Science.gov

Sample records for hemophilia cohort hgds-3

  1. Hemophilia

    MedlinePlus

    Hemophilia A; Classic hemophilia; Factor VIII deficiency; Hemophilia B; Christmas disease; Factor IX deficiency ... missing or aren't functioning like they should. Hemophilia is caused by the lack of clotting factor ...

  2. Hemophilia

    MedlinePlus

    Hemophilia is a rare disorder in which the blood does not clot normally. It is usually inherited. ... Clotting factor is a protein needed for normal blood clotting. Without it, you may bleed for a ...

  3. Men with severe hemophilia in the United States: birth cohort analysis of a large national database.

    PubMed

    Mazepa, Marshall A; Monahan, Paul E; Baker, Judith R; Riske, Brenda K; Soucie, J Michael

    2016-06-16

    The availability of longitudinal data collected prospectively from 1998 to 2011 at federally funded US hemophilia treatment centers provided an opportunity to construct a descriptive analysis of how outcomes of men with severe hemophilia have been altered by the incremental advances and setbacks in hemophilia care in the last 50 years in the United States. This surveillance collaboration with the US Centers for Disease Control and Prevention assembled the largest uniformly examined population with severe hemophilia (n = 4899 men with severe factor VIII and IX deficiency). To address the heterogeneity of this population, 4 successive birth cohorts, differentially affected by eras of hemophilia care, were examined separately in regard to demographics, complications of hemophilia and its treatment, and mortality. Severely affected men in each birth cohort were compared also with the corresponding mild hemophilia birth cohorts (n = 2587 men total) to control for outcomes that might be attributable to aging and environment independent of severely defective hemostasis. The analysis demonstrates improving access to standard of care therapy, correlating the proportion of men on prophylactic factor replacement and reduced bleeding frequency for the youngest men. Frequent bleeding persisted in one third to one half of men across all ages, however, and the disability gap between severe and mild hemophilia did not narrow. The greatest cause of death was liver failure, but attempted anti-hepatitis C virus therapy and cure were low. The study suggests a continued need for national surveillance to monitor and inform hemophilia interventions and outcomes. PMID:26983851

  4. Men with severe hemophilia in the United States: birth cohort analysis of a large national database

    PubMed Central

    Mazepa, Marshall A.; Baker, Judith R.; Riske, Brenda K.; Soucie, J. Michael

    2016-01-01

    The availability of longitudinal data collected prospectively from 1998 to 2011 at federally funded US hemophilia treatment centers provided an opportunity to construct a descriptive analysis of how outcomes of men with severe hemophilia have been altered by the incremental advances and setbacks in hemophilia care in the last 50 years in the United States. This surveillance collaboration with the US Centers for Disease Control and Prevention assembled the largest uniformly examined population with severe hemophilia (n = 4899 men with severe factor VIII and IX deficiency). To address the heterogeneity of this population, 4 successive birth cohorts, differentially affected by eras of hemophilia care, were examined separately in regard to demographics, complications of hemophilia and its treatment, and mortality. Severely affected men in each birth cohort were compared also with the corresponding mild hemophilia birth cohorts (n = 2587 men total) to control for outcomes that might be attributable to aging and environment independent of severely defective hemostasis. The analysis demonstrates improving access to standard of care therapy, correlating the proportion of men on prophylactic factor replacement and reduced bleeding frequency for the youngest men. Frequent bleeding persisted in one third to one half of men across all ages, however, and the disability gap between severe and mild hemophilia did not narrow. The greatest cause of death was liver failure, but attempted anti–hepatitis C virus therapy and cure were low. The study suggests a continued need for national surveillance to monitor and inform hemophilia interventions and outcomes. PMID:26983851

  5. Hemophilia

    MedlinePlus

    ... Clotting factor is a protein needed for normal blood clotting. Without it, you may bleed for a long ... of hemophilia are excessive bleeding and easy bruising. Blood tests can tell if you have it. The main treatment is injecting the missing clotting factor into the bloodstream. You may need it ...

  6. A Cohort Pilot Study on HIV-Associated Neuropsychological Impairments in Hemophilia Patients

    PubMed Central

    Riva, Silvia; Cutica, Ilaria; Krampe, Caspar; Reinecke, Laura F.; Russell-Edu, William; Santoro, Cristina; Rocino, Angiola; Santagostino, Elena; Rusconi, Vega; Pravettoni, Gabriella

    2015-01-01

    Despite advances in the management of HIV infection with the introduction of combination antiretroviral therapy, it is well known that HIV can directly infect the central nervous system and, as a result of such infection, neuropsychological impairments can be manifested. In this study, we tried to determine whether seropositivity was associated with a poor neuropsychological performance in patients with hemophilia and HIV. Such a cohort of patients is very often underrepresented and understudied in the HIV literature. To amend such a gap, we carried out an extensive neuropsychological evaluation on these patients, and compared their performance with that of a group of seronegative hemophilia patients. The results revealed that HIV infection in HIV-seropositive (HIV+) hemophilia patients was associated with deficits in attention, short-term memory, abstraction, and visual recognition. Such results are still preliminary and explorative due to the small cohort of patients enrolled. However, the results do seem to have some important implications for day-to-day functioning, as the level of impairment detected may cause difficulties in completing common everyday tasks such as maintaining adherence to complex medication regimens or maintaining social life activities. Continued research into the mechanisms related to HIV and neurocognitive dysfunction may provide targets for interventions that could have meaningful consequences in the real world for HIV hemophilia patients. PMID:26082706

  7. Hemophilia - resources

    MedlinePlus

    Resources - hemophilia ... 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.gov/ ...

  8. Hemophilia A

    MedlinePlus

    Factor VIII deficiency; Classic hemophilia; Bleeding disorder - hemophilia A ... When you bleed, a series of reactions take place in the body that helps blood clots form. This process is called the coagulation ...

  9. Hemophilia A

    MedlinePlus

    Genetic counseling may be recommended. Testing can identify women and girls who carry the hemophilia gene. Identify women and girls who carry the hemophilia gene. Testing can be done during pregnancy on a baby in the mother's womb.

  10. Long term survival in persons with hemophilia and chronic hepatitis C: 40 year outcomes of a large single center cohort.

    PubMed

    Eyster, M Elaine; Kong, Lan; Li, Menghan; Schreibman, Ian R

    2016-09-01

    We studied the course of chronic HCV infections in a cohort of 222 persons with hemophilia (PWH) and von Willebrand disease followed at our center since 1973. Twenty two (10%) developed end stage liver disease (ESLD). Forty years after HCV infection, cumulative incidence of ESLD was 12.3% and overall survival was 45.5%. Those who were infected with HCV only (n = 100) had a survival of 75.2%, while those infected with HIV (n = 122) had a survival of 24% (P < 0.001). Survivals were significantly longer for those infected with HCV at younger age (< 15 years) compared to those infected over age 30 years (P = 0.014). Cause specific deaths for ESLD and bleeding were 8.8% and 8.3% respectively. For HIV negative subjects, the annual hazard of death from ESLD and bleeding was near zero for the first 10 years, and then rose slowly over the next 20 years to 0.4/100py for ESLD and 0.2/100py for bleeding. Sixty subjects completed 79 treatment episodes. Sustained viral response rates increased from 7/21 (33%) between 1990 and 2001, to 17/29 (58%) between 2002 and 2011, and to 27/29 (93%), since 2012 with the advent of the directly acting antiviral agents. These results confirm the very slow ESLD progression rate in HIV negative PWH. However, the risk of death from both ESLD and bleeding increases steadily with longer duration of HCV infection. More aggressive surveillance to detect those with early fibrosis is needed now that curative treatment is possible in >95% of individuals. Am. J. Hematol. 91:E335-E340, 2016. © 2016 Wiley Periodicals, Inc. PMID:27214557

  11. Hemophilia Diagnosis

    MedlinePlus

    ... Community Counts Blood Safety Inhibitors Articles & Key Findings Free Materials Videos Starting the Conversation Playing it Safe A Look at Hemophilia Joint Range of Motion My Story Links to Other Websites ...

  12. Hemophilia Facts

    MedlinePlus

    ... Community Counts Blood Safety Inhibitors Articles & Key Findings Free Materials Videos Starting the Conversation Playing it Safe A Look at Hemophilia Joint Range of Motion My Story Links to Other Websites ...

  13. [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. PMID:24290020

  14. Genetics Home Reference: hemophilia

    MedlinePlus

    ... Help Me Understand Genetics Home Health Conditions hemophilia hemophilia Enable Javascript to view the expand/collapse boxes. Print All Open All Close All Description Hemophilia is a bleeding disorder that slows the blood ...

  15. Risk Factors for High-Titer Inhibitor Development in Children with Hemophilia A: Results of a Cohort Study

    PubMed Central

    Heller, Christine; Gutsche, Sven; Holzhauer, Susanne; Kenet, Gili; Kurnik, Karin; Iorio, Alfonso; Nowak-Göttl, Ulrike

    2013-01-01

    Among the discussed risk factors for high-titre inhibitor (HRI) development in patients with hemophilia A (HA) are high dose FVIII replacement therapy and use of recombinant FVIII concentrates (rFVIII). The aim of this study was to evaluate the aforementioned risk factors for HRI development in children with hemophilia A ≤2%. About 288 ascertained PUPs (Israel and Germany) were followed after initial HA diagnosis over 200 exposure days. Inhibitor-free survival, hazard ratios (HR), and 95% confidence intervals (CIs) were calculated. Adjustment was performed for factor VIII concentrates, median single dose over the first three months of treatment, first FVIII administration before the age of three months, presence of risk HA gene mutations, “intensive treatment moments” and “year of birth” (proxy for different treatment periods). HRI occurred in 71/288 children (24.7%). In multivariate analysis adjusted for “year of birth”, underlying risk gene mutations (HR/CI: 2.37/1.40–3.99), FVIII dose, measured per one IU increase per kgbw (HR/CI: 1.05/1.04–1.07), and first FVIII administration before the age of three months showed a significant impact on HR development. The risk of HRI development was similar for recombinant or plasmatic FVIII products. Children at risk should be treated with carefully calculated lower dose regimens, adapted to individual bleeding situations. PMID:24199202

