Cardiovascular Cohort Consortium Outcomes Study (i3C Outcomes), the first longitudinal cohort study designed to locate adults with detailed, repeated, childhood biological, physical, and socioeconomic measurements and a harmonized database. I3C Outcomes uses a Heart Health Survey (HHS) to obtain information on adult CV endpoints, using mail, email, telephone, and clinic visits in the United States (U.S.) and Australia and a national health database in Finland. Microsoft Access, REsearch Data Capture (REDCap) (U.S.), LimeSurvey (Australia), and Medidata™ Rave data systems are used to collect, transfer and organize data. Self-reported CV events are adjudicated via hospital and doctor-released medical records. After the first two study years, participants (N = 10,968) were more likely to be female (56% vs. 48%), non-Hispanic white (90% vs. 80%), and older (10.4 ± 3.8 years vs. 9.4 ± 3.3 years) at their initial childhood study visit than the currently non-recruited cohort members. Over 48% of cohort members seen during both adulthood and childhood have been found and recruited, to date, vs. 5% of those not seen since childhood. Self-reported prevalences were 0.7% Type 1 Diabetes, 7.5% Type 2 Diabetes, 33% hypertension, and 12.8% CV event. 32% of CV events were judged to be true. I3C Outcomes is uniquely able to establish evidence-based guidelines for child health care and to clarify relations to adult CV disease. Copyright © 2018 Elsevier Inc. All rights reserved.

  1. Recombinant factor VIIa analog in the management of hemophilia with inhibitors: results from a multicenter, randomized, controlled trial of vatreptacog alfa.

    PubMed

    Lentz, S R; Ehrenforth, S; Karim, F Abdul; Matsushita, T; Weldingh, K N; Windyga, J; Mahlangu, J N

    2014-08-01

    Vatreptacog alfa, a recombinant factor VIIa (rFVIIa) analog with three amino acid substitutions and 99% identity to native FVIIa, was developed to improve the treatment of hemophilic patients with inhibitors. To confirm the safety and assess the efficacy of vatreptacog alfa in treating bleeding episodes in hemophilic patients with inhibitors. In this international, multicenter, randomized, double-blind, active-controlled, crossover, confirmatory phase III trial (adept(™) 2) in patients with hemophilia A or B and inhibitors, bleeds were randomized 3 : 2 to treatment with vatreptacog alfa (one to three doses at 80 μg kg(-1) ) or rFVIIa (one to three doses at 90 μg kg(-1) ). Treatment failures after three doses of trial product (TP) were managed according to the local standard of care. In the 72 patients enrolled, 567 bleeds were treated with TP. Both vatreptacog alfa and rFVIIa gave 93% effective bleeding control at 12 h. Vatreptacog alfa was superior to rFVIIa in secondary efficacy outcomes, including the number of doses used to treat a bleed and sustained bleeding control 24-48 h after the first dose. Eight patients (11%) developed antibodies against vatreptacog alfa, including four with cross-reactivity against rFVIIa and one with an in vitro neutralizing effect to vatreptacog alfa. This large randomized controlled trial confirmed the well-established efficacy and safety profile of rFVIIa, and showed that vatreptacog alfa had similar or better efficacy than rFVIIa. However, because of the development of anti-drug antibodies, a positive benefit-risk profile is unlikely to be achieved with vatreptacog alfa. © 2014 The Authors. Journal of Thrombosis and Haemostasis published by Wiley Periodicals, Inc. on behalf of International Society on Thrombosis and Haemostasis.

  2. Birth cohorts in Asia: The importance, advantages, and disadvantages of different-sized cohorts.

    PubMed

    Kishi, Reiko; Araki, Atsuko; Minatoya, Machiko; Itoh, Sachiko; Goudarzi, Houman; Miyashita, Chihiro

    2018-02-15

    Asia contains half of the world's children, and the countries of Asia are the most rapidly industrializing nations on the globe. Environmental threats to the health of children in Asia are myriad. Several birth cohorts were started in Asia in early 2000, and currently more than 30 cohorts in 13 countries have been established for study. Cohorts can contain from approximately 100-200 to 20,000-30,000 participants. Furthermore, national cohorts targeting over 100,000 participants have been launched in Japan and Korea. The aim of this manuscript is to discuss the importance of Asian cohorts, and the advantages and disadvantages of different-sized cohorts. As for case, one small-sized (n=514) cohort indicate that even relatively low level exposure to dioxin in utero could alter birth size, neurodevelopment, and immune and hormonal functions. Several Asian cohorts focus prenatal exposure to perfluoroalkyo substances and reported associations with birth size, thyroid hormone levels, allergies and neurodevelopment. Inconsistent findings may possibly be explained by the differences in exposure levels and target chemicals, and by possible statistical errors. In a smaller cohort, novel hypotheses or preliminary examinations are more easily verifiable. In larger cohorts, the etiology of rare diseases, such as birth defects, can be analyzed; however, they require a large cost and significant human resources. Therefore, conducting studies in only one large cohort may not always be the best strategy. International collaborations, such as the Birth Cohort Consortium of Asia, would cover the inherent limitation of sample size in addition to heterogeneity of exposure, ethnicity, and socioeconomic conditions. Copyright © 2017 Elsevier B.V. All rights reserved.

  3. Exposure of FVIII in the Presence of Phosphatidyl Serine Reduces Generation of Memory B-Cells and Induces Regulatory T-Cell-Mediated Hyporesponsiveness in Hemophilia A Mice.

    PubMed

    Ramakrishnan, Radha; Davidowitz, Andrew; Balu-Iyer, Sathy V

    2015-08-01

    A major complication of replacement therapy with Factor VIII (FVIII) for hemophilia A (HA) is the development of unwanted immune responses. Previous studies showed that administration of FVIII in the presence of phosphatidyl serine (PS) reduced the development of anti-FVIII antibodies in HA mice. However, the impact of PS-mediated effects on immunological memory, such as generation of memory B-cells, is not clear. The effect of PS on memory B-cells was therefore investigated using adoptive transfer approach in FVIII(-/-) HA mice. Adoptive transfer of memory B-cells from a PS-FVIII-treated group to naïve mice followed by challenge of the recipient mice with FVIII showed a significantly reduced anti-FVIII antibody response in the recipient mice, compared with animals that received memory B-cells from free FVIII and FVIII-charge matched phosphatidyl glycerol (PG) group. The decrease in memory B-cell response is accompanied by an increase in FoxP3 expressing regulatory T-cells (Tregs). Flow cytometry studies showed that the generation of Tregs is higher in PS-treated animals as compared with FVIII and FVIII-PG treated animals. The PS-mediated hyporesponsiveness was found to be antigen-specific. The PS-FVIII immunization showed hyporesponsiveness toward FVIII rechallenge but not against ovalbumin (OVA) rechallenge, an unrelated antigen. This demonstrates that PS reduces immunologic memory of FVIII and induces antigen-specific peripheral tolerance in HA mice. © 2015 Wiley Periodicals, Inc. and the American Pharmacists Association.

  4. Cohort Profile Update: The China Jintan Child Cohort Study

    PubMed Central

    Liu, Jianghong; Cao, Siyuan; Chen, Zehang; Raine, Adrian; Hanlon, Alexandra; Ai, Yuexian; Zhou, Guoping; Yan, Chonghuai; Leung, Patrick W; McCauley, Linda; Pinto-Martin, Jennifer

    2015-01-01

    The China Jintan Child Cohort study began in 2004 with 1656 pre-school participants and a research focus on studying the impact of environmental exposures, such as lead, on children’s neurobehavioural outcomes. This population cohort now includes around 1000 of the original participants, who have been assessed three times over a period of 10 years. Since the original IJE cohort profile publication in 2010, participants have experienced a critical developmental transition from pre-school to school age and then adolescence. The study has also witnessed an increase in breadth and depth of data collection from the original aim of risk assessment. This cohort has added new directions to investigate the mechanisms and protective factors for the relationship between early health factors and child physical and mental health outcomes, with an emphasis on neurobehavioural consequences. The study now encompasses 11 domains, composed of repeated measures of the original variables and new domains of biomarkers, sleep, psychophysiology, neurocognition, personality, peer relationship, mindfulness and family dynamics. Depth of evaluation has increased from parent/teacher report to self/peer report and intergenerational family report. Consequently, the cohort has additional directions to include: (i) classmates of the original cohort participants for peer relationship assessment; and (ii) parental and grandparental measures to assess personality and dynamics within families. We welcome interest in our study and ask investigators to contact the corresponding author for additional information on data acquisition. PMID:26323725

  5. A Study of Group Dynamics in Educational Leadership Cohort and Non-Cohort Groups

    ERIC Educational Resources Information Center

    Greenlee, Bobbie J.; Karanxha, Zorka

    2010-01-01

    The purpose of this study was to examine group dynamics of educational leadership students in cohorts and make comparisons with the group dynamics characteristics of non-cohort students. Cohorts have emerged as dynamic and adaptive entities with attendant group dynamic processes that shape collective learning and action. Cohort (n=42) and…

  6. Body Esteem in a Western Australian Cleft Lip and/or Palate Cohort Across 3 Age Groups.

    PubMed

    Nicholls, Wendy; Harper, Craig; Selvey, Linda A; Robinson, Suzanne; Hartig, Gerald; Persson, Martin

    2018-04-01

    To determine if patients with cleft lip and/or palate (CL/P) from a Western Australian (WA) cohort were more dissatisfied with their body esteem than a normative non-cleft cohort, and identify demographic variables that may have significant associations with body esteem. Questionnaire study using the Body-Esteem Scale (BES) and Cleft Research Questionnaire (CRQ). Self-selected participants from a Western Australian CL/P population across 3 age groups (n=359). The BES is comprised of 3 factors: BE-Appearance, BE-Weight and BE-Attribution. Study mean BES factor scores were compared to normative non-cleft scores. Regression analysis was used to determine significant associations within each age group between BES factor scores and CRQ variables of: gender, self-reported body weight category, cleft type and importance of facial appearance rating. Study mean BE-Attribution scores were significantly lower than the normative scores and significantly lower than the mean BE-Appearance and BE-Weight factor scores within the same age groups of this study. Having a cleft type of lip and palate, being overweight, and placing a high importance on facial appearance had significant negative associations with BES scores. Maintaining a normal body weight and placing a lower level of importance on facial appearance had significant positive associations. Gender had no significant associations. In this study, the attribution aspect of body esteem had a greater negative impact on patients than their appearance and body weight. This has important implications for clinical treatment and support of patients.

  7. Cohort profile: the Spanish WORKing life Social Security (WORKss) cohort study

    PubMed Central

    López Gómez, María Andrée; Durán, Xavier; Zaballa, Elena; Sanchez-Niubo, Albert; Delclos, George L; Benavides, Fernando G

    2016-01-01

    Purpose The global economy is changing the labour market and social protection systems in Europe. The effect of both changes on health needs to be monitored in view of an ageing population and the resulting increase in prevalence of chronic health conditions. The Spanish WORKing life Social Security (WORKss) cohort study provides unique longitudinal data to study the impact of labour trajectories and employment conditions on health, in terms of sickness absence, permanent disability and death. Participants The WORKss cohort originated from the Continuous Working Life Sample (CWLS) generated by the General Directorate for the Organization of the Social Security in Spain. The CWLS contains a 4% representative sample of all individuals in contact with the Social Security system. The WORKss cohort exclusively includes individuals with a labour trajectory from 1981 or later. In 2004, the cohort was initiated with 1 022 779 Social Security members: 840 770 (82.2%) contributors and 182 009 (17.8%) beneficiaries aged 16 and older. Findings to date The WORKss cohort includes demographic characteristics, chronological data about employment history, retirement, permanent disability and death. These data make possible the measurement of incidence of permanent disability, the number of potential years of working life lost, and the number of contracts and inactive periods with the Social Security system. The WORKss cohort was linked to temporary sickness absence registries to study medical diagnoses that lead to permanent disability and consequently to an earlier exit from the labour market in unhealthy conditions. Future plans Thanks to its administrative source, the WORKss cohort study will continue follow-up in the coming years, keeping the representativeness of the Spanish population affiliated to the Social Security system. The linkage between the WORKss cohort and temporary sickness absence registries is envisioned to continue. Future plans include the linkage of

  8. Comparing the burden of illness of haemophilia between resource-constrained and unconstrained countries: the São Paulo-Toronto Hemophilia Study.

    PubMed

    Carneiro, J D A; Blanchette, V; Ozelo, M C; Antunes, S V; Villaca, P R; Young, N L; Castro, D; Brandão, L R; Carcao, M; Abad, A; Feldman, B M

    2017-09-01

    Although the regular replacement of clotting factor concentrates (prophylaxis) has been well established as the standard of care for severe haemophilia, the high cost of factor concentrates has limited access to prophylaxis in countries with under-developed or developing economies. We studied the health gap that could be addressed by providing unlimited access to clotting factor concentrates with implementation of long-term prophylaxis initiated from an early age in life. We performed a cross-sectional study of a random, representative sample of boys with moderate and severe haemophilia at three haemophilia treatment centres in Sao Paulo, Brazil, and one centre in Toronto, Canada. Canadian subjects were more often treated with prophylaxis, and began treatment at an earlier age. Fewer Canadian subjects had bleeds within the preceding 6 months (19 vs. 34, P = 0.003). Canadian subjects had lower (better) Pettersson radiographic scores (1.5 vs. 6.0, P = 0.0016), lower (better) Hemophilia Joint Health Scores (5.5 vs. 10.5, P = 0.0038), higher (better) Activity Scale for Kids scores (96.6 vs. 92.0, P = 0.033), more time spent in vigorous activity, and higher (better) social participation scores. Our findings suggest that increasing access to clotting factor concentrates for young boys with severe haemophilia is a global imperative. © 2017 John Wiley & Sons Ltd.

  9. Methods to Develop an Electronic Medical Record Phenotype Algorithm to Compare the Risk of Coronary Artery Disease across 3 Chronic Disease Cohorts.

    PubMed

    Liao, Katherine P; Ananthakrishnan, Ashwin N; Kumar, Vishesh; Xia, Zongqi; Cagan, Andrew; Gainer, Vivian S; Goryachev, Sergey; Chen, Pei; Savova, Guergana K; Agniel, Denis; Churchill, Susanne; Lee, Jaeyoung; Murphy, Shawn N; Plenge, Robert M; Szolovits, Peter; Kohane, Isaac; Shaw, Stanley Y; Karlson, Elizabeth W; Cai, Tianxi

    2015-01-01

    Typically, algorithms to classify phenotypes using electronic medical record (EMR) data were developed to perform well in a specific patient population. There is increasing interest in analyses which can allow study of a specific outcome across different diseases. Such a study in the EMR would require an algorithm that can be applied across different patient populations. Our objectives were: (1) to develop an algorithm that would enable the study of coronary artery disease (CAD) across diverse patient populations; (2) to study the impact of adding narrative data extracted using natural language processing (NLP) in the algorithm. Additionally, we demonstrate how to implement CAD algorithm to compare risk across 3 chronic diseases in a preliminary study. We studied 3 established EMR based patient cohorts: diabetes mellitus (DM, n = 65,099), inflammatory bowel disease (IBD, n = 10,974), and rheumatoid arthritis (RA, n = 4,453) from two large academic centers. We developed a CAD algorithm using NLP in addition to structured data (e.g. ICD9 codes) in the RA cohort and validated it in the DM and IBD cohorts. The CAD algorithm using NLP in addition to structured data achieved specificity >95% with a positive predictive value (PPV) 90% in the training (RA) and validation sets (IBD and DM). The addition of NLP data improved the sensitivity for all cohorts, classifying an additional 17% of CAD subjects in IBD and 10% in DM while maintaining PPV of 90%. The algorithm classified 16,488 DM (26.1%), 457 IBD (4.2%), and 245 RA (5.0%) with CAD. In a cross-sectional analysis, CAD risk was 63% lower in RA and 68% lower in IBD compared to DM (p<0.0001) after adjusting for traditional cardiovascular risk factors. We developed and validated a CAD algorithm that performed well across diverse patient populations. The addition of NLP into the CAD algorithm improved the sensitivity of the algorithm, particularly in cohorts where the prevalence of CAD was low. Preliminary data suggest that

  10. Assessing the order of magnitude of outcomes in single-arm cohorts through systematic comparison with corresponding cohorts: An example from the AMOS study

    PubMed Central

    Hamre, Harald J; Glockmann, Anja; Tröger, Wilfried; Kienle, Gunver S; Kiene, Helmut

    2008-01-01

    Background When a therapy has been evaluated in the first clinical study, the outcome is often compared descriptively to outcomes in corresponding cohorts receiving other treatments. Such comparisons are often limited to selected studies, and often mix different outcomes and follow-up periods. Here we give an example of a systematic comparison to all cohorts with identical outcomes and follow-up periods. Methods The therapy to be compared (anthroposophic medicine, a complementary therapy system) had been evaluated in one single-arm cohort study: the Anthroposophic Medicine Outcomes Study (AMOS). The five largest AMOS diagnosis groups (A-cohorts: asthma, depression, low back pain, migraine, neck pain) were compared to all retrievable corresponding cohorts (C-cohorts) receiving other therapies with identical outcomes (SF-36 scales or summary measures) and identical follow-up periods (3, 6 or 12 months). Between-group differences (pre-post difference in an A-cohort minus pre-post difference in the respective C-cohort) were divided with the standard deviation (SD) of the baseline score of the A-cohort. Results A-cohorts (5 cohorts with 392 patients) were similar to C-cohorts (84 cohorts with 16,167 patients) regarding age, disease duration, baseline affection and follow-up rates. A-cohorts had ≥ 0.50 SD larger improvements than C-cohorts in 13.5% (70/517) of comparisons; improvements of the same order of magnitude (small or minimal differences: -0.49 to 0.49 SD) were found in 80.1% of comparisons; and C-cohorts had ≥ 0.50 SD larger improvements than A-cohorts in 6.4% of comparisons. Analyses stratified by diagnosis had similar results. Sensitivity analyses, restricting the comparisons to C-cohorts with similar study design (observational studies), setting (primary care) or interventions (drugs, physical therapies, mixed), or restricting comparisons to SF-36 scales with small baseline differences between A- and C-cohorts (-0.49 to 0.49 SD) also had similar results

  11. Kidney stones and cardiovascular risk: a meta-analysis of cohort studies.

    PubMed

    Liu, Yanqiong; Li, Shan; Zeng, Zhiyu; Wang, Jian; Xie, Li; Li, Taijie; He, Yu; Qin, Xue; Zhao, Jinmin

    2014-09-01

    Recent epidemiologic evidence suggests an association between kidney stones and incident cardiovascular disease after adjusting for other cardiovascular risk factors, but results are inconsistent. Meta-analysis of cohort studies. Patients with kidney stones. Cohort studies with data for kidney stones and cardiovascular morbidity identified in PubMed, EMBASE, Cochrane Central Register of Controlled Trials, and conference proceedings through February 27, 2014. Kidney stones as determined by physician diagnosis, clinical coding, or self-reported scales. Cardiovascular disease, coronary heart disease (CHD), and stroke. 6 cohort studies that contained 49,597 patients with kidney stones and 3,558,053 controls, with 133,589 cardiovascular events, were included. Pooled results suggested that kidney stones were associated with an increased adjusted risk estimate for CHD (HR, 1.19; 95% CI, 1.05-1.35; P=0.05; n=6 cohorts) and stroke (HR, 1.40; 95% CI, 1.20-1.64; P<0.001; n=3 cohorts). In particular, kidney stones conferred HRs of 1.29 (95% CI, 1.10-1.52; n=6 cohorts) and 1.31 (95% CI, 1.05-1.65; n=4 cohorts) for myocardial infarction and coronary revascularization, respectively. Moreover, the pooled female cohorts showed a statistically significant association (HR, 1.49; 95% CI, 1.21-1.82; n=4 cohorts), whereas the male cohorts showed no association (HR, 1.15; 95% CI, 0.89-1.50; n=2 cohorts). Results may be limited by substantial heterogeneity, likelihood of residual confounding, and paucity of studies that separately evaluated for effect modification by sex. Kidney stones were associated with increased cardiovascular risk, including the risk for incident CHD or stroke. There is some suggestion that the risk may be higher in women than men. Further prospective studies are needed to determine whether the association is sex specific. Copyright © 2014 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.

  12. Employing a gain-of-function factor IX variant R338L to advance the efficacy and safety of hemophilia B human gene therapy: preclinical evaluation supporting an ongoing adeno-associated virus clinical trial.

    PubMed

    Monahan, Paul E; Sun, Junjiang; Gui, Tong; Hu, Genlin; Hannah, William B; Wichlan, David G; Wu, Zhijian; Grieger, Joshua C; Li, Chengwen; Suwanmanee, Thipparat; Stafford, Darrel W; Booth, Carmen J; Samulski, Jade J; Kafri, Tal; McPhee, Scott W J; Samulski, R Jude

    2015-02-01

    Vector capsid dose-dependent inflammation of transduced liver has limited the ability of adeno-associated virus (AAV) factor IX (FIX) gene therapy vectors to reliably convert severe to mild hemophilia B in human clinical trials. These trials also identified the need to understand AAV neutralizing antibodies and empty AAV capsids regarding their impact on clinical success. To address these safety concerns, we have used a scalable manufacturing process to produce GMP-grade AAV8 expressing the FIXR338L gain-of-function variant with minimal (<10%) empty capsid and have performed comprehensive dose-response, biodistribution, and safety evaluations in clinically relevant hemophilia models. The scAAV8.FIXR338L vector produced greater than 6-fold increased FIX specific activity compared with wild-type FIX and demonstrated linear dose responses from doses that produced 2-500% FIX activity, associated with dose-dependent hemostasis in a tail transection bleeding challenge. More importantly, using a bleeding model that closely mimics the clinical morbidity of hemophilic arthropathy, mice that received the scAAV8.FIXR338L vector developed minimal histopathological findings of synovitis after hemarthrosis, when compared with mice that received identical doses of wild-type FIX vector. Hemostatically normal mice (n=20) and hemophilic mice (n=88) developed no FIX antibodies after peripheral intravenous vector delivery. No CD8(+) T cell liver infiltrates were observed, despite the marked tropism of scAAV8.FIXR338L for the liver in a comprehensive biodistribution evaluation (n=60 animals). With respect to the role of empty capsids, we demonstrated that in vivo FIXR338L expression was not influenced by the presence of empty AAV particles, either in the presence or absence of various titers of AAV8-neutralizing antibodies. Necropsy of FIX(-/-) mice 8-10 months after vector delivery revealed no microvascular or macrovascular thrombosis in mice expressing FIXR338L (plasma FIX activity

  13. Intake of total omega-3 fatty acids, eicosapentaenoic acid and docosahexaenoic acid and risk of coronary heart disease in the Spanish EPIC cohort study.

    PubMed

    Amiano, P; Machón, M; Dorronsoro, M; Chirlaque, M Dolores; Barricarte, A; Sánchez, M-J; Navarro, C; Huerta, J M; Molina-Montes, E; Sánchez-Cantalejo, E; Urtizberea, M; Arriola, L; Larrañaga, N; Ardanaz, E; Quirós, J R; Moreno-Iribas, C; González, C A

    2014-03-01

    The evidence about the benefits of omega-3 fatty acid intake on coronary heart disease (CHD) is not consistent. We thus aimed to assess the relation between dietary intake of total omega-3 fatty acids (from plant and marine foods) and marine polyunsaturated fatty acids (PUFAs), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), on the risk of CHD in the Spanish cohort of the European Prospective Investigation into Cancer and Nutrition (EPIC). The analysis included 41,091 men and women aged 20-69 years, recruited from 1992 to 1996 and followed-up until December 2004. Omega-3 fatty acid intake was estimated from a validated dietary questionnaire. Only participants with definite incident CHD event were considered as cases. Cox regression models were used to assess the association between the intake of total omega-3 fatty acids, EPA or DHA and CHD. A total of 609 participants (79% men) had a definite CHD event. Mean intakes of total omega-3 fatty acids, EPA and DHA were very similar in the cases and in the cohort, both in men and women. In the multivariate adjusted model, omega-3 fatty acids, EPA and DHA were not related to incident CHD in either men or women. The hazard ratios (HR) for omega-3 were 1.23 in men (95% CI 0.94-15.9, p = 0.20); and 0.77 in women (95% CI 0.46-1.30, p = 0.76). In the Spanish EPIC cohort, with a relatively high intake of fish, no association was found between EPA, DHA and total omega-3 fatty acid intake and risk of CHD. Copyright © 2013 Elsevier B.V. All rights reserved.

  14. Cohort Profile: HAART Observational Medical Evaluation and Research (HOMER) Cohort

    PubMed Central

    Patterson, Sophie; Cescon, Angela; Samji, Hasina; Cui, Zishan; Yip, Benita; Lepik, Katherine J; Moore, David; Lima, Viviane D; Nosyk, Bohdan; Harrigan, P Richard; Montaner, Julio SG; Shannon, Kate; Wood, Evan; Hogg, Robert S

    2015-01-01

    Since 1986, antiretroviral therapy (ART) has been available free of charge to individuals living with HIV in British Columbia (BC), Canada, through the BC Centre of Excellence in HIV/AIDS (BC-CfE) Drug Treatment Program (DTP). The Highly Active Antiretroviral Therapy (HAART) Observational Medical Evaluation and Research (HOMER) cohort was established in 1996 to maintain a prospective record of clinical measurements and medication profiles of a subset of DTP participants initiating HAART in BC. This unique cohort provides a comprehensive data source to investigate mortality, prognostic factors and treatment response among people living with HIV in BC from the inception of HAART. Currently over 5000 individuals are enrolled in the HOMER cohort. Data captured include socio-demographic characteristics (e.g. sex, age, ethnicity, health authority), clinical variables (e.g. CD4 cell count, plasma HIV viral load, AIDS-defining illness, hepatitis C co-infection, mortality) and treatment variables (e.g. HAART regimens, date of treatment initiation, treatment interruptions, adherence data, resistance testing). Research findings from the HOMER cohort have featured in numerous high-impact peer-reviewed journals. The HOMER cohort collaborates with other HIV cohorts on both national and international scales to answer complex HIV-specific research questions, and welcomes input from external investigators regarding potential research proposals or future collaborations. For further information please contact the principal investigator, Dr Robert Hogg (robert_hogg@sfu.ca). PMID:24639444

  15. Lung cancer risk comparison among male smokers between the "six-prefecture cohort" in Japan and the British physicians' cohort.

    PubMed

    Mizuno, S; Akiba, S; Hirayama, T

    1989-12-01

    We estimated the effective duration of cigarette smoking using the data of lung cancer mortality among male smokers of a large-scale cohort study in Japan and evaluated its role in the lung cancer risk difference between male smokers of the Japanese cohort and the British physicians' cohort. By selecting male cohort members who answered that they had started smoking at ages 18-22 (average = 20.3), the subjects of our analysis, which numbered 49,013, were made relatively homogeneous in terms of age at which smoking was started. Assuming lung cancer mortality to be proportional to the 4.5th power of the effective duration of cigarette smoking, i.e., (age-theta)4.5, as was proposed on the basis of the British cohort study by Doll and Peto, the parameter theta was estimated to be 29.4 for male smokers aged 40-64 in 1966; therefore, the estimated duration of cigarette smoking was, on average, 9.1 years (95% confidence interval = 5.8-11.6) shorter than that calculated from the reported age at which smoking was started. Our findings suggested that the low lung cancer mortality relative to daily cigarette consumption in Japan resulted from the shorter duration of cigarette smoking in the Japanese cohort, possibly due to the severe shortage of cigarettes during and shortly after World War II. Once the effective duration of cigarette smoking was adjusted, lung cancer mortality in the range of 5-34 cigarettes per day was fairly comparable to that observed among the cohort of male British physicians.

  16. Cohort profile: the Spanish WORKing life Social Security (WORKss) cohort study.

    PubMed

    López Gómez, María Andrée; Durán, Xavier; Zaballa, Elena; Sanchez-Niubo, Albert; Delclos, George L; Benavides, Fernando G

    2016-03-07

    The global economy is changing the labour market and social protection systems in Europe. The effect of both changes on health needs to be monitored in view of an ageing population and the resulting increase in prevalence of chronic health conditions. The Spanish WORKing life Social Security (WORKss) cohort study provides unique longitudinal data to study the impact of labour trajectories and employment conditions on health, in terms of sickness absence, permanent disability and death. The WORKss cohort originated from the Continuous Working Life Sample (CWLS) generated by the General Directorate for the Organization of the Social Security in Spain. The CWLS contains a 4% representative sample of all individuals in contact with the Social Security system. The WORKss cohort exclusively includes individuals with a labour trajectory from 1981 or later. In 2004, the cohort was initiated with 1,022 ,79 Social Security members: 840,770 (82.2%) contributors and 182,009 (17.8%) beneficiaries aged 16 and older. The WORKss cohort includes demographic characteristics, chronological data about employment history, retirement, permanent disability and death. These data make possible the measurement of incidence of permanent disability, the number of potential years of working life lost, and the number of contracts and inactive periods with the Social Security system. The WORKss cohort was linked to temporary sickness absence registries to study medical diagnoses that lead to permanent disability and consequently to an earlier exit from the labour market in unhealthy conditions. Thanks to its administrative source, the WORKss cohort study will continue follow-up in the coming years, keeping the representativeness of the Spanish population affiliated to the Social Security system. The linkage between the WORKss cohort and temporary sickness absence registries is envisioned to continue. Future plans include the linkage of the cohort with mortality registries. Published by the BMJ

  17. The Netherlands Cohort Study – Meat Investigation Cohort; a population-based cohort over-represented with vegetarians, pescetarians and low meat consumers

    PubMed Central

    2013-01-01

    Background Vegetarian diets have been associated with lower risk of chronic disease, but little is known about the health effects of low meat diets and the reliability of self-reported vegetarian status. We aimed to establish an analytical cohort over-represented with vegetarians, pescetarians and 1 day/week meat consumers, and to describe their lifestyle and dietary characteristics. In addition, we were able to compare self-reported vegetarians with vegetarians whose status has been confirmed by their response on the extensive food frequency questionnaire (FFQ). Study methods Embedded within the Netherlands Cohort Study (n = 120,852; including 1150 self-reported vegetarians), the NLCS-Meat Investigation Cohort (NLCS-MIC) was defined by combining all FFQ-confirmed-vegetarians (n = 702), pescetarians (n = 394), and 1 day/week meat consumers (n = 1,396) from the total cohort with a random sample of 2–5 days/week- and 6–7 days/week meat consumers (n = 2,965 and 5,648, respectively). Results Vegetarians, pescetarians, and 1 day/week meat consumers had more favorable dietary intakes (e.g. higher fiber/vegetables) and lifestyle characteristics (e.g. lower smoking rates) compared to regular meat consumers in both sexes. Vegetarians adhered to their diet longer than pescetarians and 1 day/week meat consumers. 75% of vegetarians with a prevalent cancer at baseline had changed to this diet after diagnosis. 50% of self-reported vegetarians reported meat or fish consumption on the FFQ. Although the misclassification that occurred in terms of diet and lifestyle when merely relying on self-reporting was relatively small, the impact on associations with disease risk remains to be studied. Conclusion We established an analytical cohort over-represented with persons at the lower end of the meat consumption spectrum which should facilitate prospective studies of major cancers and causes of death using ≥20.3 years of follow-up. PMID:24289207

  18. Cohort Profile: HAART Observational Medical Evaluation and Research (HOMER) cohort.

    PubMed

    Patterson, Sophie; Cescon, Angela; Samji, Hasina; Cui, Zishan; Yip, Benita; Lepik, Katherine J; Moore, David; Lima, Viviane D; Nosyk, Bohdan; Harrigan, P Richard; Montaner, Julio S G; Shannon, Kate; Wood, Evan; Hogg, Robert S

    2015-02-01

    Since 1986, antiretroviral therapy (ART) has been available free of charge to individuals living with HIV in British Columbia (BC), Canada, through the BC Centre of Excellence in HIV/AIDS (BC-CfE) Drug Treatment Program (DTP). The Highly Active Antiretroviral Therapy (HAART) Observational Medical Evaluation and Research (HOMER) cohort was established in 1996 to maintain a prospective record of clinical measurements and medication profiles of a subset of DTP participants initiating HAART in BC. This unique cohort provides a comprehensive data source to investigate mortality, prognostic factors and treatment response among people living with HIV in BC from the inception of HAART. Currently over 5000 individuals are enrolled in the HOMER cohort. Data captured include socio-demographic characteristics (e.g. sex, age, ethnicity, health authority), clinical variables (e.g. CD4 cell count, plasma HIV viral load, AIDS-defining illness, hepatitis C co-infection, mortality) and treatment variables (e.g. HAART regimens, date of treatment initiation, treatment interruptions, adherence data, resistance testing). Research findings from the HOMER cohort have featured in numerous high-impact peer-reviewed journals. The HOMER cohort collaborates with other HIV cohorts on both national and international scales to answer complex HIV-specific research questions, and welcomes input from external investigators regarding potential research proposals or future collaborations. For further information please contact the principal investigator, Dr Robert Hogg (robert_hogg@sfu.ca). © The Author 2014; all rights reserved. Published by Oxford University Press on behalf of the International Epidemiological Association.

  19. 34 CFR 668.202 - Calculating and applying cohort default rates.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 34 Education 3 2010-07-01 2010-07-01 false Calculating and applying cohort default rates. 668.202 Section 668.202 Education Regulations of the Offices of the Department of Education (Continued) OFFICE OF POSTSECONDARY EDUCATION, DEPARTMENT OF EDUCATION STUDENT ASSISTANCE GENERAL PROVISIONS Cohort Default Rates...

  20. 34 CFR 668.183 - Calculating and applying cohort default rates.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 34 Education 3 2010-07-01 2010-07-01 false Calculating and applying cohort default rates. 668.183 Section 668.183 Education Regulations of the Offices of the Department of Education (Continued) OFFICE OF POSTSECONDARY EDUCATION, DEPARTMENT OF EDUCATION STUDENT ASSISTANCE GENERAL PROVISIONS Two Year Cohort Default...

  1. A Comparison of Different Methods for Evaluating Diet, Physical Activity, and Long-Term Weight Gain in 3 Prospective Cohort Studies123

    PubMed Central

    Smith, Jessica D; Hou, Tao; Hu, Frank B; Rimm, Eric B; Spiegelman, Donna; Willett, Walter C; Mozaffarian, Dariush

    2015-01-01

    Background: The insidious pace of long-term weight gain (∼1 lb/y or 0.45 kg/y) makes it difficult to study in trials; long-term prospective cohorts provide crucial evidence on its key contributors. Most previous studies have evaluated how prevalent lifestyle habits relate to future weight gain rather than to lifestyle changes, which may be more temporally and physiologically relevant. Objective: Our objective was to evaluate and compare different methodological approaches for investigating diet, physical activity (PA), and long-term weight gain. Methods: In 3 prospective cohorts (total n = 117,992), we assessed how lifestyle relates to long-term weight change (up to 24 y of follow-up) in 4-y periods by comparing 3 analytic approaches: 1) prevalent diet and PA and 4-y weight change (prevalent analysis); 2) 4-y changes in diet and PA with a 4-y weight change (change analysis); and 3) 4-y change in diet and PA with weight change in the subsequent 4 y (lagged-change analysis). We compared these approaches and evaluated the consistency across cohorts, magnitudes of associations, and biological plausibility of findings. Results: Across the 3 methods, consistent, robust, and biologically plausible associations were seen only for the change analysis. Results for prevalent or lagged-change analyses were less consistent across cohorts, smaller in magnitude, and biologically implausible. For example, for each serving of a sugar-sweetened beverage, the observed weight gain was 0.01 lb (95% CI: −0.08, 0.10) [0.005 kg (95% CI: −0.04, 0.05)] based on prevalent analysis; 0.99 lb (95% CI: 0.83, 1.16) [0.45 kg (95% CI: 0.38, 0.53)] based on change analysis; and 0.05 lb (95% CI: −0.10, 0.21) [0.02 kg (95% CI: −0.05, 0.10)] based on lagged-change analysis. Findings were similar for other foods and PA. Conclusions: Robust, consistent, and biologically plausible relations between lifestyle and long-term weight gain are seen when evaluating lifestyle changes and weight changes

  2. Estimated dietary dioxin exposure and breast cancer risk among women from the French E3N prospective cohort.

    PubMed

    Danjou, Aurélie M N; Fervers, Béatrice; Boutron-Ruault, Marie-Christine; Philip, Thierry; Clavel-Chapelon, Françoise; Dossus, Laure

    2015-03-17

    Dioxins are environmental and persistent pollutants mostly emitted from combustion facilities (e.g. waste incinerators, metal and cement industries). Known to be endocrine disrupting chemicals, dioxins are suspected to increase breast cancer (BC) risk. Although diet is considered the primary source of dioxin exposure, no previous study has been published on dietary dioxin exposure in relation to BC risk. We aimed to assess dietary dioxin exposure among women from the E3N cohort and estimate BC risk associated with this exposure. The study included 63,830 women from the E3N cohort who completed a diet history questionnaire (DHQ) in 1993 and were followed until 2008. Dietary dioxin exposure was estimated by combining consumption data from the E3N DHQ and food dioxin contamination data from a French national monitoring program. Hazard ratios (HR) and 95% confidence intervals (CI) were estimated by Cox models adjusted for BC risk factors. Mean dietary dioxin exposure was estimated at 1.3 ± 0.4 pg/kg body weight (BW)/day. A 0.4 pg/kg BW/d increase in dioxin intake was not associated with overall BC risk (HR = 1.00; 95% CI: 0.96, 1.05). A significant decrease in risk of estrogen receptor negative (ER-)/progesterone receptor negative (PR-) tumors was observed among post-menopausal women in the upper quartile of estimated dioxin intake (HR for Q4 vs. Q1: 0.65; 95% CI: 0.45, 0.96; P for trend across quartiles = 0.0463). Overall, no association between estimated dietary dioxin exposure and BC risk was found among E3N women. Further studies should include both dietary and environmental exposures to determine whether low-dose dioxin exposure is associated with BC risk.

  3. Using full-cohort data in nested case-control and case-cohort studies by multiple imputation.

    PubMed

    Keogh, Ruth H; White, Ian R

    2013-10-15

    In many large prospective cohorts, expensive exposure measurements cannot be obtained for all individuals. Exposure-disease association studies are therefore often based on nested case-control or case-cohort studies in which complete information is obtained only for sampled individuals. However, in the full cohort, there may be a large amount of information on cheaply available covariates and possibly a surrogate of the main exposure(s), which typically goes unused. We view the nested case-control or case-cohort study plus the remainder of the cohort as a full-cohort study with missing data. Hence, we propose using multiple imputation (MI) to utilise information in the full cohort when data from the sub-studies are analysed. We use the fully observed data to fit the imputation models. We consider using approximate imputation models and also using rejection sampling to draw imputed values from the true distribution of the missing values given the observed data. Simulation studies show that using MI to utilise full-cohort information in the analysis of nested case-control and case-cohort studies can result in important gains in efficiency, particularly when a surrogate of the main exposure is available in the full cohort. In simulations, this method outperforms counter-matching in nested case-control studies and a weighted analysis for case-cohort studies, both of which use some full-cohort information. Approximate imputation models perform well except when there are interactions or non-linear terms in the outcome model, where imputation using rejection sampling works well. Copyright © 2013 John Wiley & Sons, Ltd.

  4. Cost-Effectiveness Analysis of Biogeneric Recombinant Activated Factor VII (AryoSeven™) and Activated Prothrombin Complex Concentrates (FEIBA™) to Treat Hemophilia A Patients with Inhibitors in Iran.