  16. Incidence and survival of cancers among 1,054 hemophilia patients: A nationwide and 14-year cohort study.

    PubMed

    Huang, Yung-Chieh; Tsan, Yu-Tse; Chan, Wei-Cheng; Wang, Jiaan-Der; Chu, Wei-Min; Fu, Yun-Ching; Tong, Kwok-Man; Lin, Ching-Heng; Chang, Shin-Tsu; Hwang, Wen-Li

    2015-04-01

    As life expectancy increases in persons with hemophilia (PWH), more age-related diseases such as cancer emerge among this patient group. The aim of this study was to investigate incidence and survival of cancers among PWH in Taiwan. We analyzed data of 1,054 PWH retrieved from Taiwan's National Health Insurance Research Database between 1997 and 2010, by comparing variables to 10540 age- and gender-matched healthy individuals from the general population. There were 43 PWH and 178 individuals of general population with newly diagnosed cancer (RR 2.42, 95% CI 1.74-3.35). The cumulative incidences of cancer in PWH and the general population were 4.7 and 1.9%, respectively. Hepatocellular carcinoma (HCC) was the major type of cancer (17 cases) in PWH; cancer rate was still increased when HCC and HIV-related cancers were excluded (RR 1.66, 95% CI 1.06-2.59). There was no significant difference observed in lung, colorectal, or prostate cancer occurrence. Compared to the general population, PWH were younger at the time of cancer diagnosis (45.1 vs. 57.2 years old, P value < 0.001), and had fewer co-morbidities. Nineteen PWH with cancers died during the study period, and no bleeding-related death was recorded among these patients. The survival rate was not different between PWH and the general population, P = 0.86. In conclusion, the cumulative incidence of cancer among PWH was higher than the general population. PWH with cancer were younger and had fewer comorbidities, but the survival rates were similar in the two groups. PMID:25639564

  17. What Causes Hemophilia?

    MedlinePlus

    ... chromosomes, while males have one X and one Y chromosome. Only the X chromosome carries the genes related ... have hemophilia (that is, he has two normal chromosomes—X and Y). The mother is a carrier of hemophilia (that ...

  18. Hemophilia (For Teens)

    MedlinePlus

    ... very common, mostly affects guys. In rare cases, girls can have the disease and get bleeding problems ... have a 50% chance of having hemophilia. Although girls rarely develop the symptoms of hemophilia itself, they ...

  19. Frequently Asked Questions: Hemophilia

    MedlinePlus

    ... clotting factor deficiencies , and inherited platelet disorders . How serious is hemophilia? The severity of hemophilia depends on ... Pictures Young Voices Compendium of Assessment Tools Educational Games Video Library Find a Treatment Centre Haemophilia Journal ...

  20. How Is Hemophilia Diagnosed?

    MedlinePlus

    ... page from the NHLBI on Twitter. How Is Hemophilia Diagnosed? If you or your child appears to ... have bleeding problems. However, some people who have hemophilia have no recent family history of the disease. ...

  1. What is Hemophilia?

    MedlinePlus

    ... page from the NHLBI on Twitter. What Is Hemophilia? Español Hemophilia (heem-o-FILL-ee-ah) is a rare ... blood doesn't clot normally. If you have hemophilia, you may bleed for a longer time than ...

  2. Uptake of Genetic Counseling, Knowledge of Bleeding risks and Psychosocial Impact in a South African Cohort of Female Relatives of People with Hemophilia.

    PubMed

    Gillham, Anne; Greyling, Brenda; Wessels, Tina-Marie; Mbele, Bongi; Schwyzer, Rosemarie; Krause, Amanda; Mahlangu, Johnny

    2015-12-01

    In excess of 200 people with hemophilia (PWH) and their families have received genetic counseling (GC) at the Hemophilia Comprehensive Care Centre at Charlotte Maxeke Johannesburg Academic Hospital. However, very few of their at-risk female relatives have attended GC to discuss their reproductive risks and options, or their potential bleeding risks. Limited research has been conducted internationally on factors influencing uptake of GC and testing amongst female relatives of PWH. This prospective study aimed to explore the factors that influence the uptake of GC and testing by female relatives of PWH. An open-ended semi-structured interview schedule was developed. Participants included female relatives of PWH who at least had a family member who had received GC. Seventeen participants were interviewed; 7 who had GC previously and 10 who had not. All participants who had previously received GC found the service helpful and were mothers referred because their sons had hemophilia. Of those who had not had GC, possible deterrents included: being unaware of GC service, focus in clinic on PWH and not potential carriers, misunderstood risks related to hemophilia and carrier status, fear of finding out carrier status, and non-disclosure in families. Most participants were unaware of potential bleeding risks for carriers. The information will be used to provide a better service to female relatives of PWH with a goal being to set up a dedicated hemophilia carrier clinic. PMID:25828422

  3. How to Deal with Hemophilia

    MedlinePlus

    ... Hemophilia is considered a good test for gene therapy because it is caused by only one defective gene. It could ... Kids With Hemophilia Can Stay Healthy Life for a kid with hemophilia is much like ...

  4. Comprehensive care in hemophilia.

    PubMed

    Ruiz-Sáez, Arlette

    2012-04-01

    Hemophilia is a chronic and inherited X-linked bleeding disorder that requires life-long medical care. Hemophilia treatment is costly and complex partly because of the cost of the factor concentrates used in replacement therapy. However, the management of hemophilia is not based solely on achieving access to better treatment with safe factor concentrates; it also includes accurately diagnosing the disorder and providing specialized comprehensive care by a multidisciplinary team of specialists trained in hemophilia management. Comprehensive care for the person with hemophilia is defined as the continuous supervision of all medical and psychological aspects affecting the patient and his family and it demands the establishment of specialized centers, called Hemophilia Treatment Centers. The services that should be offered by a comprehensive hemophilia healthcare center are diverse and the multidisciplinary team should be coordinated preferably by a hematologist with the participation of other health professionals. It has been demonstrated that the benefits of establishing hemophilia centers are observed even in developing countries and that changes can be achieved when resources are re-organized, especially when education and training are provided at all levels. To reach these objectives, it is essential to have the participation of the patient and family members, and to strive to obtain the financial and legislative support from the State or Government in order to achieve a national comprehensive care program contemplating all the aspects needed for improving the quality of life for the community of patients with hemophilia and other bleeding disorders. PMID:22507803

  5. 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

  6. How Is Hemophilia Treated?

    MedlinePlus

    ... Intramural Research Research Resources Research Meeting Summaries Technology Transfer Clinical Trials What Are Clinical Trials? Children & Clinical ... Treating donated blood products with a detergent and heat to destroy viruses Vaccinating people who have hemophilia ...

  7. Hemophilia Data and Statistics

    MedlinePlus

    ... Community Counts Blood Safety Inhibitors Articles & Key Findings Free Materials Videos Starting the Conversation Playing it Safe A Look at Hemophilia Joint Range of Motion My Story Links to Other Websites ...

  8. Hemophilia (For Parents)

    MedlinePlus

    ... to treat. There is also a medicine called recombinant factor VII that can help prevent the body ... treating children with hemophilia. For example, when giving immunization shots that are normally given in the muscle, ...

  9. Hemophilia during pregnancy.

    PubMed Central

    Goldman, Ran D.; Blanchette, Victor; Koren, Gideon

    2003-01-01

    QUESTION: A patient in my clinic, who is 10 weeks into her first pregnancy and is a known carrier of hemophilia B, is considering the advantages and disadvantages of antenatal tests and is especially worried about a vaginal delivery thatmight cause bleeding. How should I manage her pregnancy? ANSWER: Many female carriers of hemophilia were found to have lower-than-expected levels of plasma factors, which are thought to be due to X chromosome inactivation. Chorionic villous sampling is the preferred test to determine the sex of the fetus and whether a male infant is affected with hemophilia. Vaginal delivery is not contraindicated and has been proven during the last two decades to be as safe as cesarean section. Vacuum extraction should be avoided to minimize risk of intracranial hemolysis and severe cephalhematoma. PMID:14708924

  10. 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)

  11. [Hemophilia B replacement therapy drugs].

    PubMed

    Yan, Hong; Zeng, Fanyi

    2016-02-01

    Hemophilia B is an X chromosome linked hereditary hemorrhagic disease, which is caused by the lose function mutation of factor IX (FIX), and significantly affects the patients' lifespan and life quality. The severity of hemophilia B depends on the FIX level in the plasma. By referring to the relevant literatures, we reviewed and summarized hemophilia B replacement therapies. Specifically, we focus on recombinant factor IX products on the market and those in the pipeline, especially on the long-acting factor IX drugs, to provide the basis for researches of new hemophilia B drugs. PMID:27382766

  12. Muscle Gene Therapy for Hemophilia

    PubMed Central

    Sabatino, Denise E.; Arruda, Valder R.

    2013-01-01

    Muscle-directed gene therapy for hemophilia is an attractive strategy for expression of therapeutic levels of clotting factor as evident from preclinical studies and an early phase clinical trial. Notably, local FIX expression by AAV-mediated direct intramuscular injection to skeletal muscle persists for years. Development of intravascular delivery of AAV vector approaches to skeletal muscle resulted in vector in widespread areas of the limb and increased expression of FIX in hemophilia B dogs. The use of FIX variants with improved biological activity may provide the opportunity to increase the efficacy of these approaches. Studies for hemophilia A are less developed at this point, but utilizing transgenes that improve hemostasis independent of FIX and FVIII has potential therapeutic application for both hemophilia A and B. Continuous monitoring of humoral and T cell responses to the transgene and AAV capsid in human trials will be critical for the translation of these promising approaches for muscle gene therapy for hemophilia. PMID:24883231

  13. 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. PMID:26619192

  14. Myositis ossificans in hemophilia

    SciTech Connect

    Vas, W.; Cockshott, W.P.; Martin, R.F.; Pai, M.K.; Walker, I.

    1981-10-01

    A review of the radiographs of 60 hemophilia patients showed nine (15%) with ectopic new bone formation. Three of these patients had multiple sites of involvement. The high frequency discovered in this series contrasts with the paucity of descriptions to be found in the literature. This process of myositis ossificans affects the lower half of the body and probably represents dysplastic metaplasia developing at the site of an intramuscular hematoma when remote from bone, as well as ossification of hemorrhagic lesions related to the periosteum. In conventional radiographs anatomic localization of bone foci is difficult, but use of computed tomography permits precise identification of the affected muscle. There is negligible disability associated with this condition.

  15. Iron studies in hemophilia

    SciTech Connect

    Lottenberg, R.; Kitchens, C.S.; Roessler, G.S.; Noyes, W.D.

    1981-12-01

    Although iron deficiency is not recognized as a usual complication of hemophilia, we questioned whether intermittent occult loss of blood in urine or stool might predispose hemophiliacs to chronic iron deficiency. Seven men with factor VII and one with factor IX deficiency were studied. Blood studied, bone marrow aspirates, urine and stool samples, and ferrokinetics with total-body counting up to five months were examined. These data showed no excessive loss of blood during the study period; however, marrow iron stores were decidedly decreased, being absent in four subjects. We suggest that in some hemophiliacs, iron deposits in tissues such as synovial membranes may form a high proportion of the body's total iron stores.

  16. Adenoviral Vectors for Hemophilia Gene Therapy

    PubMed Central

    Brunetti-Pierri, N; Ng, Philip

    2013-01-01

    Hemophilia is an inherited blood clotting disorder resulting from deficiency of blood coagulation factors. Current standard of care for hemophilia patients is frequent intravenous infusions of the missing coagulation factor. Gene therapy for hemophilia involves the introduction of a normal copy of the deficient coagulation factor gene thereby potentially offering a definitive cure for the bleeding disorder. A variety of approaches have been pursued for hemophilia gene therapy and this review article focuses on those that use adenoviral vectors. PMID:24883229

  17. Use of factor IX concentrates in active teenagers with hemophilia B.

    PubMed

    Tagariello, Giuseppe

    2004-06-01

    This paper addresses issues specific to the treatment of teenagers with hemophilia B. All teenagers, including those with hemophilia, are at high risk of being exposed to accident-related trauma because of activities inherent within normal adolescent development. To reduce the impact of recurrent joint bleeds, studies have shown that prophylaxis should be started at an early age, with treatment individualized due to variability in patient pharmacokinetics and product recoveries. A key factor in the acceptance and success of prophylaxis in teenagers is the training given at hemophilia treatment centers regarding self-treatment dosing and infusion schedules. Both plasma-derived and recombinant products are appropriate in this cohort, depending on the patient's and family's experiences and preferences. PMID:15322451

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

    PubMed Central

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

    2016-01-01

    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. PMID:26494839

  19. Acquired hemophilia masked by warfarin therapy.

    PubMed

    Kantor, R; Mayan, H; Puritz, L; Varon, D; Farfel, Z

    2000-03-01

    People without hemophilia but with autoantibodies specifically directed against the procoagulant activity of factor VIII are known to have acquired hemophilia. The bleeding diathesis in these patients is often severe and life-threatening. The definite laboratory diagnosis of this disorder includes demonstration of low factor VIII levels in plasma with a high titer of factor VIII inhibitors, but the initial suspicion for its presence should rise in view of a prolonged partial thromboblastin time (PTT) and a normal prothrombin time associated with an acquired bleeding disorder. Oral anticoagulant treatment is known to prolong PTT as well, and the merger of these 2 situations may cause delayed diagnosis of acquired hemophilia with devastating consequences. We describe here the first reported case of acquired hemophilia diagnosed in a patient treated with warfarin. In such patients prolonged PTT may be ascribed to warfarin therapy rather than to acquired hemophilia, thus causing a dangerous delay in diagnosis. PMID:10746834

  20. 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

  1. Hemophilia B: Molecular Pathogenesis and Mutation Analysis

    PubMed Central

    Goodeve, Anne C.

    2015-01-01

    Summary Hemophilia B is an X-chromosome-linked inherited bleeding disorder primarily affecting males, while those carrier females having reduced factor IX:C levels may also experience some bleeding issues. Genetic analysis has been undertaken for hemophilia B since the mid-1980s, both through linkage analysis to track inheritance of an affected allele and to enable determination of the familial mutation. Mutation analysis using PCR and Sanger sequencing along with dosage analysis for detection of large deletions/duplications enables mutation detection in more than 97% of hemophila B patients. Risk of inhibitory antibodies, reported in ~2% of hemophilia B patients can be predicted, especially in patients with large deletions and these individuals are also at risk of anaphylaxis, and nephrotic syndrome if they receive immune tolerance induction. Inhibitors also occur in patients with nonsense mutations, occasionally with small insertions/deletions, splice mutations and rarely with missense mutations (p.Gln237Lys and p.Gln241His). Hemophilia B results from several different mechanisms and those associated with hemophilia B Leyden, ribosome readthrough of nonsense mutations and apparently "silent" changes that do not alter amino acid coding are explored. Large databases of genetic variants in healthy individuals and patients with a range of disorders including hemophilia B are yielding useful information on sequence variant frequency to help establish possible variant pathogenicity whilst a growing range of algorithms is available to help predict pathogenicity for previously unreported variants. PMID:25851415

  2. 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. PMID:25703518

  3. Gene therapy for hemophilia B mice with scAAV8-LP1-hFIX.

    PubMed

    Lu, Wei; Zhou, Qingzhang; Yang, Hao; Wang, Hao; Gu, Yexing; Shen, Qi; Xue, Jinglun; Dong, Xiaoyan; Chen, Jinzhong

    2016-06-01

    Hemophilia B is a hemorrhagic disease caused by the deficiency of clotting factor IX (FIX). Gene therapy might be the ultimate strategy for the disease. However, two main problems that should be solved in gene therapy for hemophilia B are immunity and safety. Self-complementary adeno-associated virus serotype 8 (scAAV8), a non-human primate AAV featuring low immunogenicity and high transfection efficiency in liver cells, might be a potential vector for hemophilia B gene therapy. A strong liver-specific promoter-1 (LP1) was inserted and mutant human FIX Arg338Ala was introduced into plasmid scAAV8-LP1 to develop an optimized AAV8 vector that expresses human clotting factor FIX (hFIX). The efficiency of scAAV8-LP1-hFIX administered through normal systemic injection or hydrodynamic injection was compared. A high expression was achieved using hydrodynamic injection, and the peak hFIX expression levels in the 5 × 10(11) and 1 × 10(11) virus genome (vg) cohorts were 31.94% and 25.02% of normal level, respectively, at 60 days post-injection. From the perspective of long-term (200 days) expression, both injection methods presented promising results with the concentration value maintained above 4% of normal plasma. The results were further verified by enzyme-linked immunosorbent assay and activated partial thromboplastin time. Our study provides a potential gene therapy method for hemophilia B. PMID:27052253

  4. 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…

  5. 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…

  6. What Are the Signs and Symptoms of Hemophilia?

    MedlinePlus

    ... from the NHLBI on Twitter. What Are the Signs and Symptoms of Hemophilia? The major signs and symptoms of hemophilia are excessive bleeding and ... Children who have mild hemophilia may not have signs unless they have excessive bleeding from a dental ...

  7. Hemophilia A: Dental considerations and management

    PubMed Central

    Shastry, Shilpa Padar; Kaul, Rachna; Baroudi, Kusai; Umar, Dilshad

    2014-01-01

    Aim: To review hemophilia A with emphasis on its oral manifestations, investigations, and dental management. Materials and Methods: Search was conducted using internet-based search engines, scholarly bibliographic databases, PubMed, and Medline with key words such as “Hemophilia A,” “factor VIII,” “bleeding and clotting disorders,” and “dental management.” Results: Hemophilia comprises a group of hereditary disorders caused due to the deficiency of one or more clotting factors leading to prolonged clotting time and excessive bleeding tendencies. It is broadly divided into hemophilia A, B, and C, which occur due to deficiency of factor VIII, IX, and XI, respectively. Hemophilia A is an X-linked recessive hereditary disorder and is the most common of the three, accounting for 80–85% of the cases. Conclusion: Understanding this complex entity is very important for a dentist to provide appropriate dental treatment and avoid undesirable consequences. PMID:25625071

  8. Oral pyogenic granuloma in hemophilia: a report of 2 cases.

    PubMed

    Lindsay, Holly; Srivaths, Lakshmi V

    2014-07-01

    Pyogenic granulomas (PGs) are benign vascular lesions occurring in skin and mucous membranes, often secondary to trauma or chronic inflammation. Oral PGs have never been described previously in hemophilia. We describe 2 pediatric patients with hemophilia A, who developed PGs with inadequate factor therapy for bleeding. PG pathophysiology suggests an association with hemophilia given chronic vascular damage and low-grade inflammation at sites of bleeding in hemophilia patients. Knowledge about the occurrence of PGs in hemophilia patients is essential for prompt diagnosis and early institution of factor therapy, which in turn allows more rapid cessation of bleeding and lesion involution. PMID:24663071

  9. Sports and hemophilia: antagonist or protagonist.

    PubMed

    Buzzard, B M

    1996-07-01

    Until recent years the life for the person with hemophilia was dictated by the severity and frequency of bleeding episodes. Those with hemophilia tended to be overprotected and not allowed to participate in sporting activities normal to their peer group. The past 2 decades has seen a dramatic change in attitudes, mainly due to the introduction of factor replacement, home therapy, and comprehensive care programs. Those involved in the care of people with hemophilia now recognize that sport and exercise can reduce or prevent intraarticular hemorrhages. The arguments for and against sport as described in the literature from 1960 to 1990 are reviewed. Swimming, golf, and table tennis were recommended by doctors, whereas most contact sports, including football, were discouraged. The move toward more active pursuits brings with it an increase in sporting injuries, which is addressed in this article, but more importantly the prevention of injuries is highlighted. PMID:8653965

  10. 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

  11. Chronic immune thrombocytopenic purpura in hemophilia A.

    PubMed Central

    Reen, B. S.; Card, R. T.; McSheffrey, J. B.; Skinnider, L. F.