    PubMed

    Golestani, Mina; Eshghi, Peyman; Rasekh, Hamid Reza; Cheraghali, Abdoll Majid; Salamzadeh, Jamshid; Naderi, Majid; Managhchi, Mohammad Reza; Hoorfar, Hamid; Toogeh, Gholam Reza; Imani, Ali; Khodayari, Mohammad Taghi; Habibpanah, Behnaz; Hantooshzadeh, Razieh

    2016-01-01

    Nowadays, bypassing agents such as recombinant activated factor VII (rFVIIa) and activated prothrombin complex concentrates (aPCC) are used to treat bleeding episodes in the Hemophilia patients with inhibitors. AryoSeven® is an Iranian biogeneric rFVIIa with homogeneity of efficacy and the nature to NovoSeven in a comparative trial. The current clinical trial aimed to evaluate the cost-effectiveness of FEIBA and AryoSeven® by Decision Analytic Model according to the Iranian healthcare system. An open label, multi-center, cross-over clinical trial was designed. Patients were categorized into 3 groups based on their prior tendency to one or none of the products. To determine the premium therapeutic strategy, the Incremental cost-effectiveness ratio (ICER) was calculated. Protocol F led to more treatment success in group F than the other groups (P= 0.03). Also, there was a significant statistical difference between the mean of effectiveness scores in the groups using protocol F (P = 0.01). The effectiveness of protocol F and A were 89% and 72%, respectively. ICER cost US$ to manage an episode of bleeding to get one more unit of effectiveness using FEIBA VS. AryoSeven. Although the results showed that AryoSeven was more cost-effective compared to FEIBA, the two strategies were undominated. In other words, both medicines can be applied in the first line of the treatment if the cost of FEIBA was reduced. The present clinical trial was registered at IRCT website, under ID No.2013020612380N1.

  5. Methods to Develop an Electronic Medical Record Phenotype Algorithm to Compare the Risk of Coronary Artery Disease across 3 Chronic Disease Cohorts

    PubMed Central

    Liao, Katherine P.; Ananthakrishnan, Ashwin N.; Kumar, Vishesh; Xia, Zongqi; Cagan, Andrew; Gainer, Vivian S.; Goryachev, Sergey; Chen, Pei; Savova, Guergana K.; Agniel, Denis; Churchill, Susanne; Lee, Jaeyoung; Murphy, Shawn N.; Plenge, Robert M.; Szolovits, Peter; Kohane, Isaac; Shaw, Stanley Y.; Karlson, Elizabeth W.; Cai, Tianxi

    2015-01-01

    Background Typically, algorithms to classify phenotypes using electronic medical record (EMR) data were developed to perform well in a specific patient population. There is increasing interest in analyses which can allow study of a specific outcome across different diseases. Such a study in the EMR would require an algorithm that can be applied across different patient populations. Our objectives were: (1) to develop an algorithm that would enable the study of coronary artery disease (CAD) across diverse patient populations; (2) to study the impact of adding narrative data extracted using natural language processing (NLP) in the algorithm. Additionally, we demonstrate how to implement CAD algorithm to compare risk across 3 chronic diseases in a preliminary study. Methods and Results We studied 3 established EMR based patient cohorts: diabetes mellitus (DM, n = 65,099), inflammatory bowel disease (IBD, n = 10,974), and rheumatoid arthritis (RA, n = 4,453) from two large academic centers. We developed a CAD algorithm using NLP in addition to structured data (e.g. ICD9 codes) in the RA cohort and validated it in the DM and IBD cohorts. The CAD algorithm using NLP in addition to structured data achieved specificity >95% with a positive predictive value (PPV) 90% in the training (RA) and validation sets (IBD and DM). The addition of NLP data improved the sensitivity for all cohorts, classifying an additional 17% of CAD subjects in IBD and 10% in DM while maintaining PPV of 90%. The algorithm classified 16,488 DM (26.1%), 457 IBD (4.2%), and 245 RA (5.0%) with CAD. In a cross-sectional analysis, CAD risk was 63% lower in RA and 68% lower in IBD compared to DM (p<0.0001) after adjusting for traditional cardiovascular risk factors. Conclusions We developed and validated a CAD algorithm that performed well across diverse patient populations. The addition of NLP into the CAD algorithm improved the sensitivity of the algorithm, particularly in cohorts where the prevalence of

  6. Targeted inversion and reversion of the blood coagulation factor 8 gene in human iPS cells using TALENs.

    PubMed

    Park, Chul-Yong; Kim, Jungeun; Kweon, Jiyeon; Son, Jeong Sang; Lee, Jae Souk; Yoo, Jeong-Eun; Cho, Sung-Rae; Kim, Jong-Hoon; Kim, Jin-Soo; Kim, Dong-Wook

    2014-06-24

    Hemophilia A, one of the most common genetic bleeding disorders, is caused by various mutations in the blood coagulation factor VIII (F8) gene. Among the genotypes that result in hemophilia A, two different types of chromosomal inversions that involve a portion of the F8 gene are most frequent, accounting for almost half of all severe hemophilia A cases. In this study, we used a transcription activator-like effector nuclease (TALEN) pair to invert a 140-kbp chromosomal segment that spans the portion of the F8 gene in human induced pluripotent stem cells (iPSCs) to create a hemophilia A model cell line. In addition, we reverted the inverted segment back to its normal orientation in the hemophilia model iPSCs using the same TALEN pair. Importantly, we detected the F8 mRNA in cells derived from the reverted iPSCs lines, but not in those derived from the clones with the inverted segment. Thus, we showed that TALENs can be used both for creating disease models associated with chromosomal rearrangements in iPSCs and for correcting genetic defects caused by chromosomal inversions. This strategy provides an iPSC-based novel therapeutic option for the treatment of hemophilia A and other genetic diseases caused by chromosomal inversions.

  7. IGF-1, IGFBP-1, and IGFBP-3 polymorphisms predict circulating IGF levels but not breast cancer risk: findings from the Breast and Prostate Cancer Cohort Consortium (BPC3).

    PubMed

    Patel, Alpa V; Cheng, Iona; Canzian, Federico; Le Marchand, Loïc; Thun, Michael J; Berg, Christine D; Buring, Julie; Calle, Eugenia E; Chanock, Stephen; Clavel-Chapelon, Francoise; Cox, David G; Dorronsoro, Miren; Dossus, Laure; Haiman, Christopher A; Hankinson, Susan E; Henderson, Brian E; Hoover, Robert; Hunter, David J; Kaaks, Rudolf; Kolonel, Laurence N; Kraft, Peter; Linseisen, Jakob; Lund, Eiliv; Manjer, Jonas; McCarty, Catherine; Peeters, Petra H M; Pike, Malcolm C; Pollak, Michael; Riboli, Elio; Stram, Daniel O; Tjonneland, Anne; Travis, Ruth C; Trichopoulos, Dimitrios; Tumino, Rosario; Yeager, Meredith; Ziegler, Regina G; Feigelson, Heather Spencer

    2008-07-02

    IGF-1 has been shown to promote proliferation of normal epithelial breast cells, and the IGF pathway has also been linked to mammary carcinogenesis in animal models. We comprehensively examined the association between common genetic variation in the IGF1, IGFBP1, and IGFBP3 genes in relation to circulating IGF-I and IGFBP-3 levels and breast cancer risk within the NCI Breast and Prostate Cancer Cohort Consortium (BPC3). This analysis included 6,912 breast cancer cases and 8,891 matched controls (n = 6,410 for circulating IGF-I and 6,275 for circulating IGFBP-3 analyses) comprised primarily of Caucasian women drawn from six large cohorts. Linkage disequilibrium and haplotype patterns were characterized in the regions surrounding IGF1 and the genes coding for two of its binding proteins, IGFBP1 and IGFBP3. In total, thirty haplotype-tagging single nucleotide polymorphisms (htSNP) were selected to provide high coverage of common haplotypes; the haplotype structure was defined across four haplotype blocks for IGF1 and three for IGFBP1 and IGFBP3. Specific IGF1 SNPs individually accounted for up to 5% change in circulating IGF-I levels and individual IGFBP3 SNPs were associated up to 12% change in circulating IGFBP-3 levels, but no associations were observed between these polymorphisms and breast cancer risk. Logistic regression analyses found no associations between breast cancer and any htSNPs or haplotypes in IGF1, IGFBP1, or IGFBP3. No effect modification was observed in analyses stratified by menopausal status, family history of breast cancer, body mass index, or postmenopausal hormone therapy, or for analyses stratified by stage at diagnosis or hormone receptor status. In summary, the impact of genetic variation in IGF1 and IGFBP3 on circulating IGF levels does not appear to substantially influence breast cancer risk substantially among primarily Caucasian postmenopausal women.

  8. Cohort Default Rate Guide.

    ERIC Educational Resources Information Center

    Department of Education, Washington, DC. Default Management Div.

    This guide is designed to assist schools with their Federal Family Education Loan Program (FFEL) and the William D. Ford Federal Direct Loan (Direct Loan) Program cohort default rate. The guide is a reference tool in understanding cohort default rates and processes. This guide incorporates two former guides, the "Draft Cohort Default Rate…

  9. Feasibility of cohort studies in Estonia

    PubMed Central

    Innos, K.; Rahu, M.; Rahu, K.

    1999-01-01

    OBJECTIVES: To describe the methodology and feasibility of follow up for vital status in retrospective cohort studies in Estonia. METHODS: A cohort of 7412 workers who had been employed at two factories in Tallinn between 1946 and 1988 was followed up for vital status from the date of first employment until death, emigration, or the end of the study, 31 December 1995, whichever occurred first. The cohort was electronically linked with the National Population Registry of Estonia that was created in 1992 and includes personal identification numbers of Estonian citizens and residents, and the Mortality Database that contains information from death certificates issued in 1983-95. A manual search was carried out on several non-computerised population data sources and archives. RESULTS: By 31 December 1995, the vital status of 6780 (91.5%) subjects could be traced (4495 (60.6%) subjects were alive, 1993 (26.9%) had died, and 292 (3.9%) had emigrated). Analysis by calendar period of leaving work showed that the proportion of subjects traced was lowest in the group of workers who had left work between 1946 and 1955 (58.4%), especially those whose age at leaving work was < 30 (53.2%) or > 60 years (42.3%). Among subjects who left work in 1956-65, 1966-75, and 1976-88, the follow up rate was 84.7%, 94.6%, and 98.2%, respectively. CONCLUSIONS: The findings, which are especially important for occupational epidemiology, confirm the feasibility of conducting retrospective cohort studies in Estonia. Most of the issues discussed in the paper apply to other former Soviet countries.   PMID:10472323

  10. Prognostic factors for remission of and survival in acquired hemophilia A (AHA): results from the GTH-AH 01/2010 study

    PubMed Central

    Klamroth, Robert; Scharf, Rüdiger E.; Trappe, Ralf U.; Holstein, Katharina; Huth-Kühne, Angela; Gottstein, Saskia; Geisen, Ulrich; Schenk, Joachim; Scholz, Ute; Schilling, Kristina; Neumeister, Peter; Miesbach, Wolfgang; Manner, Daniela; Greil, Richard; von Auer, Charis; Krause, Manuela; Leimkühler, Klaus; Kalus, Ulrich; Blumtritt, Jan-Malte; Werwitzke, Sonja; Budde, Eva; Koch, Armin; Knöbl, Paul

    2015-01-01

    Acquired hemophilia A (AHA) is caused by autoantibodies against factor VIII (FVIII). Immunosuppressive treatment (IST) results in remission of disease in 60% to 80% of patients over a period of days to months. IST is associated with frequent adverse events, including infections as a leading cause of death. Predictors of time to remission could help guide IST intensity but have not been established. We analyzed prognostic factors in 102 prospectively enrolled patients treated with a uniform IST protocol. Partial remission (PR; defined as no active bleeding, FVIII restored >50 IU/dL, hemostatic treatment stopped >24 hours) was achieved by 83% of patients after a median of 31 days (range 7-362). Patients with baseline FVIII <1 IU/dL achieved PR less often and later (77%, 43 days) than patients with ≥1 IU/dL (89%, 24 days). After adjustment for other baseline characteristics, low FVIII remained associated with a lower rate of PR (hazard ratio 0.52, 95% confidence interval 0.33-0.81, P < .01). In contrast, PR achieved on steroids alone within ≤21 days was more common in patients with FVIII ≥1 IU/dL and inhibitor concentration <20 BU/mL (odds ratio 11.2, P < .0001). Low FVIII was also associated with a lower rate of complete remission and decreased survival. In conclusion, presenting FVIII and inhibitor concentration are potentially useful to tailor IST in AHA. PMID:25525118

  11. Cohort profile: cerebral palsy in the Norwegian and Danish birth cohorts (MOBAND-CP).

    PubMed

    Tollånes, Mette C; Strandberg-Larsen, Katrine; Forthun, Ingeborg; Petersen, Tanja Gram; Moster, Dag; Andersen, Anne-Marie Nybo; Stoltenberg, Camilla; Olsen, Jørn; Wilcox, Allen J

    2016-09-02

    The purpose of MOthers and BAbies in Norway and Denmark cerebral palsy (MOBAND-CP) was to study CP aetiology in a prospective design. MOBAND-CP is a cohort of more than 210 000 children, created as a collaboration between the world's two largest pregnancy cohorts-the Norwegian Mother and Child Cohort study (MoBa) and the Danish National Birth Cohort. MOBAND-CP includes maternal interview/questionnaire data collected during pregnancy and follow-up, plus linked information from national health registries. Initial harmonisation of data from the 2 cohorts has created 140 variables for children and their mothers. In the MOBAND-CP cohort, 438 children with CP have been identified through record linkage with validated national registries, providing by far the largest such sample with prospectively collected detailed pregnancy data. Several studies investigating various hypotheses regarding CP aetiology are currently on-going. Additional data can be harmonised as necessary to meet requirements of new projects. Biological specimens collected during pregnancy and at delivery are potentially available for assay, as are results from assays conducted on these specimens for other projects. The study size allows consideration of CP subtypes, which is rare in aetiological studies of CP. In addition, MOBAND-CP provides a platform within the context of a merged birth cohort of exceptional size that could, after appropriate permissions have been sought, be used for cohort and case-cohort studies of other relatively rare health conditions of infants and children. 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/

  12. Influence of lifestyle and genetic variants in the aldo-keto reductase 1C3 rs12529 polymorphism in high-risk prostate cancer detection variability assessed between US and New Zealand cohorts

    PubMed Central

    Ambs, Stefan; Tang, Wei; Zhu, Shuotun; Dorsey, Tiffany H.; Goudie, Megan; Masters, Jonathan G.; Ferguson, Lynnette R.

    2018-01-01

    Introduction The prostate-specific antigen (PSA) based prostate cancer (PC) screening is currently being debated. The current assessment is to understand the variability of detecting high-risk PC in a NZ cohort in comparison to a US cohort with better PSA screening facilities. Aldo-keto reductase 1C3 (AKR1C3) is known for multiple functions with a potential to regulate subsequent PSA levels. Therefore, we wish to understand the influence of tobacco smoking and the AKR1C3 rs12529 gene polymorphism in this variability. Method NZ cohort (n = 376) consisted of 94% Caucasians while the US cohort consisted of African Americans (AA), n = 202, and European Americans (EA), n = 232. PSA level, PC grade and stage at diagnosis were collected from hospital databases for assigning high-risk PC status. Tobacco smoking status and the AKR1C3 rs12529 SNP genotype were considered as confounding variables. Variation of the cumulative % high-risk PC (outcome variable) with increasing PSA intervals (exposure factor) was compared between the cohorts using the Kolmogorov-Smirnov test. Comparisons were carried out with and without stratifications made using confounding variables. Results NZ cohort has been diagnosed at a significantly higher mean age (66.67± (8.08) y) compared to both AA (62.65±8.17y) and EA (64.83+8.56y); median PSA (NZ 8.90ng/ml compared to AA 6.86ng/ml and EA 5.80ng/ml); and Gleason sum (NZ (7) compared EA (6)) (p<0.05). The cumulative % high-risk PC detection shows NZ cohort with a significantly lower diagnosis rates at PSA levels between >6 - <10ng/ml compared to both US groups (p<0.05). These were further compounded significantly by smoking status and genetics. Conclusions High-risk PCs recorded at higher PSA levels in NZ could be due to factors including lower levels of PSA screening and subsequent specialist referrals for biopsies. These consequences could be pronounced among NZ ever smokers carrying the AKR1C3 rs12529 G alleles making them a group that requires

  13. 34 CFR 674.5 - Federal Perkins Loan program cohort default rate and penalties.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... from an institution's cohort default rate calculation if the loan is— (A) Discharged due to death or... 34 Education 3 2011-07-01 2011-07-01 false Federal Perkins Loan program cohort default rate and... Provisions § 674.5 Federal Perkins Loan program cohort default rate and penalties. (a) Default penalty. If an...

  14. 34 CFR 674.5 - Federal Perkins Loan program cohort default rate and penalties.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... from an institution's cohort default rate calculation if the loan is— (A) Discharged due to death or... 34 Education 3 2014-07-01 2014-07-01 false Federal Perkins Loan program cohort default rate and... Provisions § 674.5 Federal Perkins Loan program cohort default rate and penalties. (a) Default penalty. If an...

  15. 34 CFR 674.5 - Federal Perkins Loan program cohort default rate and penalties.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... from an institution's cohort default rate calculation if the loan is— (A) Discharged due to death or... 34 Education 3 2010-07-01 2010-07-01 false Federal Perkins Loan program cohort default rate and... Provisions § 674.5 Federal Perkins Loan program cohort default rate and penalties. (a) Default penalty. If an...

  16. 34 CFR 674.5 - Federal Perkins Loan program cohort default rate and penalties.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... from an institution's cohort default rate calculation if the loan is— (A) Discharged due to death or... 34 Education 3 2013-07-01 2013-07-01 false Federal Perkins Loan program cohort default rate and... Provisions § 674.5 Federal Perkins Loan program cohort default rate and penalties. (a) Default penalty. If an...

  17. 34 CFR 674.5 - Federal Perkins Loan program cohort default rate and penalties.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... from an institution's cohort default rate calculation if the loan is— (A) Discharged due to death or... 34 Education 3 2012-07-01 2012-07-01 false Federal Perkins Loan program cohort default rate and... Provisions § 674.5 Federal Perkins Loan program cohort default rate and penalties. (a) Default penalty. If an...

  18. IGF-I and IGFBP-3 concentrations at 2 years: associations with anthropometry and milk consumption in an Indian cohort.

    PubMed

    Wiley, Andrea S; Joshi, Suyog M; Lubree, Himangi G; Bhat, Dattatray S; Memane, Neelam S; Raut, Deepa A; Yajnik, Chittaranjan S

    2018-04-01

    To ascertain associations between plasma insulin-like growth factor I (IGF-I), insulin-like growth factor-binding protein 3 (IGFBP-3) and their molar ratio at 2 y with neonatal size, infant growth, body composition at 2 y, and feeding practices in an Indian cohort. A cohort of 209 newborns, with 122 followed at 2 y. Anthropometry was conducted at birth and 2 y. IGF-I and IGFBP-3 concentrations were measured in cord blood and at 2 y. Maternal and child diet was assessed by food frequency questionnaires and maternal interviews. Multivariate regression was used to test for associations adjusting for confounding factors. Mean 2 y plasma IGF-I and IGFBP-3 concentrations and IGF-I/IGFBP-3 were 49.4 ng/ml (95% CI: 44.1, 54.8), 1953.8 ng/ml (CI: 1870.6, 2036.9) ng/ml, and 0.088 (CI: 0.081, 0.095), respectively. IGF-I and IGF-I/IGFBP-3 were positively associated with current length, but not body mass index or adiposity. IGF-I was higher among those with greater change in length since birth. IGF-I concentrations were higher in children who drank the most milk (>500 vs. <250 ml per day: 65.6 vs. 42.8 ng/ml, p < 0.04), received other milk <6 months compared to ≥6 months (56.3 vs. 44.8 ng/ml, p < 0.05), and in those whose mothers consumed milk daily vs. less frequently in late pregnancy (56.4 vs. 42.7 ng/ml, p < 0.01). In multivariate regression, 2 y IGF-I concentration and IGF-I/IGFBP-3 were each positively associated with current length and milk intake. IGFBP-3 was not related to anthropometry or milk intake. Plasma IGF-I concentrations and IGF-I/IGFBP-3 at 2 y are positively associated with length at 2 y and current milk intake.