    1983-01-01

    Chronic immune thrombocytopenic purpura resistant to steroid therapy occurred in a 30-year-old patient with severe hemophilia A. This association has recently been reported in other patients, and a possible relation to the acquired immune deficiency syndrome (AIDS) has been suggested. Although this patient had been treated with factor VIII concentrate for 4 years, the proportions of helper and suppressor T cells were normal, and there was no evidence of AIDS. An uncomplicated splenectomy gave excellent results. All patients with hemophilia should have their platelet counts monitored closely and should report any unusual pattern of bleeding. PMID:6686949

  12. A natural choice for hemophilia B.

    PubMed

    Koeberl, Dwight D

    2015-03-01

    In this issue of Blood, Crudele et al describe a novel study of adeno-associated virus (AAV) vector-mediated gene therapy that induced immune tolerance to factor IX (FIX) in a hemophilia B (HB) dog with previously formed anti-FIX inhibitor antibodies (IAs). PMID:25745178

  13. 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…

  14. 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)

  15. Cost–utility analysis of prophylaxis versus treatment on demand in severe hemophilia A

    PubMed Central

    Colombo, Giorgio L; Di Matteo, Sergio; Mancuso, Maria Elisa; Santagostino, Elena

    2011-01-01

    Background: Individuals with severe hemophilia A have reduced blood levels of clotting factor VIII (FVIII) leading to recurrent bleeding into joints and muscles. Primary prophylaxis with clotting factor concentrates started early in childhood prevents joint bleeds, thus avoiding joint damage and improving people’s quality of life. There remain significant differences in the implementation of primary prophylaxis worldwide mainly due to the cost of prophylaxis compared with treatment on demand. Objective: To evaluate the cost-effectiveness of primary prophylaxis with FVIII concentrates versus secondary prophylaxis, versus treatment on demand, and versus a “hybrid” (primary prophylaxis followed by on-demand treatment in adults) in individuals with severe hemophilia A. Methods: A Markov model was developed and run using different sources of clinical, cost, and utility data. The model was populated with a hypothetical cohort of 100 individuals with severe hemophilia A. The perspective of the Italian National Health System was used. Results: The baseline results showed that primary and secondary prophylaxis is cost-effective compared both with treatment on demand and with a hybrid strategy. The incremental costs per quality-adjusted life-year gained for individuals with hemophilia A receiving primary and secondary prophylaxis were €40,229 to €40,236 versus an on-demand strategy. However, the sensitivity analyses performed showed that the results were sensitive to the unit cost of clotting FVIII, bleeding frequency, and the discount rate. Conclusion: Although primary prophylaxis is a costly treatment, our results show that it is cost-effective compared with treatment on demand. PMID:21935333

  16. Emerging and future therapies for hemophilia

    PubMed Central

    Carr, Marcus E; Tortella, Bartholomew J

    2015-01-01

    The evolution of care in hemophilia is a remarkable story. Over the last 60 years, advances in protein purification, protein chemistry, donor screening, viral inactivation, gene sequencing, gene cloning, and recombinant protein production have dramatically enhanced the treatment and lives of patients with hemophilia. Recent efforts have produced enhanced half-life (EHL) clotting factors to better support prophylaxis and decrease the frequency of infusions. Medical needs remain in the areas of alternate modes of administration to decrease the need for venous access, better treatment, and prophylaxis for patients who form antibodies to clotting factors, and ultimately a cure of the underlying genetic defect. In this brief review, the authors summarize data on EHL clotting factors, introduce agents whose mode of action is not clotting factor replacement, and list current gene therapy efforts. PMID:26366108

  17. 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…

  18. 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.…

  19. Molecular approaches for improved clotting factors for hemophilia

    PubMed Central

    Powell, Jerry S.

    2013-01-01

    Hemophilia is caused by a functional deficiency of one of the coagulation proteins. Therapy for no other group of genetic diseases has seen the progress that has been made for hemophilia over the past 40 years, from a life expectancy in 1970 of ∼20 years for a boy born with severe hemophilia to essentially a normal life expectancy in 2013 with current prophylaxis therapy. However, these therapies are expensive and require IV infusions 3 to 4 times each week. These are exciting times for hemophilia because several new technologies that promise extended half-lives for factor products, with potential for improvements in quality of life for persons with hemophilia, are in late-phase clinical development. PMID:24065241

  20. FEIBA versus NovoSeven in hemophilia patients with inhibitors.

    PubMed

    Franchini, Massimo; Coppola, Antonio; Tagliaferri, Annarita; Lippi, Giuseppe

    2013-10-01

    The management of patients with congenital hemophilia who develop alloantibodies that neutralize coagulation factor activity is the most important challenge for hemophilia care providers because this complication renders replacement treatment with factor concentrates partially or completely ineffective, exposing the patients to an increased risk of morbidity and mortality. Development of inhibitors complicates the clinical course of severe hemophilia in up to 30% of patients with hemophilia A and up to 5% of those with hemophilia B. Although the ultimate goal of treatment of patients with alloantibodies against factors VIII and IX is eradication of the inhibitor, the control of bleeding through high doses of factor concentrates (low titer inhibitors) or bypassing agents (high titer inhibitors) is the mainstay of management of these patients. In this review, we summarize the main characteristics of the bypassing agents FEIBA and NovoSeven, briefly discussing available literature data, and in particular, focusing on comparative studies. PMID:24014071

  1. Gene therapy for hemophilia: past, present and future.

    PubMed

    George, Lindsey A; Fogarty, Patrick F

    2016-01-01

    After numerous preclinical studies demonstrated consistent success in large and small animal models, gene therapy has finally seen initial signs of clinically meaningful success. In a landmark study, Nathwani and colleagues reported sustained factor (F)IX expression in individuals with severe hemophilia B following adeno-associated virus (AAV)-mediated in vivo FIX gene transfer. As the next possible treatment-changing paradigm in hemophilia care, gene therapy may provide patients with sufficient hemostatic improvement to achieve the World Federation of Hemophilia's aspirational goal of "integration of opportunities in all aspects of life… equivalent to someone without a bleeding disorder." Although promising momentum supports the potential of gene therapy to replace protein-based therapeutics for hemophilia, several obstacles remain. The largest challenges appear to be overcoming the cellular immune responses to the AAV capsid; preexisting AAV neutralizing antibodies, which immediately exclude approximately 50% of the target population; and the ability to scale-up vector manufacturing for widespread applicability. Additional obstacles specific to hemophilia A (HA) include designing a vector cassette to accommodate a larger cDNA; avoiding development of inhibitory antibodies; and, perhaps the greatest difficulty to overcome, ensuring adequate expression efficiency. This review discusses the relevance of gene therapy to the hemophilia disease state, previous research progress, the current landscape of clinical trials, and considerations for promoting the future availability of gene therapy for hemophilia. PMID:26805907

  2. Utilization Patterns of Coagulation Factor Consumption for Patients with Hemophilia.

    PubMed

    Lee, Soo Ok; Yu, Su-Yeon

    2016-01-01

    Hemophilia is a serious rare disease that requires continuous management and treatment for which the medicine is costly at the annual average of 100 million KRW for an individual. The aim of this study was to investigate trends in the utilization of coagulation factor (CF) used for hemophilia treatment using the National Health Insurance database from 2010 to 2013 in Korea and compare the utilization of CF with other countries. The consumption of CF per capita (IU) in Korea was not more than other countries with similar income to Korea. However, CF usage per patient IU was higher because the prevalence rate of hemophilia in Korea was lower than in other countries while the number of serious patients was much more. Therefore, it is difficult to say that the consumption of hemophilia medicine in Korea is higher than that in other countries. The consumption and cost of hemophilia medicine in Korea is likely to increase due to the increased utilization of expensive bypassing agents and the widespread use of prophylaxis for severe hemophilia. Even during the research period, it increased slightly and other countries show a similar trend. Thus, hemophilia patient management should accompany active monitoring on the health and cost outcomes of pharmaceutical treatment in the future. This study is expected to contribute to further insight into drug policies for other countries that face similar challenges with high price pharmaceuticals. PMID:26770035

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

    PubMed Central

    Monahan, P. E.

    2016-01-01

    Summary 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. PMID:26149016

  4. 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. PMID:26149016

  5. 2 New Findings Offer Hope for Those with Severe Hemophilia

    MedlinePlus

    ... nih.gov/medlineplus/news/fullstory_159027.html 2 New Findings Offer Hope for Those With Severe Hemophilia ... while the other uncovers the promise of a new drug To use the sharing features on this ...

  6. 2 New Findings Offer Hope for Those with Severe Hemophilia

    MedlinePlus

    ... https://medlineplus.gov/news/fullstory_159027.html 2 New Findings Offer Hope for Those With Severe Hemophilia ... while the other uncovers the promise of a new drug To use the sharing features on this ...

  7. Factor VIII/factor IX prophylaxis for severe hemophilia.

    PubMed

    Carcao, Manuel; Srivastava, Alok

    2016-01-01

    Experience with clotting factor concentrate (CFC) replacement products over several decades has shown that regular replacement (prophylaxis) is the only way to prevent musculoskeletal damage in hemophilia and impact the natural history of hemophilia. Yet there is a lack of data on the optimal age to start such replacement therapy and the regimens to be used. While very early administration of high doses is certainly more effective in preventing bleeding, cost and compliance are major constraints all over the world. Starting prophylaxis with even lower doses comparable to that used in episodic therapies leads to major reduction in bleeding. Recognition of the clinical heterogeneity of hemophilia even among patients with a label of severe hemophilia in terms of their spontaneous bleeding has led to efforts aimed at individualizing CFC replacement, based on clinical responses or pharmacokinetic data of the CFC. The importance of long-term outcome assessment being combined with CFC replacement therapy cannot be overemphasized. PMID:26805901

  8. Advancements in gene transfer-based therapy for hemophilia A

    PubMed Central

    Doering, Christopher B; Spencer, H Trent

    2010-01-01

    Gene therapy has promised clinical benefit to those suffering with hemophilia A, but this benefit has not yet been realized. However, during the past two decades, basic and applied gene therapy research has progressed and the goal of gene therapy for hemophilia A is once again in our sights. The hemophilia A patient population suffers from a disease that requires invasive, lifelong management, is exorbitantly expensive to treat, has geographically limited treatment access and can become untreatable due to immune reactions to the treatment product. Subsequent to the cloning of the factor VIII gene and cDNA in the early 1980s, academic and commercial research laboratories began to pursue gene transfer-based therapies to supplement or supplant the available protein replacement therapy. However, to date, clinical trials for gene therapy of hemophilia A have been unsuccessful. Three trials have been conducted with each having tested a different gene-transfer strategy and each demonstrating that there is a considerable barrier to achieving sustained expression of therapeutic amounts of factor VIII. Recent progress has been made in gene-transfer technology and, relevant to hemophilia A, towards increasing the biosynthetic efficiency of factor VIII. These advances are now being combined to develop novel strategies to treat and possibly cure hemophilia A. PMID:20577574