  19. Cohort profile: cerebral palsy in the Norwegian and Danish birth cohorts (MOBAND-CP)

    PubMed Central

    Tollånes, Mette C; Strandberg-Larsen, Katrine; Forthun, Ingeborg; Petersen, Tanja Gram; Moster, Dag; Andersen, Anne-Marie Nybo; Stoltenberg, Camilla; Olsen, Jørn; Wilcox, Allen J

    2016-01-01

    Purpose The purpose of MOthers and BAbies in Norway and Denmark cerebral palsy (MOBAND-CP) was to study CP aetiology in a prospective design. Participants MOBAND-CP is a cohort of more than 210 000 children, created as a collaboration between the world's two largest pregnancy cohorts—the Norwegian Mother and Child Cohort study (MoBa) and the Danish National Birth Cohort. MOBAND-CP includes maternal interview/questionnaire data collected during pregnancy and follow-up, plus linked information from national health registries. Findings to date Initial harmonisation of data from the 2 cohorts has created 140 variables for children and their mothers. In the MOBAND-CP cohort, 438 children with CP have been identified through record linkage with validated national registries, providing by far the largest such sample with prospectively collected detailed pregnancy data. Several studies investigating various hypotheses regarding CP aetiology are currently on-going. Future plans Additional data can be harmonised as necessary to meet requirements of new projects. Biological specimens collected during pregnancy and at delivery are potentially available for assay, as are results from assays conducted on these specimens for other projects. The study size allows consideration of CP subtypes, which is rare in aetiological studies of CP. In addition, MOBAND-CP provides a platform within the context of a merged birth cohort of exceptional size that could, after appropriate permissions have been sought, be used for cohort and case-cohort studies of other relatively rare health conditions of infants and children. PMID:27591025

  20. Associations of Novel and Traditional Vascular Biomarkers of Arterial Stiffness: Results of the SAPALDIA 3 Cohort Study.

    PubMed

    Endes, Simon; Caviezel, Seraina; Schaffner, Emmanuel; Dratva, Julia; Schindler, Christian; Künzli, Nino; Bachler, Martin; Wassertheurer, Siegfried; Probst-Hensch, Nicole; Schmidt-Trucksäss, Arno

    There is a lack of evidence concerning associations between novel parameters of arterial stiffness as cardiovascular risk markers and traditional structural and functional vascular biomarkers in a population-based Caucasian cohort. We examined these associations in the second follow-up of the Swiss Cohort Study on Air Pollution and Lung and Heart Diseases in Adults (SAPALDIA 3). Arterial stiffness was measured oscillometrically by pulse wave analysis to derive the cardio-ankle vascular index (CAVI), brachial-ankle (baPWV) and aortic pulse wave velocity (aPWV), and amplitude of the forward and backward wave. Carotid ultrasonography was used to measure carotid intima-media thickness (cIMT) and carotid lumen diameter (LD), and to derive a distensibility coefficient (DC). We used multivariable linear regression models adjusted for several potential confounders for 2,733 people aged 50-81 years. CAVI, aPWV and the amplitude of the forward and backward wave were significant predictors of cIMT (p < 0.001). All parameters were significantly associated with LD (p < 0.001), with aPWV and the amplitude of the forward wave explaining the highest proportion of variance (2%). Only CAVI and baPWV were significant predictors of DC (p < 0.001), explaining more than 0.3% of the DC variance. We demonstrated that novel non-invasive oscillometric arterial stiffness parameters are differentially associated with specific established structural and functional local stiffness parameters. Longitudinal studies are needed to follow-up on these cross-sectional findings and to evaluate their relevance for clinical phenotypes.

  1. Cohort Profile: Sympathetic activity and Ambulatory Blood Pressure in Africans (SABPA) prospective cohort study.

    PubMed

    Malan, Leoné; Hamer, Mark; Frasure-Smith, Nancy; Steyn, Hendrik S; Malan, Nicolaas T

    2015-12-01

    Adapting to an over-demanding stressful urban environment may exhaust the psychophysiological resources to cope with these demands, and lead to sympathetic nervous system dysfunction. The evidence that an urban-dwelling lifestyle may be detrimental to the cardiometabolic health of Africans motivated the design of the Sympathetic activity and Ambulatory Blood Pressure in African Prospective cohort study. We aimed to determine neural mechanistic pathways involved in emotional distress and vascular remodelling. The baseline sample included 409 teachers representing a bi-ethnic sex cohort from South Africa. The study was conducted in 2008-09 and repeated after 3-year follow-up in 2011-12, with an 87.8% successful follow-up rate. Seasonal changes were avoided and extensive clinical assessments were performed in a well-controlled setting. Data collection included sociodemographics, lifestyle habits, psychosocial battery and genetic analysis, mental stress responses mimicking daily life stress (blood pressure and haemostatic, cardiometabolic, endothelial and stress hormones). Target organ damage was assessed in the brain, heart, kidney, blood vessels and retina. A unique highly phenotyped cohort is presented that can address the role of a hyperactive sympathetic nervous system and neural response pathways contributing to the burden of cardiometabolic diseases in Africans. © The Author 2014. Published by Oxford University Press on behalf of the International Epidemiological Association.

  2. Comparing Three South African Student Cohorts on Their Attitudes to the Rights of Working Women

    ERIC Educational Resources Information Center

    Patel, Cynthia Joan

    2016-01-01

    This study compares three cohorts (1998-1999, 2005-2006 and 2010) of undergraduate psychology students at a South African university on the level of support for working women (women in paid employment) on various issues considered to be feminist. Cohort 1 (n?=?244), cohort 2 (n?=?311) and cohort 3 (n?=?266) completed an adapted version of a…

  3. Irritable bowel syndrome and chronic fatigue 3 years after acute giardiasis: historic cohort study.

    PubMed

    Wensaas, Knut-Arne; Langeland, Nina; Hanevik, Kurt; Mørch, Kristine; Eide, Geir Egil; Rortveit, Guri

    2012-02-01

    Giardia lamblia is a common cause of gastroenteritis worldwide, but there is limited knowledge about the long-term complications. To estimate the relative risk of irritable bowel syndrome (IBS) and chronic fatigue 3 years after acute giardiasis. Controlled historic cohort study with 3 years' follow-up. Data collected by mailed questionnaire. Waterborne outbreak of giardiasis in the city of Bergen, Norway. 817 patients exposed to Giardia lamblia infection verified by detection of cysts in stool samples and 1128 matched controls. IBS and chronic fatigue. The prevalence of IBS in the exposed group was 46.1%, compared with 14.0% in the control group, and the adjusted RR=3.4 (95% CI 2.9 to 3.8). Chronic fatigue was reported by 46.1% of the exposed group and 12.0% of the controls, the adjusted RR was 4.0 (95% CI 3.5 to 4.5). IBS and chronic fatigue were associated and the RR for the exposed group of having a combination of the two outcomes was 6.8 (95% CI 5.3 to 8.5). The RR was also increased for having just one of the two syndromes, 1.8 for IBS (95% CI 1.4 to 2.3) and 2.2 for chronic fatigue (95% CI 1.7 to 2.8). Infection with Giardia lamblia in a non-endemic area was associated with a high prevalence of IBS and chronic fatigue 3 years after acute illness, and the risk was significantly higher than in the control group. This shows that the potential consequences of giardiasis are more serious than previously known. Further studies are needed, especially in areas where giardiasis is endemic.

  4. Thalassaemia and risk of cancer: a population-based cohort study.

    PubMed

    Chung, Wei-Sheng; Lin, Chun-Liang; Lin, Cheng-Li; Kao, Chia-Hung

    2015-11-01

    Studies that have investigated the epidemiological relationship between thalassaemia and cancers are scarce. Therefore, we conducted a longitudinal nationwide cohort study to determine whether patients with thalassaemia are at an increased risk of cancer. We investigated the incidence and risk of cancer in 2655 patients diagnosed with thalassaemia between 1998 and 2010 by using data from the Taiwan Longitudinal Health Insurance Database. The comparison cohort comprised 10 620 people from the general population without thalassaemia. The follow-up period extended from the diagnostic date for thalassaemia to the date of a cancer diagnosis, censoring or 31 December 2011. We used Cox proportional hazard regression models to analyse the risks of cancer. The incidences of cancer were 3.96 and 2.60/1000 person-years for the thalassaemia and comparison cohorts, respectively. The overall incidence of cancer was 52% higher in the thalassaemia cohort than in the comparison cohort, with an adjusted HR (aHR) of 1.54 (95% CI 1.15 to 2.07). Patients with thalassaemia had a considerably higher risk of haematological malignancy (aHR=5.32, 95% CI 2.18 to 13.0) and abdominal cancer (aHR=1.96, 95% CI 1.22 to 3.15) than did the comparison cohort. Furthermore, patients with thalassaemia with transfusion exhibited a 9.31-fold risk for developing haematological malignancy and a 9.12-fold risk for developing abdominal cancer compared with those who did not receive transfusion. This nationwide retrospective cohort study indicates that patients with thalassaemia carried substantial risks of haematological malignancy and abdominal cancer compared with those of the general population. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

  5. [Quality standards for epidemiologic cohort studies : An evaluated catalogue of requirements for the conduct and preparation of cohort studies].

    PubMed

    Schmidt, Carsten Oliver; Krabbe, Christine E M; Schössow, Janka; Berger, Klaus; Enzenbach, Cornelia; Kamtsiuris, Panagiotis; Schöne, Gina; Houben, Robin; Meisinger, Christa; Bamberg, Fabian; Hendel, Thomas; Selder, Sonja; Nonnemacher, Michael; Moebus, Susanne; Stausberg, Jürgen

    2018-01-01

    Cohort studies are a longitudinal observational study type. They are firmly established within epidemiology to assess the course of diseases and risk factors. Yet, standards to describe and evaluate quality characteristics of cohort studies need further development. Within the TMF ("Technologie- und Methodenplattform für die vernetzte medizinische Forschung e. V.") project "Quality management standards in cohort studies", a catalogue of requirements was compiled and evaluated, focusing on the preparation and conduct of epidemiologic cohort studies. The catalogue of requirements was established based on a consensus process between representatives of seven German epidemiologic cohort studies. For this purpose, a set of expert meetings (telephone, face-to-face, web-based) was conducted and the importance of each element of the catalogue was assessed as well as its implementation. A catalogue of requirements with 138 requirements was consented. It is structured into ten sections: 1. Study documentation; 2. Selection of instruments; 3. Study implementation, 4. Organizational structure; 5. Qualification and certification; 6. Participant recruitment; 7. Preparation, conduct and follow-up processing of examinations; 8. Study logistics and maintenance, 9. Data capture and data management; 10. Reporting and monitoring. In total, 41 elements were categorized as being essential, 91 as important, and 6 as less important. The catalogue of requirements provides a guideline to improve the preparation and operation of cohort studies. The evaluation of the importance and degree of implementation of requirements depended on the study design. With adaptations, the catalogue might be transferable to other study types.

  6. Medical symptoms among pilots associated with work and home environments: a 3-year cohort study.

    PubMed

    Fu, Xi; Lindgren, Torsten; Norbäck, Dan

    2015-05-01

    To study associations between the cockpit environment, psychosocial work environment, home environment, and medical symptoms in a cohort of commercial pilots followed over 3 yr. A standardized questionnaire was mailed in February-March 1997 to all Stockholm-based pilots on duty in a Scandinavian flight company (N = 622); 577 (93%) participated. During this time smoking was allowed on long haul flights, but not on shorter flights. Smoking was prohibited on all flights after September 1997. The same questionnaire was sent to the cohort of 577 pilots in February-March 2000; 436 participated (76%). The questionnaire contained questions on symptoms, the psychosocial work environment, and the home environment. Associations were investigated using multiple logistic and ordinal regression. Symptoms were common, especially eye symptoms (38.5%), nose symptoms (39.9%), and tiredness (29.9%). Pilots exposed to environmental tobacco smoke (ETS) on long haul flights had more eye symptoms (odds ratio = 1.91) and tiredness (odds ratio = 2.73). These symptoms were reduced when no longer exposed to ETS. Those who started working on long haul flights developed more nose symptoms. Pilots reporting increased work demands developed more nose and dermal symptoms and tiredness and those with decreased work control developed more eye symptoms. Pilots living in new houses, multifamily houses, and in recently painted homes reported more symptoms. Eliminating ETS exposure on board reduced medical symptoms. Further work to reduce ETS exposure globally is needed. Psychosocial aspects of the work environment for commercial pilots should be considered, as well as the home environment.

  7. A clinical research analytics toolkit for cohort study.

    PubMed

    Yu, Yiqin; Zhu, Yu; Sun, Xingzhi; Tao, Ying; Zhang, Shuo; Xu, Linhao; Pan, Yue

    2012-01-01

    This paper presents a clinical informatics toolkit that can assist physicians to conduct cohort studies effectively and efficiently. The toolkit has three key features: 1) support of procedures defined in epidemiology, 2) recommendation of statistical methods in data analysis, and 3) automatic generation of research reports. On one hand, our system can help physicians control research quality by leveraging the integrated knowledge of epidemiology and medical statistics; on the other hand, it can improve productivity by reducing the complexities for physicians during their cohort studies.

  8. Musculoskeletal disorders in a 3 year longitudinal cohort of dental hygiene students.

    PubMed

    Hayes, Melanie J; Smith, Derek R; Taylor, Jane A

    2014-02-01

    Musculoskeletal disorders (MSDs) are a significant occupational health issue for the dental hygiene profession. There is increasing evidence that these problems commence during undergraduate training; however, there is a surprising lack of studies investigating how MSD develops in student groups over the course of their study. The aim of this study was to determine the longitudinal MSD trends among a cohort of undergraduate dental hygiene students at an Australian university. A previously validated self-reporting questionnaire was distributed to dental hygiene students in 3 consecutive years from 2008 to 2010. MSDs were most commonly reported in the neck (ranging from 66 to 68%) and lower back (ranging from 61 to 68%), with a marked increase in reported lower back pain by the final year of study. This study not only supports mounting evidence that MSDs are a common problem for dental hygiene students, but further demonstrates the magnitude of this occupational health issue across the training program. These findings are concerning for a group yet to embark on their professional careers, given that it raises some serious questions about career longevity and the efficacy of preventive measures.

  9. Development of quantitative exposure data for a pooled exposure-response analysis of 10 silica cohorts.

    PubMed

    Mannetje, Andrea 't; Steenland, Kyle; Checkoway, Harvey; Koskela, Riitta-Sisko; Koponen, Matti; Attfield, Michael; Chen, Jingqiong; Hnizdo, Eva; DeKlerk, Nicholas; Dosemeci, Mustafa

    2002-08-01

    Comprehensive quantitative silica exposure estimates over time, measured in the same units across a number of cohorts, would make possible a pooled exposure-response analysis for lung cancer. Such an analysis would help clarify the continuing controversy regarding whether silica causes lung cancer. Existing quantitative exposure data for 10 silica-exposed cohorts were retrieved from the original investigators. Occupation- and time-specific exposure estimates were either adopted/adapted or developed for each cohort, and converted to milligram per cubic meter (mg/m(3)) respirable crystalline silica. Quantitative exposure assignments were typically based on a large number (thousands) of raw measurements, or otherwise consisted of exposure estimates by experts (for two cohorts). Median exposure level of the cohorts ranged between 0.04 and 0.59 mg/m(3) respirable crystalline silica. Exposure estimates were partially validated via their successful prediction of silicosis in these cohorts. Existing data were successfully adopted or modified to create comparable quantitative exposure estimates over time for 10 silica-exposed cohorts, permitting a pooled exposure-response analysis. The difficulties encountered in deriving common exposure estimates across cohorts are discussed. Copyright 2002 Wiley-Liss, Inc.

  10. 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

  11. Predictive Accuracy of the Veterans Aging Cohort Study (VACS) Index for Mortality with HIV Infection: A North American Cross Cohort Analysis

    PubMed Central

    Justice, AC; Modur, S; Tate, JP; Althoff, KN; Jacobson, LP; Gebo, K; Kitahata, M; Horberg, M; Brooks, J; Buchacz, K; Rourke, SB; Rachlis, A; Napravnik, S; Eron, J; Willig, H; Moore, R; Kirk, GD; Bosch, R; Rodriguez, B; Hogg, RS; Thorne, J; Goedert, JJ; Klein, M; Gill, MJ; Deeks, S; Sterling, TR; Anastos, K; Gange, SJ

    2013-01-01

    Background By supplementing an index composed of HIV biomarkers and age (Restricted Index) with measures of organ injury, the Veterans Aging Cohort Study (VACS) Index more completely reflects risk of mortality. We compare the accuracy of the VACS and Restricted Indices 1) among subjects outside the Veterans Healthcare System (VA), 2) over 1–5 years of prior exposure to antiretroviral therapy (ART), and 3) within important patient subgroups. Methods We used data from 13 cohorts in the North American AIDS Cohort Collaboration (NA-ACCORD, n=10, 835) limiting analyses to HIV-infected subjects with at least 12 months exposure to ART. Variables included demographic, laboratory (CD4 count, HIV-1 RNA, hemoglobin, platelets, aspartate and alanine transaminase, creatinine and hepatitis C status), and survival. We used C statistic and net reclassification improvement (NRI) to test discrimination varying prior ART exposure from 1–5 years. We then combined VA (n=5,066) and NA-ACCORD data, fit a parametric survival model, and compared predicted to observed mortality by cohort, gender, age, race, and HIV-1 RNA level. Results Mean follow-up was 3.3 years (655 deaths). Compared with the Restricted Index, the VACS Index showed greater discrimination (C statistic: 0.77 vs. 0.74; NRI 12%; p<0.0001). NRI was highest among those with HIV-1 RNA<500 copies/ml (25%) and age ≥50 years (20%). Predictions were similar to observed mortality among all subgroups. Conclusion VACS Index scores discriminate risk and translate into accurate mortality estimates over 1–5 years of exposures to ART and for diverse patient subgroups from North American PMID:23187941

  12. Increasing Use of Nonmedical Analgesics Among Younger Cohorts in the United States: A Birth Cohort Effect

    PubMed Central

    Miech, Richard; Bohnert, Amy; Heard, Kennon; Boardman, Jason

    2017-01-01

    Purpose Nonmedical use of prescription pain drugs (hereafter ‘analgesics’) has increased substantially in recent years. It is not known whether today’s youth are disproportionately driving this increase or, instead, the trend is a general one that has affected cohorts of all ages similarly. To address this question we present the first age-period-cohort analysis of nonmedical use of analgesics. Methods Data come from the National Survey on Drug Use and Health, a series of annual, nationally-representative, cross-sectional surveys of the U.S. civilian, non-institutionalized population. The analysis focuses on the years 1985 to 2009 and uses the recently developed ‘intrinsic estimator’ algorithm to disentangle age-period-cohort effects. Results Substantial increases in the prevalence of nonmedical analgesics use have occurred across all cohorts and ages in recent years, but this increase is significantly amplified among today’s adolescents. The odds of past-year, nonmedical analgesics use for today’s youngest cohort (born 1980–1994) are higher than would be expected on the basis of their age and broad, historical period influences that have increased use across people of all ages and cohorts. The independent influence of cohort on past-year, nonmedical analgesics use is about 40% higher for today’s youth cohort than any of the cohorts that came before them. This finding is present among men, women, non-Hispanic whites, non-Hispanic blacks, and Hispanics. Conclusions Although nonmedical use of analgesics is evident among all ages, cohorts, and periods, today’s younger cohorts warrant special attention for substance abuse policies and interventions targeted at reversing the increase in nonmedical analgesics use. PMID:23260832

  13. Anti-pentraxin 3 auto-antibodies might be protective in lupus nephritis: a large cohort study.

    PubMed

    Yuan, Mo; Tan, Ying; Pang, Yun; Li, Yong-Zhe; Song, Yan; Yu, Feng; Zhao, Ming-Hui

    2017-11-01

    Anti-pentraxin 3 (PTX3) auto-antibodies were found to be associated with the absence of renal involvement in systemic lupus erythematosus (SLE). This study is to investigate the prevalence of anti-PTX3 auto-antibodies and their clinical significance based on a large Chinese lupus nephritis cohort. One hundred and ninety-six active lupus nephritis patients, 150 SLE patients without clinical renal involvement, and 100 healthy controls were enrolled. Serum anti-PTX3 auto-antibodies and PTX3 levels were screened by enzyme-linked immunosorbent assay (ELISA). The associations between anti-PTX3 auto-antibodies and clinicopathological parameters in lupus nephritis were further analyzed. Anti-PTX3 auto-antibodies were less prevalent in active lupus nephritis patients compared with SLE without renal involvement (19.4% (38/196) versus 40.7% (61/150), p < .001). The serum levels of anti-PTX3 auto-antibodies were negatively correlated with proteinuria in lupus nephritis (r = -.143, p = .047). The levels of proteinuria, serum creatinine, and the prevalence of thrombotic microangiopathy were significantly higher in patients with higher PTX3 levels (≥3.207 ng/ml) and without anti-PTX3 auto-antibodies compared with patients with lower PTX3 levels (<3.207 ng/ml) and with anti-PTX3 auto-antibodies (4.79 (3.39-8.28) versus 3.95 (1.78-7.0), p = .03; 168.84 ± 153.63 versus 101.44 ± 47.36, p = .01; 34.1% (14/41) versus 0% (0/9), p = .04; respectively). Anti-PTX3 auto-antibodies were less prevalent in active lupus nephritis patients compared with SLE without renal involvement and associated with less severe renal damage, especially with the combined evaluation of serum PTX3 levels.