  9. 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

  10. 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. PMID:26619194

  11. Visuoperceptual sequelae in children with hemophilia and intracranial hemorrhage

    PubMed Central

    Matute, Esmeralda; O’Callaghan, Erin T.; Murray, Joan; Tlacuilo-Parra, Alberto

    2015-01-01

    Background The goal of this study was to examine the impact of focal brain injuries on the outcomes of visual perception and visuospatial abilities in Mexican children with hemophilia who have experienced intracranial hemorrhages. Methods We assessed ten boys who had hemophilia with intracranial hemorrhage (HIC), six boys who had hemophilia without intracranial hemorrhage (HH), and ten boys without hemophilia (CTL). The Verbal (VIQ), Performance IQs (PIQ), and Full Scale IQs (FSIQ) from the Wechsler Intelligence Scale for Children—Mexican Revision, Visual Perception, and Visuospatial Abilities domains, which are from a neuropsychological assessment battery for Spanish-speaking children (ENI), were employed for our analysis. Results The results showed that the HIC group performed in the low-average range on the PIQ and FSIQ, which was lower than the HH group. The HIC group showed low performance on visual perception tests, such as line orientation, fragmented objects, and overlapping figures, compared with their matched controls. Conclusions The results suggest that it is not the ability to recognize objects that is impaired in the HIC group, but the ability to identify objects under less favorable conditions. Our findings may have therapeutic and rehabilitative implications for the management of children with hemophilia and early focal brain lesions. PMID:26835360

  12. Longer-acting clotting factor concentrates for hemophilia.

    PubMed

    Powell, J S

    2015-06-01

    Hemophilia, when severe, leads to spontaneous life-threatening bleeding episodes. Current therapy requires frequent intravenous infusions. Most patients must limit their physical activities to avoid bleeding when the factor activity levels are below normal. In 2014, new therapeutic factor VIII and IX products were approved in Canada and the U.S. Over the next couple of years, other new factor products will likely be approved. These new factors have been engineered to have improved pharmacokinetic properties, including extended half-life in circulation, thus providing major therapeutic advances for patients with hemophilia. In the completed clinical trials, over 700 patients have successfully used these longer acting products regularly for more than one year. These promising new therapies should allow patients with hemophilia to use fewer infusions to prevent spontaneous bleeding or to treat bleeding episodes, and to provide appropriate clotting factor levels for different physical activities. PMID:26149018

  13. Acquired Hemophilia A Successfully Treated with Rituximab

    PubMed Central

    D’Arena, Giovanni; Grandone, Elvira; Di Minno, Matteo Nicola Dario; Musto, Pellegrino; Di Minno, Giovanni

    2015-01-01

    Acquired hemophilia A (AHA) is a rare bleeding disorder due to the development of specific autoantibodies against factor VIII. The anti-CD20 monoclonal antibody Rituximab has been proven to be effective in obtaining a long-term suppression of inhibitors of AHA, besides other immunosuppressive standard treatments. Here we describe a case of idiopathic AHA in a 60-year old man successfully treated with rituximab. He showed a complete clinical response with a normalization of clotting parameters after 5 weekly courses of rituximab given at a dose of 375 mg/sqm., but after stopping rituximab, an initial worsening of coagulation parameters induced the addition of 3 further courses. At present, the patient is in complete clinical and hematological remission after 200 days. This case confirms that Rituximab may be a safe and useful tool to treat AHA and, a prolonged administration can overcome the initial resistance. However, the precise position of this drug in the therapeutic strategy (first or second-line, alone or in combination with other drugs) remains to be established and warrants further investigation. PMID:25745551

  14. Evolution of the Treatments for Hemophilia.

    PubMed

    Guelcher, Christine J

    2016-01-01

    Although hemophilia has been recognized for centuries as an inherited disorder primarily affecting males, advances in treatments have been very recent. Initial availability of plasma-derived therapies offered significant improvements in morbidity and mortality, but the transmission of viruses quickly negated the benefit of early factor replacement products. After developing successful viral inactivation methods and subsequently developing recombinant technology, the manufacturing of factor concentrates became much safer. Access to safer factor products allowed for a shift from the treatment of bleeds to prevention, called prophylaxis. Although dosing and interval vary, prevention of joint disease is now a realistic goal. Unfortunately, despite advances in the safety of therapy, some patients are unable to use factor replacement products because they develop antibodies, known as inhibitors. Eradication of inhibitors is possible in the majority of patients, but it is expensive and takes time. Management of acute bleeding may require significantly higher doses of factor replacement or the use of a bypassing agent. As a result, patients with inhibitors are at increased risk for sequelae, including joint disease, life-threatening bleeding, infectious complications with central vascular access devices, and thrombotic complications. PMID:27379680

  15. Surgery-associated acquired hemophilia A.

    PubMed

    Theodossiades, G; Tsevrenis, V; Nomikou, E; Dadiotis, L; Kontopoulou-Griva, I

    2001-11-01

    We present two patients who acquired factor VIII antibodies in the immediate postoperative period. One patient was receiving warfarin that was temporarily discontinued but reintroduced after the procedure. Preoperatively, none gave a history of bleeding, even with past surgeries, and both had normal coagulation tests. Within days of surgery, hemorrhage with prolonged activated partial thromboplastin time, low factor VIII levels, and demonstrable factor VIII antibodies were observed. For the patient who was receiving warfarin the severe bleeding was attributed, at the beginning, only to the high international normalized ratio (INR), which resulted in a fatal delay in diagnosis and appropriate treatment. We would like to raise awareness of surgery as a precipitating cause of acquired hemophilia, which is something to be considered with unusual postoperative bleeding. This syndrome is remarkable for its abrupt onset within days of surgery, severe bleeding but potential successful outcome with combined hemostatic control with recombinant activated FVII (rFVIIa) and elimination of the antibody by immunosuppression. PMID:11757731

  16. 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. PMID:27131224

  17. Physical and psychosocial challenges in adult hemophilia patients with inhibitors

    PubMed Central

    duTreil, Sue

    2014-01-01

    Numerous challenges confront adult hemophilia patients with inhibitors, including difficulty in controlling bleeding episodes, deterioration of joints, arthritic pain, physical disability, emotional turmoil, and social issues. High-intensity treatment regimens often used in the treatment of patients with inhibitors also impose significant scheduling, economic, and emotional demands on patients and their families or primary caregivers. A comprehensive multidisciplinary assessment of the physical, emotional, and social status of adult hemophilia patients with inhibitors is essential for the development of treatment strategies that can be individualized to address the complex needs of these patients. PMID:25093002

  18. Acquired hemophilia A in a patient with systemic lupus erythematosus.

    PubMed

    Ishikawa, T; Tsukamoto, N; Suto, M; Uchiumi, H; Mitsuhashi, H; Yokohama, A; Maesawa, A; Nojima, Y; Naruse, T

    2001-06-01

    A patient with systemic lupus erythematosus (SLE) developed acquired hemophilia A. The patient, a 24-year-old Japanese woman, was referred to our hospital because of uncontrollable bleeding following a tooth extraction. Laboratory examination revealed prolonged APTT (116 seconds), reduced factor VIII activity (2.8 %) and the presence of factor VIII inhibitor at a titer of 46.5 Bethesda units/ml. Transfusion of prothrombin complex concentrate and activated prothrombin complex concentrate followed by administration of prednisolone and cyclophosphamide successfully arrested bleeding and reduced the factor VIII inhibitor level. Acquired hemophilia A is a rare but lethal condition. Rapid diagnosis and introduction of adequate therapies are critical. PMID:11446683

  19. 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

  20. HLA Class I and KIR Genes Do Not Protect Against HIV Type 1 Infection in Highly Exposed Uninfected Individuals With Hemophilia A

    PubMed Central

    Vince, Nicolas; Bashirova, Arman A.; Lied, Alexandra; Gao, Xiaojiang; Dorrell, Lucy; McLaren, Paul J.; Fellay, Jacques; Carrington, Mary

    2014-01-01

    A recent genome-wide association study (GWAS) involving patients with hemophilia A who were exposed to but uninfected with human immunodeficiency virus type 1 (HIV-1) did not reveal genetic variants associated with resistance to HIV-1 infection, beyond homozygosity for CCR5-Δ32. Since variation in HLA class I and KIR genes is not well interrogated by standard GWAS techniques, we tested whether these 2 loci were involved in protection from HIV-1 infection in the same hemophilia cohort, using controls from the general population. Our data indicate that HLA class I alleles, presence or absence of KIR genes, and functionally relevant combinations of the HLA/KIR genotypes are not involved in resistance to parenterally transmitted HIV-1 infection. PMID:24719475

  1. Adeno-associated viral vectors for the treatment of hemophilia.

    PubMed

    High, Katherine A; Anguela, Xavier M

    2016-04-15

    Gene transfer studies for the treatment of hemophilia began more than two decades ago. A large body of pre-clinical work evaluated a variety of vectors and target tissues, but by the start of the new millennium it became evident that adeno-associated viral (AAV)-mediated gene transfer to the liver held great promise as a therapeutic tool. The transition to the clinical arena uncovered a number of unforeseen challenges, mainly in the form of a human-specific immune response against the vector that poses a significant limitation in the application of this technology. While the full nature of this response has not been elucidated, long-term expression of therapeutic levels of factor IX is already a reality for a small number of patients. Extending this success to a greater number of hemophilia B patients remains a major goal of the field, as well as translating this strategy to clinical therapy for hemophilia A. This review summarizes the progress of AAV-mediated gene therapy for the hemophilias, along with its upcoming prospects and challenges. PMID:26614390

  2. 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…

  3. Desmopressin in mild hemophilia A: indications, limitations, efficacy, and safety.

    PubMed

    Lethagen, Stefan

    2003-02-01

    Replacement therapy with blood products has long been the only available therapeutic option for patients with bleeding disorders. Plasma-derived cryoprecipitate and factor (F) VIII concentrates, which have been used for hemophilia A patients, involve the risk of transmitting blood-borne diseases. Both plasma-derived and recombinant FVIII concentrates are expensive, and there is a global shortage. The synthetic vasopressin analogue desmopressin acetate (1-deamino-[8-D-arginine]-vasopressin, DDAVP) increases plasma concentrations of coagulation FVIII and von Willebrand factor (vWF) two fold to six fold through endogenous release. The drug is an attractive therapeutic alternative because it carries no risk of transmission of infectious diseases. Desmopressin is today a widely used hemostatic agent not only in patients with mild hemophilia A or von Willebrand disease (vWD) but also in those with congenital or acquired platelet dysfunction. There is a long clinical experience with the drug because it has been used for prevention of bleedings in connection with invasive procedures and for treatment of bleedings since the mid-1970s. Not all hemophilia A patients can be treated. The clinical usefulness depends on the postdesmopressin plasma concentration of FVIII, which in turn depends on the patient's basal FVIII level. Therefore, a test dose is recommended in candidate patients. In general, only the mildest hemophilia A patients respond sufficiently. Optimal hemostatic effect is achieved with a dosage of 0.3 microg/kg given intravenously. An intranasal desmopressin spray is suitable for the home treatment. PMID:12640572