  14. Validation of the Children's Eating Behavior Questionnaire in 3 year old children of a multi-ethnic Asian population: The GUSTO cohort study.

    PubMed

    Quah, Phaik Ling; Cheung, Yin Bun; Pang, Wei Wei; Toh, Jia Ying; Saw, Seang-Mei; Godfrey, Keith M; Yap, Fabian; Chong, Yap Seng; Mary, Chong Foong-Fong

    2017-06-01

    The Children's Eating Behaviour Questionnaire (CEBQ) was developed to measure eating behaviors related to obesity risk in children. However, this questionnaire has not been validated for use in South East Asia, where parenting practices are different from those in western countries and child obesity rates are increasing. The aim of this study was to examine the validity of the CEBQ administered to mothers of children aged 3 years in Singapore. Confirmatory factor analysis (CFA) was used to examine if the original 35-item, 8-factor model was supported in our cohort. Participants were 636 mother-child dyads (mean (SD) child age = 36.7 (1.6) months), from the Growing Up in Singapore Towards healthy Outcomes (GUSTO) birth cohort in which the mothers were characterized in pregnancy and children were followed up to age 3 years. The CFA showed a poor model fit; RMSEA = 0.072 (PCLOSE<0.001), SRMR = 0.094, CFI = 0.826, and TLI = 0.805. Exploratory factor analysis revealed a 35 item, 7-factor structure (factor loadings ≥ 0.35): enjoyment of food, food fussiness, emotional overeating, desire to drink, emotional under eating, satiety responsiveness and slowness in eating. Cronbach's alpha estimates ranged from 0.70 to 0.88 for the 7 subscales. Convergent validity tests via correlation analysis revealed that emotional under eating (r = -0.14), slowness in eating (r = -0.16) and satiety responsiveness (r = -0.11) were negatively correlated with BMI z-score at 3 years, while enjoyment of food (r = 0.12) was positively correlated, p < 0.05. In conclusion, we found a revised 7-factor structure of the CEBQ more appropriate for examining eating behavior in 3 year old children in the Singapore setting. Further replication studies in a separate cohort study are warranted before further use of these factor structures generated. Copyright © 2017 Elsevier Ltd. All rights reserved.

  15. Exploring educational disparities in risk of preterm delivery: a comparative study of 12 European birth cohorts.

    PubMed

    Poulsen, Gry; Strandberg-Larsen, Katrine; Mortensen, Laust; Barros, Henrique; Cordier, Sylvaine; Correia, Sofia; Danileviciute, Asta; van Eijsden, Manon; Fernández-Somoano, Ana; Gehring, Ulrike; Grazuleviciene, Regina; Hafkamp-de Groen, Esther; Henriksen, Tine Brink; Jensen, Morten Søndergaard; Larrañaga, Isabel; Magnus, Per; Pickett, Kate; Raat, Hein; Richiardi, Lorenzo; Rouget, Florence; Rusconi, Franca; Stoltenberg, Camilla; Uphoff, Eleonora P; Vrijkotte, Tanja G M; Wijga, Alet H; Vrijheid, Martine; Osler, Merete; Andersen, Anne-Marie Nybo

    2015-05-01

    An association between education and preterm delivery has been observed in populations across Europe, but differences in methodology limit comparability. We performed a direct cross-cohort comparison of educational disparities in preterm delivery based on individual-level birth cohort data. The study included data from 12 European cohorts from Denmark, England, France, Lithuania, the Netherlands, Norway, Italy, Portugal, and Spain. The cohorts included between 2434 and 99 655 pregnancies. The association between maternal education and preterm delivery (22-36 completed weeks of gestation) was reported as risk ratios, risk differences, and slope indexes of inequality with 95% confidence intervals (CIs). Singleton preterm live delivery proportion varied between 3.7% and 7.5%. There were large variations between the cohorts in the distribution of education and maternal characteristics. Nevertheless, there were similar educational differences in risk of preterm delivery in 8 of the 12 cohorts with slope index of inequality varying between 2.2 [95% CI 1.1, 3.3] and 4.0 [95% CI 1.4, 6.6] excess preterm deliveries per 100 singleton deliveries among the educationally most disadvantaged, and risk ratio between the lowest and highest education category varying from 1.4 [95% CI 1.1, 1.8] to 1.9 [95% CI 1.2, 3.1]. No associations were found in the last four cohorts. Educational disparities in preterm delivery were found all over Europe. Despite differences in the distributions of education and preterm delivery, the results were remarkably similar across the cohorts. For those few cohorts that did not follow the pattern, study and country characteristics did not explain the differences. © 2015 John Wiley & Sons Ltd.

  16. NCI Cohort Consortium Membership

    Cancer.gov

    The NCI Cohort Consortium membership is international and includes investigators responsible for more than 40 high-quality cohorts who are studying large and diverse populations in more than 15 different countries.

  17. ACTN3 R577X and ACE I/D gene variants influence performance in elite sprinters: a multi-cohort study.

    PubMed

    Papadimitriou, Ioannis D; Lucia, Alejandro; Pitsiladis, Yannis P; Pushkarev, Vladimir P; Dyatlov, Dmitry A; Orekhov, Evgeniy F; Artioli, Guilherme G; Guilherme, João Paulo L F; Lancha, Antonio H; Ginevičienė, Valentina; Cieszczyk, Pawel; Maciejewska-Karlowska, Agnieszka; Sawczuk, Marek; Muniesa, Carlos A; Kouvatsi, Anastasia; Massidda, Myosotis; Calò, Carla Maria; Garton, Fleur; Houweling, Peter J; Wang, Guan; Austin, Krista; Druzhevskaya, Anastasiya M; Astratenkova, Irina V; Ahmetov, Ildus I; Bishop, David J; North, Kathryn N; Eynon, Nir

    2016-04-13

    To date, studies investigating the association between ACTN3 R577X and ACE I/D gene variants and elite sprint/power performance have been limited by small cohorts from mixed sport disciplines, without quantitative measures of performance. To examine the association between these variants and sprint time in elite athletes. We collected a total of 555 best personal 100-, 200-, and 400-m times of 346 elite sprinters in a large cohort of elite Caucasian or African origin sprinters from 10 different countries. Sprinters were genotyped for ACTN3 R577X and ACE ID variants. On average, male Caucasian sprinters with the ACTN3 577RR or the ACE DD genotype had faster best 200-m sprint time than their 577XX (21.19 ± 0.53 s vs. 21.86 ± 0.54 s, p = 0.016) and ACE II (21.33 ± 0.56 vs. 21.93 ± 0.67 sec, p = 0.004) counterparts and only one case of ACE II, and no cases of ACTN3 577XX, had a faster 200-m time than the 2012 London Olympics qualifying (vs. 12 qualified sprinters with 577RR or 577RX genotype). Caucasian sprinters with the ACE DD genotype had faster best 400-m sprint time than their ACE II counterparts (46.94 ± 1.19 s vs. 48.50 ± 1.07 s, p = 0.003). Using genetic models we found that the ACTN3 577R allele and ACE D allele dominant model account for 0.92 % and 1.48 % of sprint time variance, respectively. Despite sprint performance relying on many gene variants and environment, the % sprint time variance explained by ACE and ACTN3 is substantial at the elite level and might be the difference between a world record and only making the final.

  18. Cohort Profile Update: The Norwegian Mother and Child Cohort Study (MoBa).

    PubMed

    Magnus, Per; Birke, Charlotte; Vejrup, Kristine; Haugan, Anita; Alsaker, Elin; Daltveit, Anne Kjersti; Handal, Marte; Haugen, Margaretha; Høiseth, Gudrun; Knudsen, Gun Peggy; Paltiel, Liv; Schreuder, Patricia; Tambs, Kristian; Vold, Line; Stoltenberg, Camilla

    2016-04-01

    This is an update of the Norwegian Mother and Child Cohort Study (MoBa) cohort profile which was published in 2006. Pregnant women attending a routine ultrasound examination were initially invited. The first child was born in October 1999 and the last in July 2009. The participation rate was 41%. The cohort includes more than 114 000 children, 95 000 mothers and 75 000 fathers. About 1900 pairs of twins have been born. There are approximately 16 400 women who participate with more than one pregnancy. Blood samples were obtained from both parents during pregnancy and from mothers and children (umbilical cord) after birth. Samples of DNA, RNA, whole blood, plasma and urine are stored in a biobank. During pregnancy, the mother responded to three questionnaires and the father to one. After birth, questionnaires were sent out when the child was 6 months, 18 months and 3 years old. Several sub-projects have selected participants for in-depth clinical assessment and exposure measures. The purpose of this update is to explain and describe new additions to the data collection, including questionnaires at 5, 7, 8 and 13 years as well as linkages to health registries, and to point to some findings and new areas of research. Further information can be found at [www.fhi.no/moba-en]. Researchers interested in collaboration and access to the data can complete an electronic application available on the MoBa website above. © The Author 2016; all rights reserved. Published by Oxford University Press on behalf of the International Epidemiological Association.

  19. The role of birth cohorts in studies of adult health: the New York women's birth cohort.

    PubMed

    Terry, Mary Beth; Flom, Julie; Tehranifar, Parisa; Susser, Ezra

    2009-09-01

    Epidemiological studies investigating associations between early life factors and adult health are often limited to studying exposures that can be reliably recalled in adulthood or obtained from existing medical records. There are few US studies with detailed data on the pre- and postnatal environment whose study populations are now in adulthood; one exception is the Collaborative Perinatal Project (CPP). We contacted former female participants of the New York site of the CPP who were born from 1959 to 1963 and were prospectively followed for 7 years to examine whether the pre- and postnatal environment is associated with adult health in women 40 years after birth. The New York CPP cohort is particularly diverse; at enrolment, the race/ethnicity distribution of mothers was approximately 30% White, 40% Black and 30% Puerto Rican. Of the 841 eligible women, we successfully traced 375 women (45%) and enrolled 262 women (70% of those traced). Baseline data were available for all eligible women, and we compared those who participated with the remaining cohort (n = 579). Higher family socio-economic status at age 7, availability of maternal social security number, and White race/ethnicity were statistically significantly associated with a higher probability of tracing. Of those traced, race/ethnicity was associated with participation, with Blacks and Puerto Ricans less likely to participate than Whites (OR = 0.5, 95% CI 0.3, 0.8, and OR = 0.5, 95% CI 0.3, 1.0, respectively). In addition, higher weight at 7 years was associated with lower participation (OR = 0.95, 95% CI 0.92, 0.99), but this association was observed only among the non-White participants. None of the other maternal characteristics, infant or early childhood growth measures was associated with participation or with tracing, either overall or within each racial/ethnic subgroup. Daughters' recall of early life factors such as pre-eclampsia (sensitivity = 24%) and birthweight were generally poor, with the

  20. Birth cohorts in asthma and allergic diseases: Report of a NIAID, NHLBI, MeDALL joint workshop

    PubMed Central

    Bousquet, J; Gern, JE; Martinez, FD; Anto, JM; Johnson, CC; Holt, PG; Lemanske, RF; Le Souef, PN; Tepper, R; von Mutius, ERM; Arshad, SH; Bacharier, LB; Becker, A; Belanger, K; Bergstrom, A; Bernstein, D; Cabana, MD; Carroll, KN; Castro, M; Cooper, PJ; Gillman, MW; Gold, DR; Henderson, J; Heinrich, J; S-J, Hong; Jackson, DJ; Keil, T; Kozyrskyj, AL; Lodrup-Carlsen, K; Miller, RL; Momas, I; Morgan, WJ; Noel, P; Ownby, DR; Pinart, M; Ryan, P; Schwaninger, JM; Sears, MR; Simpson, A; Smit, HA; Stern, D; Subbarao, P; Valenta, R; Wang, X; Weiss, ST; Wood, R; Wright, AL; Wright, RJ; Togias, A; Gergen, PJ

    2014-01-01

    Population-based birth cohorts on asthma and allergies increasingly provide new insights into the development and natural history of the diseases. Over 130 birth cohorts focusing on asthma and allergy have been initiated in the last 30 years. A NIAID (National Institute of Allergy and Infectious Diseases), NHLBI (National Heart Lung and Blood Institute), MeDALL (Mechanisms of the Development of Allergy, Framework Programme 7 of the European Commission) joint workshop was held in Bethesda, MD, USA September 11–12, 2012 with 3 objectives (1) documenting the knowledge that asthma/allergy birth cohorts have provided, (2) identifying the knowledge gaps and inconsistencies and (3) developing strategies for moving forward, including potential new study designs and the harmonization of existing asthma birth cohort data. The meeting was organized around the presentations of 5 distinct workgroups: (1) clinical phenotypes, (2) risk factors, (3) immune development of asthma and allergy, (4) pulmonary development and (5) harmonization of existing birth cohorts. This manuscript presents the workgroup reports and provides web links (AsthmaBirthCohorts.niaid.nih.gov or www.medall-fp7.eu) where the reader will find tables describing the characteristics of the birth cohorts included in this report, type of data collected at differing ages, and a selected bibliography provided by the participating birth cohorts. PMID:24636091

  1. Change of sleep quality from pre- to 3 years post-solid organ transplantation: The Swiss Transplant Cohort Study

    PubMed Central

    Denhaerynck, Kris; Huynh-Do, Uyen; Binet, Isabelle; Hadaya, Karine; De Geest, Sabina

    2017-01-01

    Background Poor sleep quality (SQ) is common after solid organ transplantation; however, very little is known about its natural history. We assessed the changes in SQ from pre- to 3 years post-transplant in adult heart, kidney, liver and lung recipients included in the prospective nation-wide Swiss Transplant Cohort Study. We explored associations with selected variables in patients suffering persistent poor SQ compared to those with good or variable SQ. Methods Adult single organ transplant recipients enrolled in the Swiss Transplant Cohort Study with pre-transplant and at least 3 post-transplant SQ assessment data were included. SQ was self-reported pre-transplant (at listing), then at 6, 12, 24 and 36 months post-transplant. A single SQ item was used to identify poor (0–5) and good sleepers (6–10). Between organ groups, SQ was compared via logistic regression analysis with generalized estimating equations. Within the group reporting persistently poor SQ, we used logistic regression or Kaplan-Meier analysis as appropriate to check for differences in global quality of life and survival. Results In a sample of 1173 transplant patients (age: 52.1±13.2 years; 65% males; 66% kidney, 17% liver, 10% lung, 7% heart) transplanted between 2008 and 2012, pre- transplant poor SQ was highest in liver (50%) and heart (49%) recipients. Overall, poor SQ decreased significantly from pre-transplant (38%) to 24 months post-transplant (26%) and remained stable at 3 years (29%). Patients reporting persistently poor SQ had significantly more depressive symptomatology and lower global quality of life. Conclusion Because self-reported poor SQ is related to poorer global quality of life, these results emphasize the need for further studies to find suitable treatment options for poor SQ in transplant recipients. PMID:29020112

  2. Disease fatality and bias in survival cohorts.

    PubMed

    Barry, Vaughn; Klein, Mitchel; Winquist, Andrea; Darrow, Lyndsey A; Steenland, Kyle

    2015-07-01

    Simulate how the effect of exposure on disease occurrence and fatality influences the presence and magnitude of bias in survivor cohorts, motivated by an actual survivor cohort under study. We simulated a cohort of 50,000 subjects exposed to a disease-causing exposure over time and followed forty years, where disease incidence was the outcome of interest. We simulated this 'inception' cohort under different assumptions about the effect of exposure on disease occurrence and fatality after disease occurrence. We then created a corresponding 'survivor' (or 'cross-sectional') cohort, where cohort enrollment took place at a specific date after exposure began in the inception cohort; subjects dying prior to that enrollment date were excluded. The disease of interest caused all deaths in our simulations, but was not always fatal. In the survivor cohort, person-time at risk began before enrollment for all subjects who did not die prior to enrollment. We compared exposure-disease associations in each inception cohort to those in corresponding survivor cohorts to determine how different assumptions impacted bias in the survivor cohorts. All subjects in both inception and survivor cohorts were considered equally susceptible to the effect of exposure in causing disease. We used Cox proportional hazards regression to calculate effect measures. There was no bias in survivor cohort estimates when case fatality among diseased subjects was independent of exposure. This was true even when the disease was highly fatal and more highly exposed subjects were more likely to develop disease and die. Assuming a positive exposure-response in the inception cohort, survivor cohort rate ratios were biased downwards when case fatality was greater with higher exposure. Survivor cohort effect estimates for fatal outcomes are not always biased, although precision can decrease. Copyright © 2015 Elsevier Inc. All rights reserved.

  3. Trait anxiety levels before and after antidepressant treatment: a 3-wave cohort study.

    PubMed

    Nabi, Hermann; Virtanen, Marianna; Singh-Manoux, Archana; Hagger-Johnson, Gareth; Pentti, Jaana; Kivimäki, Mika; Vahtera, Jussi

    2013-06-01

    The aim of this study was to examine change in "trait anxiety" levels assessed repeatedly before and after antidepressant treatment in a large cohort of men and women. A total of 18,732 participants of the Finnish Public Sector Study with no initial record of depression or self-reported doctor diagnosis of depression completed the short form of the Spielberger Trait-Anxiety Inventory in 2000-2002 (T1), 2004-2005 (T2), and 2008-2009 (T3). We used prescription data from the nationwide Drug Prescription Register to identify antidepressant treatment between T1 and T2 (n = 710). Both men (β = 0.435, P < 0.001) and women (β = 0.300, P < 0.001) who received antidepressant treatment had higher trait anxiety levels at T1. Mixed models analyses of repeated measures showed a small but statistically significant decrease in trait anxiety scores for the overall sample of men (β = 0.023, P = 0.033) and women (β = 0.011, P = 0.031) between T1 and T3. The interaction term between time and antidepressant treatment status suggested a greater decrease in trait anxiety levels among men receiving antidepressant treatment, with an adjusted excess decrease in mean trait anxiety scores of 0.163 (P = 0.012) between T1 and T3. We found some evidence suggesting that this is also the case in women, although the evidence in our data was less consistent for women. This large-scale study provides evidence suggesting that antidepressant treatment is associated with a reduction in trait anxiety levels, particularly in men.