  4. Medicine betrayed: hemophilia patients and HIV in the US.

    PubMed

    Keshavjee, S; Weiser, S; Kleinman, A

    2001-10-01

    The contamination of blood products by HIV in the early 1980s resulted in thousands of deaths among people with hemophilia in the United States and elsewhere. In the US, industry, government, physicians, and advocacy groups were implicated in this tragedy. In response to pleas from members of the US hemophilia community, the Institute of Medicine (IOM) of the National Academy of Science convened a public hearing to identify the institutional determinants of the HIV/AIDS epidemic among US hemophilia patients. The resulting IOM Report (1995) established a narrative of the crisis and indicated necessary improvements to the management of the US blood supply. The Report, however, failed to address the hemophilia community's demands for accountability and retribution. In this paper we explore the moral and social dimensions of this tragedy through narrative analysis of the original testimonies of hemophilia sufferers, interviews with some patients and their families, and a re-examination of the text of the IOM Report itself. We examine the process by which this crisis was addressed--through the discourses of science and law--and how it was ultimately framed as a failure of management and oversight rather than a moral failure of the for-profit health-care system. Thus, while the Report and its aftermath demonstrate powerfully how testimonials of suffering can influence public policy, by not addressing what is at stake for the victims--failure to protect patients in an era of increasingly commodified health care--it led to an exculpatory solution that obfuscated the moral dimensions of suffering. PMID:11556777

  5. Thoracoscopic lobectomy in a lung cancer patient with severe hemophilia: A case report

    PubMed Central

    LIN, XING-YU; YANG, ZHI-GUANG; ZHANG, PENG; LIU, YUN-PENG; WANG, CHENG-XIANG; SHAO, GUO-GUANG

    2015-01-01

    Hemophilia is a hereditary disease with impaired blood coagulation due to a genetic deficiency of blood coagulation factors. Hemophilia often causes spontaneous life-threatening bleeding, so patients with hemophilia are often not suitable for any surgery that may cause iatrogenic bleeding and threaten the life of the patient. Therefore, surgery in lung cancer patients with hemophilia is extremely rare. The present study reported the case of a lung cancer patient with hemophilia who presented with a persistent cough. A mass was revealed by computed tomography and the patient underwent a successful thoracoscopic right lower lobectomy. The study discusses the patient's diagnosis and treatment options for hemophilia A and lung cancer, including indications for thoracoscopic lobectomy, pre-operative preparation and post-operative care, and other treatment options are discussed. The literature is also reviewed on this subject. PMID:26722282

  6. Rheumatological management of patients with hemophilia. Part 1: joint manifestations.

    PubMed

    Alcalay, Michel; Deplas, Adeline

    2002-10-01

    The advent of factor VIII and IX replacement therapy has radically changed the physiognomy of hemophilia. In patients with no inhibitors, early replacement therapy shortens the immobilization and decreases the structural and functional alterations related to recurrent hemarthrosis. Routine prophylactic replacement therapy before or after the first episode of hemarthrosis is still rarely used in France. Recurrent hemarthrosis in the same joint can cause synovitis and chronic arthropathy. Injection synovectomy is now the preferred treatment, as opposed to secondary prophylactic replacement therapy and to arthroscopic or open synovectomy. The palliative treatment of chronic arthropathy is difficult and rests on analgesics and rehabilitation therapy, with orthotic devices and/or surgery where appropriate. The treatment of hemophilia is far more difficult in patients with inhibitors and, consequently, considerable hope is being placed in gene therapy, whose first results are encouraging. PMID:12477227

  7. Acquired hemophilia complicated by cardiorenal syndrome type 3

    PubMed Central

    Sharma, Rakesh; Dash, Sananta Kumar; Chawla, Rajesh; Kansal, Sudha; Agrawal, Devender Kumar; Dua, Harsh

    2013-01-01

    Development of autoantibodies against coagulation factor VIII (FVIII) leads to a rare condition defined as acquired hemophilia (AH). If not diagnosed and treated early, AH may be associated with high mortality and morbidity. A 65-year-old woman presented with history of macrohematuria, acute renal failure, cardiogenic shock, and acute respiratory failure. Blood investigation revealed azotemia, prolonged activated partial thromboplastin time (aPTT), coagulation FVIII level of <1%, and presence of FVIII inhibitor. Echocardiography showed global hypokinesia and ultrasonography and computed tomography (CT) revealed bilateral hydroureteronephrosis. The final diagnosis was acquired hemophilia A, complicated by acute obstructive renal failure and cardiorenal syndrome (CRS) type 3. Patient was managed with mechanical ventilation, heparin-free hemodialysis, negative fluid balance, recombinant activated factor VII, and prednisolone. Hematuria was relieved, renal function improved, and cardiac function showed improvement on repeat echocardiography. Patient was discharged on prednisolone with subsequent follow ups. PMID:24501492

  8. Clinical profile of hemophilia patients in Jodhpur Region

    PubMed Central

    Payal, Vikas; Sharma, Pramod; Goyal, Vishnu; Jora, Rakesh; Parakh, Manish; Payal, Deepika

    2016-01-01

    Background: Hemophilia is widely distributed all over the world, but little is known about its clinical profile in resource-limited regions. An insight into its clinical spectrum will help in the formulation of policies to improve the situation in these areas. Aims: To study the clinical profile of hemophiliacs (age <18 years) in Jodhpur region and screen them for transfusion-transmitted infections. Materials and Methods: A cross-sectional study conducted in the Department of Pediatrics, Umaid Hospital, Dr. S. N. Medical College, Jodhpur, over a period of 12 months. Result: Out of a total of 56 cases enrolled, 51 (91%) cases were diagnosed as hemophilia A while 5 (9%) were diagnosed as hemophilia B. Positive family history was found in 26 (46%) cases. According to their factor levels, 25 (44%) cases had severe disease, 20 (36%) had moderate disease, and 11 (20%) had mild disease. The mean age of onset of symptoms and diagnosis was 1.73 ± 1.43 and 3.87 ± 3.84 years, respectively. First clinical presentation was posttraumatic bleed in 20 (36%), gum bleeds in 17 (30%), epistaxis in 4 (7%), joint bleeds in 4 (7%), skin bleeds in 4 (7%), and circumcision bleed in 3 (5%) cases. Knee joint was the predominant joint affected by hemarthrosis in 38 (68%), followed by ankle in 29 (52%), elbow in 20 (36%), and hip joint in 7 (13%) cases. All patients had a negative screening test for transfusion-transmitted infections. Conclusion: Occurrence of posttraumatic bleeds and gum bleeds in an otherwise normal child should warn the clinician for evaluation of hemophilia. PMID:27011682

  9. Acquired hemophilia A: A rare cause of gross hematuria

    PubMed Central

    Hosier, Gregory W.; Mason, Ross J.; Sue Robinson, K.; Bailly, Gregory G.

    2015-01-01

    Acquired hemophilia A is a rare condition caused by spontaneous development of factor VIII inhibitor. This condition most commonly presents with multiple hemorrhagic symptoms and isolated hematuria is exceedingly rare. Early diagnosis is important, as this condition carries a high mortality rate (13–22%). We present a case of an 82-year-old man with isolated hematuria caused by a factor VIII inhibitor who was successfully treated with recombinant activated factor VII concentrate, as well as prednisone and cyclophosphamide. PMID:26834904

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

    PubMed Central

    2012-01-01

    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. PMID:23237078

  11. Hemophilia A in Brazil – epidemiology and treatment developments

    PubMed Central

    Ferreira, Adriana Aparecida; Leite, Isabel Cristina Gonçalves; Bustamante-Teixeira, Maria Teresa; Guerra, Maximiliano Ribeiro

    2014-01-01

    Hemophilia A is an inherited disorder characterized by deficiency of coagulation factor VIII, which predisposes patients to bleeding events. Treatment is based on replacement of the deficient factor, in a therapeutic or prophylactic manner. Brazil is the country with the third largest population of people with hemophilia, for which the public health system provides free comprehensive care. Maintaining an updated registry of patients, documenting the prevalence of complications, and assessing the effectiveness of resource use are indispensable elements in the design of a well-coordinated national program. According to sociodemographic, clinical, and laboratory data collected by the computerized Brazilian system on coagulopathies, in June 2013, there were 9,122 registered patients with hemophilia A in Brazil, of which 36.1% had a severe form of the disease. Clotting factor inhibitors were present in 7.5%, but 25.7% of records did not provide this type of data. Around 70% of the patients belonged to the economically active population, being between 15 and 59 years old. Infection by the human immunodeficiency virus was present in 23.4% of the patients tested and infection by hepatitis C virus antibodies in 59.3%. Infection by the hepatitis B virus and human T-lymphotropic virus was also reported. The high percentage of incomplete records regarding serological data shows the fragility of the information system to date. There was also no information available on the prevalence of permanent or disabling joint damage. Although few hemophiliacs receive adequate care in developing countries, and despite Brazil exhibiting great social inequalities, the Ministry of Health has made significant advances in the treatment of hemophilia A. The gradual increase in importation of factor VIII concentrate enabled the implementation of primary and secondary modalities of prophylaxis, in addition to the induction of immune tolerance. There are also plans to set up a factory in the

  12. Genome-editing technologies for gene correction of hemophilia.

    PubMed

    Park, Chul-Yong; Lee, Dongjin R; Sung, Jin Jea; Kim, Dong-Wook

    2016-09-01

    Hemophilia is caused by various mutations in blood coagulation factor genes, including factor VIII (FVIII) and factor IX (FIX), that encode key proteins in the blood clotting pathway. Although the addition of therapeutic genes or infusion of clotting factors may be used to remedy hemophilia's symptoms, no permanent cure for the disease exists. Moreover, patients often develop neutralizing antibodies or experience adverse effects that limit the therapy's benefits. However, targeted gene therapy involving the precise correction of these mutated genes at the genome level using programmable nucleases is a promising strategy. These nucleases can induce double-strand breaks (DSBs) on genomes, and repairs of such induced DSBs by the two cellular repair systems enable a targeted gene correction. Going beyond cultured cell systems, we are now entering the age of direct gene correction in vivo using various delivery tools. Here, we describe the current status of in vivo and ex vivo genome-editing technology related to potential hemophilia gene correction and the prominent issues surrounding its application in patients with monogenic diseases. PMID:27357631

  13. Understanding patient preferences and willingness to pay for hemophilia therapies

    PubMed Central

    Chaugule, Shraddha S; Hay, Joel W; Young, Guy

    2015-01-01

    Background Despite clearly improved clinical outcomes for prophylaxis compared to on-demand therapy, on average only 56% of patients diagnosed with severe hemophilia receive prophylactic factor replacement therapy in the US. Prophylaxis rates generally drop as patients transition from childhood to adulthood, partly due to patients becoming less adherent when they reach adulthood. Assessment of patient preferences is important because these are likely to translate into increased treatment satisfaction and adherence. In this study, we assessed preferences and willingness to pay (WTP) for on-demand, prophylaxis, and longer acting prophylaxis therapies in a sample of US hemophilia patients. Methods Adult US hemophilia patients and caregivers (N=79) completed a discrete-choice survey that presented a series of trade-off questions, each including a pair of hypothetical treatment profiles. Using a mixed logit model for analysis, we compared the relative importance of five treatment characteristics: 1) out-of-pocket treatment costs (paid by patients), 2) factor dose adjustment, 3) treatment side effects, 4) availability of premixed factor, and 5) treatment effectiveness and dosing frequency. Based on these attribute estimates, we calculated patients’ WTP. Results Out-of-pocket treatment costs (P<0.001), side effects (P<0.001), and treatment effectiveness and dosing frequency (P<0.001) were found to be statistically significant in the model. Patients were willing to pay US $410 (95% confidence interval: $164–$656) out of pocket per month for thrice-weekly prophylaxis therapy compared to on-demand therapy and $360 (95% confidence interval: $145–$575) for a switch from thrice-weekly to once-weekly prophylaxis therapy. Conclusion Improvements in treatment effectiveness and dosing frequency, treatment side effects, and out-of-pocket costs per month were the greatest determinants of hemophilia treatment choice and WTP. The positive preferences and WTP for longer acting

  14. 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. PMID:27046799

  15. Inhibitors in childhood hemophilia A: genetic and treatment-related risk factors for development and eradication.

    PubMed

    DiMichele, Donna M

    2013-01-01

    The development of neutralizing antibodies remains a serious complication of hemophilia replacement therapy. Factor VIII inhibiting antibodies (inhibitors) occur commonly following replacement therapy in hemophilia A, creating a significant burden of clinical disease. This article will review our current understanding of risk factors and their known impact on inhibitor development in previously untreated or minimally treated children with severe and mild hemophilia A. It will also explore how the most recently elucidated immunology of inhibitor development might hold important clues to more effective inhibitor eradication and prevention in this heavily impacted patient population. PMID:23109404

  16. Management of Pregnancy in a Patient with Severe Hemophilia Type A

    PubMed Central

    Sharma, Vipra; Khalid, Aysha; Cohen, Alice J.

    2012-01-01

    Hemophilia type A is a rare inherited bleeding disorder with a diversity of clinical manifestations ranging from persistent bleeding after minor trauma, spontaneous deep muscle or joint hemorrhage, to intracranial hemorrhage. As an X-linked disorder, hemophilia is rare in females and therefore there is little experience with pregnancy and no standardized guidelines to prevent bleeding antepartum, at delivery, and postpartum. We report the clinical course and management of a woman with severe hemophilia A who on two occasions had uncomplicated pregnancies and vaginal deliveries at term utilizing bolus recombinant factor VIII concentrate. PMID:23943706

  17. Barriers and perceived limitations to early treatment of hemophilia

    PubMed Central

    Saxena, Kapil

    2013-01-01

    Early treatment of bleeds in hemophilia patients, both with and without inhibitors, has been shown to be of immense benefit in the overall clinical outcome. Despite the advantages of treating the bleeding episodes early, significant barriers and limitations remain. The aim of this review is to highlight the various barriers and perceived limitations to early therapy of bleeding episodes, especially in patients who have developed inhibitors to factor VIII. The peer-reviewed literature was searched for articles on hemophilia patients, with and without inhibitors, and early treatment, to identify the barriers to early treatment and potential impact on patient outcomes. The most important barrier is the educational barrier, which involves lack of awareness among patients regarding the signs of a bleed, as well as importance of early therapy. It is also common for parents or caregivers of school-age children to exhibit inconvenience and scheduling barriers. Distance to the treatment center can also play a role here. Some patients experience financial barriers related to cost of clotting factor products, insurance coverage, or insurance caps and out-of-pocket costs. Rarely, there can also be problems related to venous access or home infusion. Lastly, multiple psychosocial barriers can prevent adherence to treatment regimens. Identification and addressing these individual barriers will result in improved compliance rates, prevent joint damage, be more cost-effective, and lead to better overall health of these patients. PMID:23700376

  18. Acquired Hemophilia A: A Frequently Overlooked Autoimmune Hemorrhagic Disorder

    PubMed Central

    Takeda, Tomohiro

    2014-01-01

    Acquired hemophilia A (AHA) is a rare hemorrhagic disease in which autoantibodies against coagulation factor VIII- (FVIII-) neutralizing antibodies (inhibitors) impair the intrinsic coagulation system. As the inhibitors developed in AHA are autoantibodies, the disease may have an autoimmune cause and is often associated with autoimmune disease. Although acute hemorrhage associated with AHA may be fatal and is costly to treat, AHA is often unrecognized or misdiagnosed. AHA should thus be considered in the differential diagnosis particularly in postpartum women and the elderly with bleeding tendency or prolonged activated partial thromboplastin time. Cross-mixing tests and measurement of FVIII-binding antibodies are useful to confirm AHA diagnosis. For treatment of acute hemorrhage, hemostatic therapy with bypassing agents should be provided. Unlike in congenital hemophilia A with inhibitors, in which immune tolerance induction therapy using repetitive infusions of high-dose FVIII concentrates is effective for inhibitor eradication, immune tolerance induction therapy has shown poor efficacy in treating AHA. Immunosuppressive treatment should thus be initiated to eradicate inhibitors as soon as the diagnosis of AHA is confirmed. PMID:24741588

  19. Obstacles and future of gene therapy for hemophilia

    PubMed Central

    Arruda, Valder R; Samelson-Jones, Ben J

    2015-01-01

    Introduction The recent success of early-phase clinical trials for adeno-associated viral (AAV) liver-directed gene therapy for hemophilia B (HB) demonstrates the potential for gene therapy, in the future, to succeed protein-based prophylaxis therapy for HB. Significant obstacles, however, need to be overcome prior to widespread adoption. The largest obstacles include immune responses to the AAV capsid including preexisting neutralizing antibodies (NAbs) and a delayed cellular immune response. Emerging evidence suggests that the latter is vector-dose dependent. Furthermore, the development and eradication of inhibitors remains a significant safety concern. Similarly, biological differences between Factor VIII and Factor IX (FIX) impose challenges to direct adoption of the successes for HB to hemophilia A (HA). Areas covered The advantages and limitations of the current strategies addressing these obstacles for gene therapy for HB and HA are discussed, as well as vector manufacturing issues relevant to widespread adoption. Alternative strategies including both ex-vivo and in-vivo lentiviral-based methods are discussed, though we focus on AAV-based approaches because of their recent clinical success and potential. Expert opinion Our opinion is that these obstacles can be overcome with current approaches, and AAV-based gene therapy for HB will likely translate into future clinical care. Innovative approaches are, however, likely needed to solve the current problems obstructing HA gene therapy. PMID:26900534

  20. Brain abnormalities in male children and adolescents with hemophilia: detection with MR imaging. The Hemophilia Growth and Development Study Group.

    PubMed

    Wilson, D A; Nelson, M D; Fenstermacher, M J; Bohan, T P; Hopper, K D; Tilton, A; Mitchell, W G; Contant, C F; Maeder, M A; Donfield, S M

    1992-11-01

    Cranial magnetic resonance (MR) imaging was performed in 124 male patients (aged 7-19 years), from 14 institutions, in whom a diagnosis of moderate to severe hemophilia was made. Blood tests in all subjects were negative for human immunodeficiency virus. Findings in MR studies were abnormal in 25 (20.2%) subjects. Six lesions in five subjects were classified as congenital. The most commonly identified congenital lesion was a posterior fossa collection of cerebrospinal fluid (five cases). Twenty-two subjects had acquired lesions that were probably related to the hemophilia or its treatment. The most commonly acquired lesions were single- or multifocal areas of high signal intensity within the white matter on T2-weighted images noted in 14 (11.3%) subjects. Two subjects had large focal areas of brain atrophy, and six had some degree of diffuse cerebral cortical atrophy. Three subjects (2.4%) had hemorrhagic lesions. To the authors' knowledge, the unexpected finding of small, focal, nonhemorrhagic white matter lesions has not previously been reported. PMID:1410372

  1. Bilateral recurrent external obturator muscle hematoma: An unusual cause of pelvic pain in hemophilia

    PubMed Central

    ARPACI, TANER; SASMAZ, ILGEN; AKBAS, TUGANA; EKEN, ALPER; OZGUR, ANIL; ANTMEN, BULENT

    2016-01-01

    Following joint hemorrhages, intramuscular hemorrhages are the second most prevalent bleeding pattern in hemophiliac patients. Hematomas of the iliopsoas muscle are a well-known complication of hemophilia; however, obturator muscle hematomas are rare. We herein report a case of spontaneous bleeding of the bilateral external obturator muscles, which occured three times within a period of 9 months in a hemophilia patient with factor VIII inhibitors. To the best of our knowledge, this is the first published case of an obturator externus muscle hematoma in hemophilia. In addition to hip hemarthrosis, iliopsoas hematomas and acute appendicitis, obturator muscle hematoma should be considered as one of the diagnostic alternatives for pelvic pain in hemophiliaψ patients. Magnetic resonance imaging enables rapid diagnosis of obturator muscle hematoma. PMID:27073678

  2. Is executive function intact after pediatric intracranial hemorrhage? A sample of Mexican children with hemophilia.

    PubMed

    Morales, Guadalupe; Matute, Esmeralda; Murray, Joan; Hardy, David J; O'Callaghan, Erin T; Tlacuilo-Parra, Alberto

    2013-10-01

    The goal of this study was to examine executive functioning outcomes in children with hemophilia who have suffered intracranial hemorrhage. We assessed 10 boys with hemophilia with intracranial hemorrhage; 6 boys with hemophilia without intracranial hemorrhage; and 10 healthy boys as controls. Intellectual functioning was assessed with subscales from the Wechsler Intelligence Scale for Children-Mexican Revision. Concept formation and reasoning, cognitive flexibility, and planning and organization domains from a neuropsychological assessment battery for Spanish-speaking children were employed for our analysis. Results indicated that children with intracranial hemorrhage demonstrated significant impairment on some measures of executive function compared with the control groups. All differences reflected poorer performance by the intracranial hemorrhage group. These results may reflect the impact of disruption to immature brain circuits and the deficiency of functional specificity within the immature brain. This is the only known study examining neuropsychological functioning in Mexican youth with hemophilia. PMID:23872342

  3. 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. PMID:26619193

  4. Labeled factor IX kinetics in patients with hemophilia-B

    SciTech Connect

    Smith, K.J.; Thompson, A.R.