  4. Cohort profile: LIFEWORK, a prospective cohort study on occupational and environmental risk factors and health in the Netherlands.

    PubMed

    Reedijk, Marije; Lenters, Virissa; Slottje, Pauline; Pijpe, Anouk; Peeters, Petra H; Korevaar, Joke C; Bueno-de-Mesquita, Bas; Verschuren, W M Monique; Verheij, Robert A; Pieterson, Inka; van Leeuwen, Flora E; Rookus, Matti A; Kromhout, Hans; Vermeulen, Roel C H

    2018-02-03

    LIFEWORK is a large federated prospective cohort established in the Netherlands to quantify the health effects of occupational and environmental exposures. This cohort is also the Dutch contribution to the international Cohort Study of Mobile Phone Use and Health (COSMOS). In this paper, we describe the study design, ongoing data collection, baseline characteristics of participants and the repeatability of key questionnaire items. 88 466 participants were enrolled in three cohort studies in 2011-2012. Exposure information was collected by a harmonised core questionnaire, or modelled based on occupational and residential histories; domains include air pollution (eg, nitrogen dioxide (NO 2 ), particulate matter with diameter ≤2.5 µm (PM 2.5 )), noise, electromagnetic fields (EMF), mobile phone use, shift work and occupational chemical exposures. Chronic and subacute health outcomes are assessed by self-report and through linkage with health registries. Participants had a median age of 51 years at baseline (range 19-87), and the majority are female (90%), with nurses being over-represented. Median exposure levels of NO 2 , PM 2.5 , EMF from base stations and noise at the participants' home addresses at baseline were 22.9 µg/m 3 , 16.6 µg/m 3 , 0.003 mWm 2 and 53.1 dB, respectively. Twenty-two per cent of participants reported to have started using a mobile phone more than 10 years prior to baseline. Repeatability for self-reported exposures was moderate to high (weighted kappa range: 0.69-1) for a subset of participants (n=237) who completed the questionnaire twice. We are actively and passively observing participants; we plan to administer a follow-up questionnaire every 4-5 years-the first follow-up will be completed in 2018-and linkage to cause-of-death and cancer registries occurs on a (bi)annual basis. This prospective cohort offers a unique, large and rich resource for research on contemporary occupational and environmental health risks and will

  5. Cohort profile: LIFEWORK, a prospective cohort study on occupational and environmental risk factors and health in the Netherlands

    PubMed Central

    Peeters, Petra H; Korevaar, Joke C; Bueno-de-Mesquita, Bas; Verschuren, W M Monique; Verheij, Robert A; Pieterson, Inka; van Leeuwen, Flora E

    2018-01-01

    Purpose LIFEWORK is a large federated prospective cohort established in the Netherlands to quantify the health effects of occupational and environmental exposures. This cohort is also the Dutch contribution to the international Cohort Study of Mobile Phone Use and Health (COSMOS). In this paper, we describe the study design, ongoing data collection, baseline characteristics of participants and the repeatability of key questionnaire items. Participants 88 466 participants were enrolled in three cohort studies in 2011–2012. Exposure information was collected by a harmonised core questionnaire, or modelled based on occupational and residential histories; domains include air pollution (eg, nitrogen dioxide (NO2), particulate matter with diameter ≤2.5 µm (PM2.5)), noise, electromagnetic fields (EMF), mobile phone use, shift work and occupational chemical exposures. Chronic and subacute health outcomes are assessed by self-report and through linkage with health registries. Findings to date Participants had a median age of 51 years at baseline (range 19–87), and the majority are female (90%), with nurses being over-represented. Median exposure levels of NO2, PM2.5, EMF from base stations and noise at the participants’ home addresses at baseline were 22.9 µg/m3, 16.6 µg/m3, 0.003 mWm2 and 53.1 dB, respectively. Twenty-two per cent of participants reported to have started using a mobile phone more than 10 years prior to baseline. Repeatability for self-reported exposures was moderate to high (weighted kappa range: 0.69–1) for a subset of participants (n=237) who completed the questionnaire twice. Future plans We are actively and passively observing participants; we plan to administer a follow-up questionnaire every 4–5 years—the first follow-up will be completed in 2018—and linkage to cause-of-death and cancer registries occurs on a (bi)annual basis. This prospective cohort offers a unique, large and rich resource for research on contemporary

  6. A Study of Psychological Distress in Two Cohorts of First-Year Medical Students that Underwent Different Admission Selection Processes

    PubMed Central

    Yusoff, Muhamad Saiful Bahri; Rahim, Ahmad Fuad Abdul; Baba, Abdul Aziz; Ismail, Shaiful Bahari; Esa, Ab Rahman

    2012-01-01

    Background: Medical training is often regarded as a stressful period. Studies have previously found that 21.6%–50% of medical students experience significant psychological distress. The present study compared the prevalence and levels of psychological distress between 2 cohorts of first-year medical students that underwent different admission selection processes. Methods: A comparative cross-sectional study was conducted by comparing 2 cohorts of first-year medical students; 1 group (cohort 1) was selected based purely on academic merit (2008/2009 cohort) and the other group (cohort 2) was selected based on academic merit, psychometric assessment, and interview performance (2009/2010 cohort). Their distress levels were measured by the General Health Questionnaire, and scores higher than 3 were considered indicative of significant psychological distress. Results: The prevalence (P = 0.003) and levels (P = 0.001) of psychological distress were significantly different between the 2 cohorts. Cohort 1 had 1.2–3.3 times higher risk of developing psychological distress compared to cohort 2 (P = 0.007). Conclusion: Cohort 2 had better psychological health than cohort 1 and was less likely to develop psychological distress. This study provided evidence of a potential benefit of multimodal student selection based on academic merit, psychometric assessment, and interview performance. This selection process might identify medical students who will maintain better psychological health. PMID:23610547

  7. Satisfaction with social networks: an examination of socioemotional selectivity theory across cohorts.

    PubMed

    Lansford, J E; Sherman, A M; Antonucci, T C

    1998-12-01

    This study examines L. L. Carstensen's (1993, 1995) socioemotional selectivity theory within and across three cohorts spanning 4 decades. Socioemotional selectivity theory predicts that as individuals age, they narrow their social networks to devote more emotional resources to fewer relationships with close friends and family. Data from 3 cohorts of nationally representative samples were analyzed to determine whether respondents' satisfaction with the size of their social networks differed by age, cohort, or both. Results support socioemotional selectivity theory: More older adults than younger adults were satisfied with the current size of their social networks rather than wanting larger networks. These findings are consistent across all cohorts. Results are discussed with respect to social relationships across the life course.

  8. Long-chain n-3 and n-6 polyunsaturated fatty acids and risk of atrial fibrillation: Results from a Danish cohort study.

    PubMed

    Mortensen, Lotte Maxild; Lundbye-Christensen, Søren; Schmidt, Erik Berg; Calder, Philip C; Schierup, Mikkel Heide; Tjønneland, Anne; Parner, Erik T; Overvad, Kim

    2017-01-01

    Studies of the relation between polyunsaturated fatty acids and risk of atrial fibrillation have been inconclusive. The risk of atrial fibrillation may depend on the interaction between n-3 and n-6 polyunsaturated fatty acids as both types of fatty acids are involved in the regulation of systemic inflammation. We investigated the association between dietary intake of long chain polyunsaturated fatty acids (individually and in combination) and the risk of atrial fibrillation with focus on potential interaction between the two types of polyunsaturated fatty acids. The risk of atrial fibrillation in the Diet, Cancer and Health Cohort was analyzed using the pseudo-observation method to explore cumulative risks on an additive scale providing risk differences. Dietary intake of long chain polyunsaturated fatty acids was assessed by food frequency questionnaires. The main analyses were adjusted for the dietary intake of n-3 α-linolenic acid and n-6 linoleic acid to account for endogenous synthesis of long chain polyunsaturated fatty acids. Interaction was assessed as deviation from additivity of absolute association measures (risk differences). Cumulative risks in 15-year age periods were estimated in three strata of the cohort (N = 54,737). No associations between intake of n-3 or n-6 long chain polyunsaturated fatty acids and atrial fibrillation were found, neither when analyzed separately as primary exposures nor when interaction between n-3 and n-6 long chain polyunsaturated fatty acids was explored. This study suggests no association between intake of long chain polyunsaturated fatty acids and risk of atrial fibrillation.

  9. GATA3 rs3824662 gene polymorphism as possible risk factor in a cohort of Egyptian patients with pediatric acute lymphoblastic leukemia and its prognostic impact.

    PubMed

    Mosaad, Youssef M; Elashery, Rasha; Darwish, Ahmad; Sharaf Eldein, Omar A; Barakat, Tarek; Marouf, Samy; Abou El-Khier, Noha T; Youssef, Laila F; Fawzy, Iman M

    2017-03-01

    To investigate the possible role of GATA3 rs3824662 polymorphism as risk factor for the development of acute lymphoblastic leukemia (ALL) in a cohort of Egyptian children and to evaluate its prognostic role. Typing of GATA3 rs3824662 polymorphism was done using real-time PCR for 116 patients with ALL and 273 healthy controls. The A allele and AA genotype were significantly higher in ALL patients (p = .015 and .016, respectively) especially B-ALL (p = .014 and .01, respectively). The AA genotype was associated with shorter disease free survival (DFS) in univariate (p = .017) and multivariate cox regression analysis (p = .028), increased incidence of relapse (p = .008) and poor prognosis (p = .028) in pediatric ALL. The GATA3 rs3824662 A allele and AA genotype may be risk factors for the development of pediatric ALL especially B-ALL in the studied cohort of Egyptian patients. The AA genotype is associated with shorter DSF, increased incidence of relapse and poor prognosis in pediatric ALL.

  10. Plasma Concentrations and Dietary Intakes of Choline and Betaine in Association With Atrial Fibrillation Risk: Results From 3 Prospective Cohorts With Different Health Profiles.

    PubMed

    Zuo, Hui; Svingen, Gard F T; Tell, Grethe S; Ueland, Per M; Vollset, Stein E; Pedersen, Eva R; Ulvik, Arve; Meyer, Klaus; Nordrehaug, Jan E; Nilsen, Dennis W T; Bønaa, Kaare H; Nygård, Ottar

    2018-04-12

    Although choline metabolism has been associated with atherosclerotic heart disease, less research attention has been paid to the associations of choline and its oxidative metabolite betaine with cardiac arrhythmias. We evaluated associations of plasma concentrations and dietary intakes of choline and betaine with long-term atrial fibrillation (AF) risk in a community-based cohort, HUSK ([the Hordaland Health Study] n=6949), and validated the findings in 2 patient cohorts: the Western Norway Coronary Angiography Cohort (n=4164) and the NORVIT (Norwegian B-Vitamin) Trial (n=3733). Information on AF was obtained from the CVDNOR (Cardiovascular Disease in Norway) project. In HUSK, WECAC (Western Norway Coronary Angiography Cohort), and NORVIT, 552, 411, and 663 AF cases were identified during a median follow-up time of 10.9, 7.3, and, 8.7 years, respectively. Plasma concentrations of choline and betaine were significantly positively associated with later AF risk after multivariable adjustments in HUSK. Such associations were independently replicated in the 2 external prospective patient cohorts. The pooled hazard ratio was 1.13 (95% confidence interval 1.08-1.19, P <0.001) and 1.16 (95% confidence interval 1.10-1.22, P <0.001) per SD increment for log-transformed choline and betaine, respectively. Moreover, dietary intake of choline was marginally associated with AF risk (pooled hazard ratio 1.29, 95% confidence interval 1.01-1.66, fifth versus first quintile), whereas no significant association was observed between dietary betaine and AF risk. Our findings indicate that plasma concentrations as well as dietary intake of choline, but not betaine, are associated with subsequent risk of AF, suggesting a potential role of choline metabolism in the pathogenesis of AF. URL: https://www.clinicaltrials.gov.Unique identifier: NCT00671346. © 2018 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.

  11. Pulmonary artery enlargement and cystic fibrosis pulmonary exacerbations: a cohort study

    PubMed Central

    Wells, J. Michael; Farris, Roopan F.; Gosdin, Taylor A.; Dransfield, Mark T.; Wood, Michelle E.; Bell, Scott C.; Rowe, Steven M.

    2017-01-01

    Background Acute pulmonary exacerbations are associated with progressive lung function decline and increased mortality in cystic fibrosis (CF). The role of pulmonary vascular disease in pulmonary exacerbations is unknown. We investigated the association between pulmonary artery enlargement (PA:A>1), a marker of pulmonary vascular disease, and exacerbations. Methods We analyzed clinical, computed tomography (CT), and prospective exacerbation data in a derivation cohort of 74 adult CF patients, measuring the PA:A at the level of the PA bifurcation. We then replicated our findings in a validation cohort of 190 adult CF patients. Patients were separated into groups based on the presence or absence of a PA:A>1 and were followed for 1-year in the derivation cohort and 2-years in the validation cohort. The primary endpoint was developing ≥1 acute pulmonary exacerbation during follow-up. Linear and logistic regression models were used to determine associations between clinical factors, the PA:A ratio, and pulmonary exacerbations. We used Cox regression to determine time to first exacerbation in the validation cohort. Findings We found that PA:A>1 was present in n=37/74 (50%) of the derivation and n=89/190 (47%) of the validation cohort. In the derivation cohort, n=50/74 (68%) had ≥1 exacerbation at 1 year and n=133/190 (70%) in the validation cohort had ≥1 exacerbation after 2 years. PA:A>1 was associated with younger age in both cohorts and with elevated sweat chloride (100.5±10.9 versus 90.4±19.9mmol/L, difference between groups 10.1mmol/L [95%CI 2.5–17.7], P=0.017) in the derivation group. PA:A>1 was associated with exacerbations in the derivation (OR 3.49, 95%CI 1.18–10.3, P=0.023) and validation (OR 2.41, 95%CI 1.06–5.52, P=0.037) cohorts when adjusted for confounders. Time to first exacerbation was shorter in PA:A>1 versus PA:A<1 [HR 1.66 (95%CI 1.18–2.34), P=0.004] in unadjusted analysis, but not when adjusted for sex, BMI, prior exacerbation

  12. Mortality of first world war military personnel: comparison of two military cohorts.

    PubMed

    Wilson, Nick; Clement, Christine; Summers, Jennifer A; Bannister, John; Harper, Glyn

    2014-12-16

    To identify the impact of the first world war on the lifespan of participating military personnel (including in veterans who survived the war). Comparison of two cohorts of military personnel, followed to death. Military personnel leaving New Zealand to participate in the first world war. From a dataset of the New Zealand Expeditionary Forces, we randomly selected participants who embarked on troopships in 1914 and a comparison non-combat cohort who departed on troopships in late 1918 (350 in each group). Lifespan based on dates of birth and death from a range of sources (such as individual military files and an official database of birth and death records). A quarter of the 1914 cohort died during the war, with deaths from injury predominating (94%) over deaths from disease (6%). This cohort had a significantly shorter lifespan than the late 1918 "non-combat" cohort, with median ages of death being 65.9 versus 74.2, respectively (a difference of 8.3 years shown also in Kaplan-Meier survival curves, log rank P<0.001). The difference for the lifespan of veterans in the postwar period was more modest, with median ages of death being 72.6 versus 74.3, respectively (a difference of 1.7 years, log rank P=0.043). There was no evidence for differences between the cohorts in terms of occupational class, based on occupation at enlistment. Military personnel going to the first world war in 1914 from New Zealand lost around eight years of life (relative to a comparable military cohort). In the postwar period they continued to have an increased risk of premature death. © Wilson et al 2014.

  13. Extent of Atypical Hyperplasia Stratifies Breast Cancer Risk in Two Independent Cohorts of Women

    PubMed Central

    Degnim, Amy C.; Dupont, William D.; Radisky, Derek C.; Vierkant, Robert A.; Frank, Ryan D.; Frost, Marlene H.; Winham, Stacey J.; Sanders, Melinda E.; Smith, Jeffrey R.; Page, David L.; Hoskin, Tanya L.; Vachon, Celine M.; Ghosh, Karthik; Hieken, Tina J.; Denison, Lori A.; Carter, Jodi M.; Hartmann, Lynn C.; Visscher, Daniel W.

    2016-01-01

    Background Women with atypical hyperplasia (AH) on breast biopsy have a substantially increased risk of breast cancer (BC). Here we report BC risk with AH extent and subtype in two separate cohorts. Methods All samples containing AH were included from two cohorts of benign breast disease, Mayo Clinic and Nashville. Histology review quantified the number of foci of atypical ductal hyperplasia (ADH) and atypical lobular hyperplasia (ALH). BC risk was stratified for number of AH foci within AH subtypes. Results The study included 708 Mayo and 466 Nashville AH subjects. In the Mayo Cohort, increasing foci of AH was associated with a significant increase in risk of BC, both for ADH (RR’s of 2.61, 5.21, and 6.36 for 1, 2, and 3+ foci, p=0.006 for linear trend) and for ALH (RR’s of 2.56, 3.50, and 6.79 for 1, 2, and 3+ foci, p=0.001 for linear trend). In the Nashville Cohort, RR’s of BC for ADH were 2.70, 5.17, and 15.06 for 1, 2, and 3+ foci respectively (p<0.001 for linear trend); for ALH, RR’s also increased but not significantly (2.61, 3.48, and 4.02, p=0.148). Combining both Mayo and Nashville samples, risk increased significantly for 1, 2, and 3+ foci: RR’s of 2.65, 5.19, and 8.94 for ADH (p<0.001), and 2.58, 3.49, and 4.97 for ALH (p=0.001). Conclusions In two independent cohort studies of benign breast disease, extent of atypia stratifies long-term breast cancer risk for ADH and ALH. PMID:27352219

  14. Birth weight and stuttering: Evidence from three birth cohorts.

    PubMed

    McAllister, Jan; Collier, Jacqueline

    2014-03-01

    Previous studies have produced conflicting results with regard to the association between birth weight and developmental stuttering. This study sought to determine whether birth weight was associated with childhood and/or adolescent stuttering in three British birth cohort samples. Logistic regression analyses were carried out on data from the Millenium Cohort Study (MCS), British Cohort Study (BCS70) and National Child Development Study (NCDS), whose initial cohorts comprised over 56,000 individuals. The outcome variables were parent-reported stuttering in childhood or in adolescence; the predictors, based on prior research, were birth weight, sex, multiple birth status, vocabulary score and mother's level of education. Birth weight was analysed both as a categorical variable (low birth weight, <2500g; normal range; high birth weight, ≥4000g) and as a continuous variable. Separate analyses were carried out to determine the impact of birth weight and the other predictors on stuttering during childhood (age 3, 5 and 7 and MCS, BCS70 and NCDS, respectively) or at age 16, when developmental stuttering is likely to be persistent. None of the multivariate analyses revealed an association between birth weight and parent-reported stuttering. Sex was a significant predictor of stuttering in all the analyses, with males 1.6-3.6 times more likely than females to stutter. Our results suggest that birth weight is not a clinically useful predictor of childhood or persistent stuttering. Copyright © 2013 Elsevier Inc. All rights reserved.

  15. A model of female labor supply in Italy using cohort data.

    PubMed

    Colombino, U; De Stavola, B

    1985-01-01

    This paper develops a behavioral model of Italy's female labor supply using cohort data from 1959 to 1981. Both time-series trends and cross-section patterns by age groups of female participation rates in Italy show rather flat profiles. Using an approximate procedure to obtain an estimate of the relevant wage that is the mean of the wages distribution across the whole female population in a given cohort, results show that the flat time-series profile is presumbly produced by economic incentives effects that counterbalance each other. Interaction terms reveal that cross-section profiles by age group do not reflect steady-state dynamics; aging and the presence of children under 6 are less disincentive to younger cohorts. As is typical of most developed countries, this process implies for Italian female participation the emergence of the bimodal cross-section profile by age groups. In the last 20 years, participation rates for all women decreased slightly during the 1st 10 years and then increased, reaching in 1981 a higher level than in 1961. The dependent variable used in the estimation equation is the ratio between particpant (employed and unemployed) women belonging to a cohort; and the total number of women belonging to a cohort in a given year. Results show that as a cohort increases, the negative effects of age and of children are reduced. The results reveal some main points about rather flat participation rate profiles: 1) a very powerful female wage effect, 2) an equally powerful male wage negative effect, and 3) significant interactions,with a positive sign, between cohort and age and between cohort and children. Moreover, younger cohorts, other things being equal, participate more than older cohorts. This is attributable to the fact that the presence of children under 6 and the aging process are less of a disincentive for them than for older cohorts. Overall, the structure of lifetime participation is changing; younger cohorts participation rates

  16. Associations between social networks and life satisfaction among older Japanese: Does birth cohort make a difference?

    PubMed

    Kobayashi, Erika; Liang, Jersey; Sugawara, Ikuko; Fukaya, Taro; Shinkai, Shoji; Akiyama, Hiroko

    2015-12-01

    Japanese older people experienced drastic changes in family structure and values after World War II at different life stages by birth cohorts. We examined how linkages between different types of social ties and life satisfaction (LS) vary across cohorts, in conjunction with age and survey year differences. Data from face-to-face interviews conducted in 1987, 1999, and 2012 with a nationally representative sample of older Japanese (N = 4,917) were analyzed. The participants were members of 4 birth cohorts (C1: 1901-1912, C2: 1913-1924, C3: 1925-1936, C4: 1937-1949), categorized into 6 groups based on cohort and age at time of measurement (young-old [YO]: 63-74; old-old [OO]: 75-86): C1OO, C2YO, C2OO, C3YO, C3OO, and C4YO. Effects of social networks on LS among the 6 groups were compared simultaneously and separately by gender using the Amos software. There were significant cohort variations in the linkages between family network and LS. The positive association between being married and LS was stronger for later cohorts (C3, C4) among men, whereas that of co-residence with a child and LS was stronger for the earlier cohorts (C1, C2) among women. Moreover, the positive association between meeting with nonfamily members and LS increased from 1987 to 2012 among women, indicating a period effect over a cohort effect. The effects of being married and participation in community groups on LS also changed with age. Our results suggest that linkages between social relations and LS should be interpreted within the context of individual and social changes over time. (c) 2015 APA, all rights reserved).

  17. Age-period-cohort analysis of suicides among Japanese 1950-2003: a Bayesian cohort model analysis.

    PubMed

    Ooe, Yosuke; Ohno, Yuko; Nakamura, Takashi

    2009-07-01

    The suicide rate in Japan is one of the highest in the world and presents us with a considerable challenge. Demographic statistics show that the number of suicides is on the rise, and at roughly 30,000 people per year have committed suicide since 1998. Suicide trends are not only related to economic boom and bust but also to certain generations and age groups. During the 1950s, there was a remarkably high suicide rate among people in their 20s, and this cohort was identical to that of the middle-age generation in the 1980s. It is important to separately understand both the trend of suicide rates and the numbers analyzed to determine the different factors that influence suicide. These include age, time period, cohort, interaction between age and time period, and changes in population composition. We performed an age-period-cohort analysis of annual trends of suicide rates by age group in Japan using a Bayesian cohort model. With the help of the Nakamura method, we have been able to break down the effects of age, time period, cohort, and the age-by-period interaction. The cohort comprised of people born in the 1930s demonstrated a relatively high suicide rate. Men currently in their 50s also belong to a high suicide rate cohort. Regarding the period effect, business cycles and by-period interaction effect, it became apparent that the high suicide rate among young adults in their early 20s around 1960 was slowing, especially among men. Instead, there was an obvious recent trend for men in their late 50s to have the highest suicide rate. This study confirmed that age-period-cohort analysis can describe these trends of suicide mortality of the Japanese.

  18. Returning findings within longitudinal cohort studies: the 1958 birth cohort as an exemplar.

    PubMed

    Wallace, Susan E; Walker, Neil M; Elliott, Jane

    2014-01-01

    Population-based, prospective longitudinal cohort studies are considering the issues surrounding returning findings to individuals as a result of genomic and other medical research studies. While guidance is being developed for clinical settings, the process is less clear for those conducting longitudinal research. This paper discusses work conducted on behalf of The UK Cohort and Longitudinal Study Enhancement Resource programme (CLOSER) to examine consent requirements, process considerations and specific examples of potential findings in the context of the 1958 British Birth cohort. Beyond deciding which findings to return, there are questions of whether re-consent is needed and the possible impact on the study, how the feedback process will be managed, and what resources are needed to support that process. Recommendations are made for actions a cohort study should consider taking when making vital decisions regarding returning findings. Any decisions need to be context-specific, arrived at transparently, communicated clearly, and in the best interests of both the participants and the study.

  19. Serum Fractalkine (CX3CL1) and Cardiovascular Outcomes and Diabetes: Findings From the Chronic Renal Insufficiency Cohort (CRIC) Study.

    PubMed

    Shah, Rachana; Matthews, Gregory J; Shah, Rhia Y; McLaughlin, Catherine; Chen, Jing; Wolman, Melanie; Master, Stephen R; Chai, Boyang; Xie, Dawei; Rader, Daniel J; Raj, Dominic S; Mehta, Nehal N; Budoff, Matthew; Fischer, Michael J; Go, Alan S; Townsend, Raymond R; He, Jiang; Kusek, John W; Feldman, Harold I; Foulkes, Andrea S; Reilly, Muredach P

    2015-08-01

    Cardiometabolic disease is a major cause of morbidity and mortality in persons with chronic kidney disease (CKD). Fractalkine (CX3CL1) is a potential mediator of both atherosclerosis and metabolic disease. Studies of the relationship of CX3CL1 with risk of cardiovascular disease (CVD) events and metabolic traits are lacking, particularly in the high-risk setting of CKD. Cross-sectional and longitudinal observational analysis. Adults with CKD from 7 US sites participating in the Chronic Renal Insufficiency Cohort (CRIC) Study. Quartiles of plasma CX3CL1 levels at baseline. Baseline estimated glomerular filtration rate from a creatinine and cystatin C-based equation, prevalent and incident CVD, diabetes, metabolic syndrome and its criteria, homeostatic model assessment of insulin resistance, hemoglobin A1c level, myocardial infarction, all-cause mortality, and the composite outcome of myocardial infarction/all-cause mortality. Among 3,687 participants, baseline CX3CL1 levels were associated positively with several CVD risk factors and metabolic traits, lower estimated glomerular filtration rate, and higher levels of inflammatory cytokines, as well as prevalent CVD (OR, 1.09; 95% CI, 1.01-1.19; P=0.03). Higher CX3CL1 level also was associated with prevalent diabetes (OR, 1.26; 95% CI, 1.16-1.38; P<0.001) in adjusted models. During a mean follow-up of 6 years, there were 352 deaths, 176 myocardial infarctions, and 484 composite outcomes. In fully adjusted models, 1-SD higher CX3CL1 level increased the hazard for all-cause mortality (1.11; 95% CI, 1.00-1.22; P=0.02) and the composite outcome (1.09; 95% CI, 1.00-1.19; P=0.04). Study design did not allow evaluation of changes over time, correlation with progression of phenotypes, or determination of causality of effect. Circulating CX3CL1 level may contribute to both atherosclerotic CVD and diabetes in a CKD cohort. Further studies are required to establish mechanisms through which CX3CL1 affects the pathogenesis of

  20. Age, time period, and birth cohort differences in self-esteem: Reexamining a cohort-sequential longitudinal study.

    PubMed

    Twenge, Jean M; Carter, Nathan T; Campbell, W Keith

    2017-05-01

    Orth, Trzesniewski, and Robins (2010) concluded that the nationally representative Americans' Changing Lives (ACL) cohort-sequential study demonstrated moderate to large age differences in self-esteem, and no birth cohort (generational) differences in the age trajectory. In a reanalysis of these data using 2 different statistical techniques, we find significant increases in self-esteem that could be attributed to birth cohort or time period. First, hierarchical linear modeling analyses with birth cohort as a continuous variable (vs. the multiple group formulation used by Orth et al.) find that birth cohort has a measurable influence on self-esteem through its interaction with age. Participants born in later years (e.g., 1960) were higher in self-esteem and were more likely to increase in self-esteem as they aged than participants born in earlier years (e.g., 1920). However, the estimated age trajectory up to age 60 is similar in Orth et al.'s results and in the results from our analyses including cohort. Second, comparing ACL respondents of the same age in 1986 versus 2002 (a time-lag design) yields significant birth cohort differences in self-esteem, with 2002 participants of the same age higher in self-esteem than those in 1986. Combined with some previous studies finding significant increases in self-esteem and positive self-views over time, these results suggest that cultural change in the form of cohort and time period cannot be ignored as influences in cross-sectional and longitudinal studies. (PsycINFO Database Record (c) 2017 APA, all rights reserved).

  1. Weight and Veterans' Environments Study (WAVES) I and II: Rationale, Methods, and Cohort Characteristics.

    PubMed

    Zenk, Shannon N; Tarlov, Elizabeth; Powell, Lisa M; Wing, Coady; Matthews, Stephen A; Slater, Sandy; Gordon, Howard S; Berbaum, Michael; Fitzgibbon, Marian L

    2018-03-01

    To present the rationale, methods, and cohort characteristics for 2 complementary "big data" studies of residential environment contributions to body weight, metabolic risk, and weight management program participation and effectiveness. Retrospective cohort. Continental United States. A total of 3 261 115 veterans who received Department of Veterans Affairs (VA) health care in 2009 to 2014, including 169 910 weight management program participants and a propensity score-derived comparison group. The VA MOVE! weight management program, an evidence-based lifestyle intervention. Body mass index, metabolic risk measures, and MOVE! participation; residential environmental attributes (eg, food outlet availability and walkability); and MOVE! program characteristics. Descriptive statistics presented on cohort characteristics and environments where they live. Forty-four percent of men and 42.8% of women were obese, whereas 4.9% of men and 9.9% of women engaged in MOVE!. About half of the cohort had at least 1 supermarket within 1 mile of their home, whereas they averaged close to 4 convenience stores (3.6 for men, 3.9 for women) and 8 fast-food restaurants (7.9 for men, 8.2 for women). Forty-one percent of men and 38.6% of women did not have a park, and 35.5% of men and 31.3% of women did not have a commercial fitness facility within 1 mile. Drawing on a large nationwide cohort residing in diverse environments, these studies are poised to significantly inform policy and weight management program design.

  2. Nonkin in older adults' personal networks: more important among later cohorts?

    PubMed

    Suanet, Bianca; van Tilburg, Theo G; Broese van Groenou, Marjolein I

    2013-07-01

    Research on age-related changes in personal networks has found compelling evidence for socioemotional selectivity theory and exchange theory holding that older adults experience a decline in less emotionally close nonkin relations as they age. However, recent societal developments are likely to have increased the salience of nonkin relations. We hypothesize that age-related decline in the proportion of nonkin in personal networks has been delayed or is slower in late birth cohorts of older adults compared with earlier cohorts. Seven observations by the Longitudinal Aging Study Amsterdam covering a time span of 17 years since 1992 were analyzed using multilevel regression analysis. The sample had 12,949 person-year observations from 3,516 respondents born between 1908 and 1937. Age-related decline in the proportion of nonkin is absent for cohorts born after 1922 and large for cohorts born in 1922 and before. Mediating variables for health and other resources did not explain cohort differences in age-related change. The salience of nonkin relationships is likely to have increased due to societal changes, resulting in absence or delay of decline in later cohorts. The findings raise the need for a reevaluation of old age and the creation of new theoretical perspectives.

  3. Cohort profile: the Western Australian Sleep Health Study.

    PubMed

    Mukherjee, Sutapa; Hillman, David; Lee, Jessica; Fedson, Annette; Simpson, Laila; Ward, Kim; Love, Gregory; Edwards, Cass; Szegner, Bernadett; Palmer, Lyle John

    2012-03-01

    Epidemiologic and genetic studies of obstructive sleep apnoea (OSA) are limited by a lack of large-scale, well-characterized OSA cohorts. These studies require large sample size to provide adequate power to detect differences between groups. This study describes the development of such a cohort (The Western Australian Sleep Health Study) in OSA patients of Caucasian-European origin attending the only public sleep clinic in Western Australia (WA). The main aim of the study is to phenotype 4,000 OSA patients in order to define the genetics of OSA and its co-morbidities. Almost all underwent laboratory-based attended polysomnography (PSG). Currently complete data (questionnaire, biochemistry, DNA, and PSG) has been obtained on over 3,000 individuals and will reach the target of 4,000 individuals by the end of 2010. In a separate but related study, we have developed a sleep study database containing data from all patients who have undergone PSG at the sleep laboratory since its inception in 1988 until the present day (over 30,000 PSG studies representing data from approximately 20,000 individuals). In addition, data from both cohorts have been linked prospectively to statutory health data collected by the WA Department of Health. This study will be the largest sleep clinic cohort database internationally with access to genetic and epidemiological data. It is unique among sleep clinic cohorts because of its size, the breadth of data collected and the ability to link prospectively to statutory health data. It will be a major tool to comprehensively assess genetic and epidemiologic factors determining OSA and its co-morbidities.

  4. Timing of eczema onset and risk of food allergy at 3 years of age: A hospital-based prospective birth cohort study.

    PubMed

    Shoda, Tetsuo; Futamura, Masaki; Yang, Limin; Yamamoto-Hanada, Kiwako; Narita, Masami; Saito, Hirohisa; Ohya, Yukihiro

    2016-11-01

    Although recent studies suggest that eczema in early childhood is important in the development of food allergy, the importance of the timing of eczema onset has not been fully clarified. This study aim to identify an association between the timing of eczema onset and development of food allergy in a prospective birth cohort study. Data were obtained from the Tokyo Children's Health, Illness and Development (T-CHILD) study, which is a hospital-based birth cohort study currently in progress in Japan. A total of 1550 children were born to the recruited women. Outcome data for children were collected from questionnaires completed at 6 months, 1 and 3 years of age. Association between the timing of eczema onset and development of food allergy was estimated by logistic regression analyses. All analysis were performed using SPSS software with a two-sided 5% significance level. Eczema in the first year of life was a significant risk factor in multivariate analysis (aOR 3.90, 95% CI 2.34-6.52, p<0.001). In each age (by month) stratum, infants with onset of eczema within the first 1-2 months after birth had the highest risk of food allergy at 3 years of age (aOR 6.61, 95% CI 3.27-13.34, p<0.001). Infants with early eczema onset (especially within the first 1-4 months after birth) were found to have an increased risk of developing food allergy at 3 years of age. Our findings may contribute to a better understanding of the timing of eczema onset as a potentially modifiable risk factor and to defining those who may need to be on guard for food allergy. Copyright © 2016 Japanese Society for Investigative Dermatology. Published by Elsevier Ireland Ltd. All rights reserved.

  5. International Childhood Cancer Cohort Consortium

    Cancer.gov

    An alliance of several large-scale prospective cohort studies of children to pool data and biospecimens from individual cohorts to study various modifiable and genetic factors in relation to cancer risk

  6. Serum Fractalkine (CX3CL1) and Cardiovascular Outcomes and Diabetes: Findings From the Chronic Renal Insufficiency Cohort (CRIC) Study

    PubMed Central

    Shah, Rachana; Matthews, Gregory J.; Shah, Rhia Y.; McLaughlin, Catherine; Chen, Jing; Wolman, Melanie; Master, Stephen R.; Chai, Boyang; Xie, Dawei; Rader, Daniel J; Raj, Dominic S.; Mehta, Nehal N.; Budoff, Matthew; Fischer, Michael J.; Go, Alan S.; Townsend, Raymond R.; He, Jiang; Kusek, John W.; Feldman, Harold I.; Foulkes, Andrea S.; Reilly, Muredach P.

    2015-01-01

    Background Cardiometabolic disease is a major cause of morbidity and mortality in persons with chronic kidney disease (CKD). Fractalkine (CX3CL1) is a potential mediator of both atherosclerosis and metabolic disease. Studies on the relationship of CX3CL1 with risk of CVD events and metabolic traits are lacking, particularly in the high-risk setting of CKD. Study Design Cross-sectional and longitudinal observational analysis. Setting & Participants Adults with CKD from 7 US sites participating in the Chronic Renal Insufficiency Cohort (CRIC) Study. Predictor Quartiles of plasma CX3CL1 levels at baseline. Outcomes Baseline estimated glomerular filtration rate (eGFR) from a creatinine- and cystatin C–based equation, prevalent and incident CVD, diabetes, metabolic syndrome and its criteria, homeostatic model assessment of insulin resistance, hemoglobin A1C, myocardial infarction, all-cause mortality, and the composite outcome of myocardial infarction/all-cause mortality. Results Among 3687 participants, baseline CX3CL1 levels were positively associated with several CVD risk factors and metabolic traits, lower eGFR, and higher levels of inflammatory cytokines as well as prevalent CVD (OR, 1.09; 95% CI, 1.01–1.19; p=0.03). Higher CX3CL1 was also associated with prevalent diabetes (OR, 1.26; 95% CI, 1.16–1.38; p<0.001) in adjusted models. During a mean follow up of 6 years, there were 352 deaths, 176 myocardial infarctions, and 484 with composite outcomes. In fully-adjusted models, 1-SD higher CX3CL1 increased the hazard for all-cause mortality (1.11; 95% CI, 1.00–1.22; p=0.02) and the composite outcome (1.09; 95% CI, 1.00–1.19; p=0.04). Limitations Study design did not allow evaluation of changes over time, correlation with progression of phenotypes, or determination of causality of effect. Conclusions Circulating CX3CL1 may contribute to both atherosclerotic CVD and diabetes in a CKD cohort. Further studies are required to establish mechanisms through which CX

  7. Cohort profile: effect of malaria in early pregnancy on fetal growth in Benin (RECIPAL preconceptional cohort)

    PubMed Central

    Accrombessi, Manfred; Yovo, Emmanuel; Cottrell, Gilles; Agbota, Gino; Gartner, Agnès; Martin-Prevel, Yves; Fanou-Fogny, Nadia; Djossinou, Diane; Zeitlin, Jennifer; Tuikue-Ndam, Nicaise; Bodeau-Livinec, Florence; Houzé, Sandrine; Jackson, Nicola; Ayemonna, Paul; Massougbodji, Achille; Cot, Michel; Fievet, Nadine; Briand, Valérie

    2018-01-01

    Purpose REtard de Croissance Intra-uterin et PALudisme (RECIPAL) is an original preconceptional cohort designed to assess the consequences of malaria during the first trimester of pregnancy, which is a poorly investigated period in Africa and during which malaria may be detrimental to the fetus. Participants For this purpose, a total of 1214 women of reproductive age living in Sô-Ava and Akassato districts (south Benin) were followed up monthly from June 2014 to December 2016 until 411 of them became pregnant. A large range of health determinants was collected both before and during pregnancy from the first weeks of gestation to delivery. Five Doppler ultrasound scans were performed for early dating of the pregnancy and longitudinal fetal growth assessment. Findings to date Pregnant women were identified at a mean of 6.9 weeks of gestation (wg). Preliminary results confirmed the high prevalence of malaria in the first trimester of pregnancy, with more than 25.4% of women presenting at least one microscopic malarial infection during this period. Most infections occurred before six wg. The prevalence of low birth weight, small birth weight for gestational age (according to INTERGROWTH-21st charts) and preterm birth was 9.3%, 18.3% and 12.6%, respectively. Future plans REtard de Croissance Intra-uterin et PALudisme (RECIPAL) represents at this time a unique resource that will provide information on multiple infectious (including malaria), biological, nutritional and environmental determinants in relation to health outcomes in women of reproductive age, pregnant women and their newborns. It will contribute to better define future recommendations for the prevention of malaria in early pregnancy and maternal malnutrition in Africa. It confirms that it is possible to constitute a preconceptional pregnancy cohort in Africa and provides valuable information for researchers starting cohorts in the future. PMID:29317419

  8. Dementia and vagotomy in Taiwan: a population-based cohort study

    PubMed Central

    Lin, Shih-Yi; Lin, Cheng-Li; Wang, I-Kuan; Lin, Cheng-Chieh; Lin, Chih-Hsueh; Hsu, Wu-Huei

    2018-01-01

    Objective Truncal vagotomy is associated with a decreased risk of subsequent Parkinson disease (PD), although the effect of vagotomy on dementia is unclear. In response, we investigated the risk of dementia in patients who underwent vagotomy. Setting Population-based cohort study. Participants A total of 155 944 patients who underwent vagotomy (vagotomy cohort) and 155 944 age-matched, sex-matched and comorbidity-matched controls (non-vagotomy cohort) were identified between 2000 and 2011. Primary and secondary outcome measures All patient data were tracked until the diagnosis of dementia, death or the end of 2011. The cumulative incidence of subsequent dementia and HRs were calculated. Results The mean ages of the study patients in the vagotomy and non-vagotomy cohorts were 56.6±17.4 and 56.7±17.3 years, respectively. The overall incidence density rate for dementia was similar in the vagotomy and non-vagotomy cohorts (2.43 and 2.84 per 1000 person-years, respectively). After adjustment for age, sex and comorbidities such as diabetes, hypertension, hyperlipidaemia, stroke, depression, coronary artery disease and PD, the patients in the vagotomy cohort were determined to not be at a higher risk of dementia than those in the non-vagotomy cohort (adjusted HR=1.09, 95% CI 0.87 to 1.36). Moreover, the patients who underwent truncal vagotomy were not associated with risk of dementia (adjusted HR=1.04, 95% CI 0.87 to 1.25), compared with the patients who did not undergo vagotomy. Conclusion Vagotomy, either truncal or selective, is not associated with risk of dementia. PMID:29602843

  9. Compression or expansion of disability among two birth cohorts of US adults with diabetes during the past 20 years?

    PubMed Central

    Bardenheier, Barbara H; Lin, Ji; Zhuo, Xiaohui; Ali, Mohammed K; Thompson, Theodore J; Cheng, Yiling J; Gregg, Edward W

    2016-01-01

    Summary Background The life expectancy of the average American with diabetes has increased, but the level of health and functioning of those extra years are not known. Methods Comparing adults aged 50 to 70 with (n=3,027) and without diabetes (n=9,750), we assessed incident disability, remission from disability, and mortality between population-based Cohort 1 (born 1931-1941, followed 1992 to 2002) and Cohort 2 (born 1942-1947, followed 2002 to 2012), from the Health and Retirement Study. Disability was defined by mobility loss, some difficulty with ≥1 instrumental activities of daily living (IADL), and some difficulty with ≥1 activities of daily living (ADL). Age-specific probabilities representing the two birth cohorts in the U.S. were entered into a five-state Markov model to estimate the number of years of disabled and disability-free life by age 70. Findings Among persons with diabetes, compared with Cohort 1(n=1,071), Cohort 2 (n=300) experienced more disability-free and total years of life, later onset of disability, and fewer disabled years lost. Solutions to the simulations of the Markov models suggest that among 50 year old diabetic men this amounted to a 0.8 to 2.3 year delay in disability across the 3 metrics (mobility p=0.01, IADL p=0.24, ADL p=0.01), while living 0.7 to 1.3 years longer (mobility p<0.0001, IADL p=0.001, ADL p<0.0001); results were similar for women. Parallel improvements in disabled life were gained across cohorts of non-diabetic adults (cohort 1 n=9,218; cohort 2 n=2,727), although non-diabetic adults in both cohort 1 and cohort 2 had significantly more disability-free years (e.g., cohort 1: non-diabetic men from age 50: 17.0 vs diabetic men: 13.0; cohort 2: non-diabetic men from age 50: 17.9 vs diabetic men: 14.8) and fewer life years lost (e.g., cohort 1: non-diabetic men from age 50: 1.2 vs diabetic men: 2.8; cohort 2: non-diabetic men from age 50: 0.6 vs diabetic men: 1.5) than diabetic adults within the two cohorts (p< 0

  10. Time trends in cigarette smoking in two German cohorts--results from EPIC Germany.

    PubMed

    Rohrmann, S; Kroke, A; Boeing, H; Becker, N

    2003-08-01

    Smoking prevention is less advanced in Germany compared with other European and North American countries, and fewer data exist, especially on the consumption habits at the individual level over time. EPIC Germany, which is part of a European multicentre study on diet and cancer, collected data on individual smoking behaviour and allows for consideration of the changing consumption pattern for both centres and different age groups. Within EPIC 25 546 and 27 548 participants, respectively, were recruited in Heidelberg and Potsdam. Data on smoking habits were collected by means of a computer-guided interview during the baseline examination between 1994 and 1998. For each birth cohort smoking prevalence and mean number of cigarettes smoked per day at different ages were calculated. Additionally, the prevalence of non-filter cigarette smoking was computed. Smoking prevalence in the 1990s was still higher among men (Heidelberg 16.3-32.3%; Potsdam 18.2-29.3%) than among women (Heidelberg 12.8-32.0%; Potsdam 10.4-27.8%). However, the percentage of women smokers was still increasing. Filter cigarettes comprised a growing percentage of the cigarettes smoked, but especially among men differences between both German cohorts can still be seen: depending on age, 10.0-12.7% of men in the Heidelberg cohort smoked non-filter cigarettes, but only 1.1-2.3% in the Potsdam cohort. The quantity smoked was higher in the Heidelberg than in the Potsdam cohort with respect to the mean number of cigarettes smoked per day as well as the pack-years of smoking. In conclusion, smoking habits in the Potsdam and the Heidelberg cohorts did not strongly differ by smoking prevalence. However, they did differ according to the quantity and quality of smoking. These differences, as well as the changes over the last 40 years may contribute to a changing pattern of diseases in different groups of the German population.

  11. Carpal tunnel syndrome and computer exposure at work in two large complementary cohorts

    PubMed Central

    Mediouni, Z; Bodin, J; Dale, A M; Herquelot, E; Carton, M; Leclerc, A; Fouquet, N; Dumontier, C; Roquelaure, Y; Evanoff, B A; Descatha, A

    2015-01-01

    Objectives The boom in computer use and concurrent high rates in musculoskeletal complaints and carpal tunnel syndrome (CTS) among users have led to a controversy about a possible link. Most studies have used cross-sectional designs and shown no association. The present study used longitudinal data from two large complementary cohorts to evaluate a possible relationship between CTS and the performance of computer work. Settings and participants The Cosali cohort is a representative sample of a French working population that evaluated CTS using standardised clinical examinations and assessed self-reported computer use. The PrediCTS cohort study enrolled newly hired clerical, service and construction workers in several industries in the USA, evaluated CTS using symptoms and nerve conduction studies (NCS), and estimated exposures to computer work using a job exposure matrix. Primary and secondary outcome measures During a follow-up of 3–5 years, the association between new cases of CTS and computer work was calculated using logistic regression models adjusting for sex, age, obesity and relevant associated disorders. Results In the Cosali study, 1551 workers (41.8%) completed follow-up physical examinations; 36 (2.3%) participants were diagnosed with CTS. In the PrediCTS study, 711 workers (64.2%) completed follow-up evaluations, whereas 31 (4.3%) had new cases of CTS. The adjusted OR for the group with the highest exposure to computer use was 0.39 (0.17; 0.89) in the Cosali cohort and 0.16 (0.05; 0.59) in the PrediCTS cohort. Conclusions Data from two large cohorts in two different countries showed no association between computer work and new cases of CTS among workers in diverse jobs with varying job exposures. CTS is far more common among workers in non-computer related jobs; prevention efforts and work-related compensation programmes should focus on workers performing forceful hand exertion. PMID:26353869

  12. Nested Cohort - R software package

    Cancer.gov

    NestedCohort is an R software package for fitting Kaplan-Meier and Cox Models to estimate standardized survival and attributable risks for studies where covariates of interest are observed on only a sample of the cohort.

  13. Allergic rhinitis and associated risk of migraine among children: a nationwide population-based cohort study.

    PubMed

    Wang, I-Chung; Tsai, Jeng-Dau; Lin, Cheng-Li; Shen, Te-Chun; Li, Tsai-Chung; Wei, Chang-Ching

    2016-03-01

    Increased frequency of migraine was reported in adults with allergic rhinitis (AR). Although migraine is less common in children than in adults, it can begin in early childhood and persist into adulthood. We conducted this population-based cohort study to investigate the incidence and subsequent risk of migraine in children with AR. From 2000 to 2007, 461,850 children with recently diagnosed AR and 460,718 non-AR controls were included in the study. By the end of 2008, incidences of migraine in both cohorts, the AR to non-AR cohort hazard ratios (HRs), and confidence intervals (CIs) were measured. The incidence of migraine during the study period was 3.2-fold higher in the AR cohort (95% CI, 2.97 to 3.46) than in the non-AR cohort (11.4 vs 3.49 per 10000 person-years). The risk was greater for boys than for girls, and for children aged <6 years. The HR for migraine in children with AR was 1.44 (95% CI, 1.31 to 1.58) for those with ≤2 annual AR-related medical visits, whereas, 14.8 (95% CI, 13.6 to 16.2) for those with >4 visits (p < 0.0001, the trend test). The risk of migraine development in the AR cohort was highest within the first year after AR diagnosis (HR 4.89; 95% CI, 3.98 to 6.00). Children with AR were more likely to have migraine without aura than migraine with aura. Children with AR had a higher incidence and subsequent risk of migraine. Physicians should be more aware of migraine in children with AR who complain of headache. © 2015 ARS-AAOA, LLC.

  14. The Chinese Children and Families Cohort Study

    PubMed Central

    Potischman, Nancy; Fang, Liwen; Hao, Ling; Bailey, Regan R.; Berrigan, David; Berry, Robert John; Brodie, Alison; Chao, Ann; Chen, Jing; Dodd, Kevin; Feng, Yajing; Ma, Guansheng; He, Yuna; Fan, Jing; Kimlin, Michael; Kitahara, Cari; Linet, Martha; Li, Zhu; Liu, Ailing; Liu, Yashan; Sampson, Joshua; Su, Joseph; Sun, Jiandong; Tasevska, Natasha; Yang, Lichen; Yang, Ruilan; Zhang, Qian; Wang, Ning; Wang, Linhong; Yu, Wang

    2018-01-01

    This article reports the study design, methodological issues and early results of a pilot study testing methods for collecting nutrition, physical activity, and ultraviolet (UV) radiation exposure data in a groundbreaking study in China. Epidemiological studies suggest that exposures across the entire life course, including in utero, early childhood, and adolescence, may be important in the etiology of adult cancers and other chronic diseases. The Chinese Children and Families Cohort Study intends to follow-up subjects from the 1993 to 1995 Community Intervention Program of folic acid supplementation for the prevention of neural tube defects. This cohort is unique in that only folic acid exposure during pregnancy varies between groups as other supplements were not available, and there were nutrient deficiencies in the populations. Prior to launching a large-scale follow-up effort, a pilot study was conducted to assess the feasibility of recontacting original study participants to collect extensive diet, physical activity, and UV radiation exposure data in this population. The pilot study included 92 mothers and 184 adolescent children aged 14 to 17 years from 1 urban and 1 rural Community Intervention Program site. Subjects completed a Food Frequency Questionnaire, a 3-day food record, a physical activity questionnaire, a 3-day sun exposure diary together with 3 days of personal UV dosimetry, and 7 days of pedometry measurements and provided blood, saliva, and toenail samples. Grip strength and body composition measurements were taken, and ambient solar UV radiation was monitored in both study sites. While most of the assessments were successful, future studies would likely require different dietary intake instruments. The purpose of this report is to describe the study design and methodological issues emerging from this pilot work relevant for the follow-up of this large birth cohort. PMID:29930434

  15. A comparison of Cox and logistic regression for use in genome-wide association studies of cohort and case-cohort design.

    PubMed

    Staley, James R; Jones, Edmund; Kaptoge, Stephen; Butterworth, Adam S; Sweeting, Michael J; Wood, Angela M; Howson, Joanna M M

    2017-06-01

    Logistic regression is often used instead of Cox regression to analyse genome-wide association studies (GWAS) of single-nucleotide polymorphisms (SNPs) and disease outcomes with cohort and case-cohort designs, as it is less computationally expensive. Although Cox and logistic regression models have been compared previously in cohort studies, this work does not completely cover the GWAS setting nor extend to the case-cohort study design. Here, we evaluated Cox and logistic regression applied to cohort and case-cohort genetic association studies using simulated data and genetic data from the EPIC-CVD study. In the cohort setting, there was a modest improvement in power to detect SNP-disease associations using Cox regression compared with logistic regression, which increased as the disease incidence increased. In contrast, logistic regression had more power than (Prentice weighted) Cox regression in the case-cohort setting. Logistic regression yielded inflated effect estimates (assuming the hazard ratio is the underlying measure of association) for both study designs, especially for SNPs with greater effect on disease. Given logistic regression is substantially more computationally efficient than Cox regression in both settings, we propose a two-step approach to GWAS in cohort and case-cohort studies. First to analyse all SNPs with logistic regression to identify associated variants below a pre-defined P-value threshold, and second to fit Cox regression (appropriately weighted in case-cohort studies) to those identified SNPs to ensure accurate estimation of association with disease.

  16. Effect of breast-feeding on the development of atopic dermatitis during the first 3 years of life--results from the GINI-birth cohort study.

    PubMed

    Laubereau, Birgit; Brockow, Inken; Zirngibl, Angelika; Koletzko, Sibylle; Gruebl, Armin; von Berg, Andrea; Filipiak-Pittroff, Birgit; Berdel, Dietrich; Bauer, Carl Peter; Reinhardt, Dietrich; Heinrich, Joachim; Wichmann, H-Erich

    2004-05-01

    To investigate if exclusive breast-feeding for 4 months is associated with atopic dermatitis during the first 3 years of life. Data on 3903 children were taken from yearly parental-administered questionnaires from a birth cohort study in Germany (recruited 1995-1998) comprised of a noninterventional (NI) and an interventional (I) subgroup. Outcomes were physician-diagnosed atopic dermatitis (AD) and itchy rash. Multiple logistic regression was performed for the entire cohort and stratified by family history of allergy and by study group adjusting for a fixed set of risk factors for allergies. Exclusive breast-feeding (52 % of children) was not associated with higher risk for AD either in the entire cohort (OR(adj,) 0.95; 95% CI, 0.79-1.14) or if stratified by family history of AD. In the I subgroup, but not in the NI subgroup, exclusive breast-feeding showed a significant protective effect on AD if compared with conventional cow's milk formula (OR(adj), 0.64; 95% CI, 0.45-0.90). These findings do not support the hypothesis that exclusive breast-feeding is a risk factor for development of atopic dermatitis but is protective if compared with conventional cow's milk. Observational studies might not be able to effectively control for selection bias and reverse causation.

  17. Characterization of the anti-factor VIII immunoglobulin profile in patients with hemophilia A by use of a fluorescence-based immunoassay

    PubMed Central

    Boylan, Brian; Rice, Anne S.; Dunn, Amy L.; Tarantino, Michael D.; Brettler, Doreen B.; Barrett, John C.; Miller, Connie H.

    2015-01-01

    Summary Background The development of neutralizing antibodies, referred to as inhibitors, against factor VIII (FVIII) is a major complication associated with FVIII infusion therapy for the treatment of hemophilia A (HA). Previous studies have shown that a subset of HA patients and a low percentage of healthy individuals harbor non-neutralizing anti-FVIII antibodies that do not elicit the clinical manifestations associated with inhibitor development. Objective Assess HA patients' anti-FVIII antibody profiles as potential predictors of clinical outcomes. Methods A fluorescence immunoassay (FLI) was used to detect anti-FVIII antibodies in 491 samples from 371 HA patients. Results Assessments of antibody profiles showed that the presence of anti-FVIII IgG1, IgG2, or IgG4 correlated qualitatively and quantitatively with the presence of a FVIII inhibitor as reported by the Nijmegen-Bethesda assay (NBA). Forty-eight patients with a negative inhibitor history contributed serial samples to the study, including seven patients who had negative NBA titers initially and later converted to NBA-positive. The FLI detected anti-FVIII IgG1 in five of those seven patients prior to their conversion to NBA-positive. Five of 15 serial-sample patients who had a negative inhibitor history and a positive anti-FVIII IgG1 later developed an inhibitor, compared to 2 of 33 patients with a negative inhibitor history without anti-FVIII IgG1. Conclusions These data provide a rationale for future studies designed both to monitor the dynamics of anti-FVIII antibody profiles in HA patients as a potential predictor of future inhibitor development and to assess the value of the anti-FVIII FLI as a supplement to traditional inhibitor testing. PMID:25354263

  18. Analysis of Clinical Cohort Data Using Nested Case-control and Case-cohort Sampling Designs. A Powerful and Economical Tool.

    PubMed

    Ohneberg, K; Wolkewitz, M; Beyersmann, J; Palomar-Martinez, M; Olaechea-Astigarraga, P; Alvarez-Lerma, F; Schumacher, M

    2015-01-01

    Sampling from a large cohort in order to derive a subsample that would be sufficient for statistical analysis is a frequently used method for handling large data sets in epidemiological studies with limited resources for exposure measurement. For clinical studies however, when interest is in the influence of a potential risk factor, cohort studies are often the first choice with all individuals entering the analysis. Our aim is to close the gap between epidemiological and clinical studies with respect to design and power considerations. Schoenfeld's formula for the number of events required for a Cox' proportional hazards model is fundamental. Our objective is to compare the power of analyzing the full cohort and the power of a nested case-control and a case-cohort design. We compare formulas for power for sampling designs and cohort studies. In our data example we simultaneously apply a nested case-control design with a varying number of controls matched to each case, a case cohort design with varying subcohort size, a random subsample and a full cohort analysis. For each design we calculate the standard error for estimated regression coefficients and the mean number of distinct persons, for whom covariate information is required. The formula for the power of a nested case-control design and the power of a case-cohort design is directly connected to the power of a cohort study using the well known Schoenfeld formula. The loss in precision of parameter estimates is relatively small compared to the saving in resources. Nested case-control and case-cohort studies, but not random subsamples yield an attractive alternative for analyzing clinical studies in the situation of a low event rate. Power calculations can be conducted straightforwardly to quantify the loss of power compared to the savings in the num-ber of patients using a sampling design instead of analyzing the full cohort.

  19. Exposure matrix development for the Libby cohort.

    PubMed

    Noonan, C W

    2006-11-01

    The Libby, MT, cohort includes current and former residents with potential historical exposure to asbestos-contaminated vermiculite. This cohort includes individuals with a broad range of exposure experiences and work histories. While both occupational and nonoccupational exposure pathways were found to be relevant in recent investigations of health effects among this cohort, there has not been a comprehensive approach to characterizing these varied exposure pathways. Any approach toward assessing historical exposures among this population must account for three general categories: (1) occupational exposures, (2) residential exposures, and (3) exposures related to a variety of nonoccupational activities thought to be associated with vermiculite/asbestos exposure in this community. First, a job exposure matrix is commonly used in occupational epidemiology to assess historical worker exposures, allowing for the incorporation of numerous occupational categories and weighting factors applied to specific jobs for different time periods. Second, residential exposures can best be quantified by integrating individuals' residential histories with data on environmental asbestos contamination in the community. Previous soil or sediment sampling as well as air modeling could inform estimates of time- and spatial-dependent exposure concentrations for a residential exposure matrix. Finally, exposure opportunities due to nonoccupational activities could be weighted by factors such as time, geography, environmental sampling, and an assessment of the relative importance for each pathway. These three matrices for occupational, residential, and activity exposure pathways could be combined or used separately to provide a more comprehensive and quantitative, or semiquantitative, assessment of individual exposure in future epidemiological studies of this cohort.

  20. Hemophilia

    MedlinePlus

    ... disorders: coagulation factor deficiencies. In: Goldman L, Schafer AI, eds. Goldman-Cecil Medicine . 25th ed. ... Florida Cancer Specialists & Research Institute, Wellington, FL. Review provided by ...