    1981-09-01

    Labeled factor IX was infused five time into four patients with hemophilia-B. Ten-minute plasma recovery average 35% (SD +/- 2) and the mean T 1/2 beta-phase elimination was 23 hr (+/- 5). No alteration in the postinfusion 125I-factor-IX could be detected by radioautography of plasma samples run on polyacrylamide gels or on crossed-immunoelectrophoresis. Label was excreted into the urine as free 125I-iodide. Kinetics were similar when the labeled preparation was infused alone or with a commercial concentrate containing unlabeled factor IX. Infusion of factor IX in man is best described by a two-compartment open pharmacokinetic model where factor IX is distributed in a space larger than the plasma volume.

  5. Joint Function and Arthropathy Severity in Patients with Hemophilia

    PubMed Central

    Goto, Miwa; Takedani, Hideyuki; Nitta, Osamu; Kawama, Kennosuke

    2015-01-01

    Background: The Arnold-Hilgartner classification is one of the most popular evaluation systems for the progression hemophilic arthropathy. A previous study reported an association between arthropathy severity and arc range of motion (ROM). However, associations between arthropathy severity and angular ROM and muscle strength remain unclear. AIM: The purpose of this study was to clarify the association between joint function and arthropathy severity in hemophilia. Methods: We studied the knee, ankle, and elbow joints of 31 patients with hemophilia (PWH). The condition of the affected joints was evaluated on the basis of the interview data, joint function measurements, and roentgenography of the affected joints. In assessment of joint function, we evaluated knee strength (flexor, extensor) and grip strength as well as the passive ROM of the elbow, knee, and ankle. During the interview, all patients were asked about the history of intra-articular bleeding over the past year and pain. Results: As arthropathy severity worsened, knee flexor strength, knee extensor strength, grip strength, and ROM (elbow flexion, elbow extension, knee flexion, knee extension, and ankle extension) significantly decreased. Even patients with mild arthropathies experienced knee extensor weakness and extension limitation. In addition, joint function of severe ankle arthropathy was significantly related to the history of intra-articular bleeding and pain. Conclusion: Our results suggest that physical therapy is necessary to improve joint function in PWH and mild or no arthropathy. Pain control and prophylactic hematological management are necessary for patients with severe arthropathy because intra-articular bleeding and pain significantly decrease joint function. PMID:26733762

  6. 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

  7. Economic costs of hemophilia and the impact of prophylactic treatment on patient management.

    PubMed

    Chen, Sheh-Li

    2016-04-01

    Hemophilia is a rare congenital bleeding disorder characterized by spontaneous and potentially life-threatening bleeding episodes. In addition to its clinical burden on the patient, the condition also places a significant economic burden on healthcare payers, patients/caregivers, and society. Hemophilia is associated with staggering direct costs from hospitalizations, outpatient visits, and drug treatments, as well as high indirect costs from diminished work productivity and absenteeism from work and school. Additionally, hemophilia incurs tremendous intangible costs, including reduced quality of life, pain and suffering, and the emotional and physical toll on the patient and caregivers. The evolution of treatment patterns in hemophilia has transformed the once-fatal disease into a chronic but potentially well-managed condition through the use of prophylaxis treatment. However, other complications, such as development of inhibitory antibodies, have added to the complexity of managing the disease and its costs. To ensure optimal treatment outcomes and disease management, there is a critical need to understand the utilization of healthcare resources in the treatment of hemophilia and to educate patients on the importance of treatment adherence and compliance to reduce long-term effects on musculoskeletal health. PMID:27266809

  8. The World Federation of Hemophilia: 40 years of improving haemophilia care worldwide.

    PubMed

    Jones, Peter; Robillard, Line

    2003-11-01

    In 2003, the World Federation of Hemophilia marks its 40th anniversary. Established in 1963 by Frank Schnabel, a person with hemophilia from Montreal, Canada, the WFH has grown into its role as an independent, not-for-profit representative of the global haemophilia community. Since then, its biannual world congresses have provided an opportunity to exchange information on research and treatment. Today, more than 3,000 delegates attend these congresses. Until the early 1990s, the WFH's other major function was the International Hemophilia Training Centre programme, offering training fellowships and workshops to medical and paramedical staff from developing countries. In 1982, AIDS was reported in people with haemophilia who had received tainted blood products. The WFH developed task forces and committees to monitor safety and supply issues and set up the Global Forum on the Safety and Supply of Treatment Products. In the mid-1990s, twinning programmes were established for treatment centres and national haemophilia organizations. Twinning facilitates the exchange of training, coaching, and expertise. In the late 1990s, the WFH expanded and began working with local organizations and health authorities in a number of countries to improve the diagnosis and care of persons with hemophilia. The federation currently has ongoing projects in 25 developing countries. On World Hemophilia Day, April 17, 2003, the WFH launched the Global Alliance for Progress (GAP) in haemophilia which aims to double the number of people with haemophilia diagnosed and receiving treatment in up to 40 developing countries over a 10-year period. PMID:14750930

  9. Treatment of hemophilia: a review of current advances and ongoing issues

    PubMed Central

    Coppola, Antonio; Di Capua, Mirko; Di Minno, Matteo Nicola Dario; Di Palo, Mariagiovanna; Marrone, Emiliana; Ieranò, Paola; Arturo, Claudia; Tufano, Antonella; Cerbone, Anna Maria

    2010-01-01

    Replacement of the congenitally deficient factor VIII or IX through plasma-derived or recombinant concentrates is the mainstay of treatment for hemophilia. Concentrate infusions when hemorrhages occur typically in joint and muscles (on-demand treatment) is able to resolve bleeding, but does not prevent the progressive joint deterioration leading to crippling hemophilic arthropathy. Therefore, primary prophylaxis, ie, regular infusion of concentrates started after the first joint bleed and/or before the age of two years, is now recognized as first-line treatment in children with severe hemophilia. Secondary prophylaxis, whenever started, aims to avoid (or delay) the progression of arthropathy and improve patient quality of life. Interestingly, recent data suggest a role for early prophylaxis also in preventing development of inhibitors, the most serious complication of treatment in hemophilia, in which multiple genetic and environmental factors may be involved. Treatment of bleeds in patients with inhibitors requires bypassing agents (activated prothrombin complex concentrates, recombinant factor VIIa). However, eradication of inhibitors by induction of immune tolerance should be the first choice for patients with recent onset inhibitors. The wide availability of safe factor concentrates and programs for comprehensive care has now resulted in highly satisfactory treatment of hemophilia patients in developed countries. Unfortunately, this is not true for more than two-thirds of persons with hemophilia, who live in developing countries. PMID:22282697

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

    PubMed Central

    Pollpeter, Molly J.

    2016-01-01

    Background 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. Objective To investigate the survival and lethal bleeding frequency in two strains of E-16 hemophilia A mice. Methods 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. Results and Conclusions 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. PMID:27144769

  11. Profile of efraloctocog alfa and its potential in the treatment of hemophilia A

    PubMed Central

    George, Lindsey A; Camire, Rodney M

    2015-01-01

    Hemophilia care has improved dramatically over the past 50 years, evolving from plasma concentrates, to purified plasma proteins, to recombinant clotting factors. These collective developments allowed for home delivery of on-demand and prophylactic treatment, resulting in the reduction of hemophilia morbidity and mortality and improved quality of life. Although efficacious in treating bleeding, conventional factor products’ half-lives require frequent venipuncture, which remains a significant burden to patients. Despite the remarkable advances in hemophilia care, no improvements have, until now, been made to the pharmacokinetic properties of factor products. Multiple strategies have more recently been employed to generate novel bioengineered products that, with great hope, represent the next wave of progress in hemophilia care. The use of these products will undoubtedly raise important discussion about choosing conventional factor over new long-acting factor products. Incorporation of these therapies into clinical care is accompanied by unanswered safety questions that will likely be evaluated only in postmarketing surveillance analysis. Further, these products may change current treatment paradigms with unclear cost repercussions and feasibility. This paper will review efraloctocog alfa (FVIII-Fc) and its role in the treatment of hemophilia A. PMID:25977610

  12. Nested Cohort

    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. Acquired immunodeficiency syndrome among patients attending hemophilia treatment centers and mortality experience of hemophiliacs in the United States.

    PubMed

    Johnson, R E; Lawrence, D N; Evatt, B L; Bregman, D J; Zyla, L D; Curran, J W; Aledort, L M; Eyster, M E; Brownstein, A P; Carman, C J

    1985-06-01

    The acquired immunodeficiency syndrome (AIDS) was first recognized among hemophiliacs in 1982. The authors have conducted investigations to determine the onset and incidence of AIDS among hemophiliacs and to determine trends in hemophilia mortality since the introduction of clotting-factor concentrates in the late 1960s. A survey of United States hemophilia treatment centers, supported by the Centers for Disease Control and the National Hemophilia Foundation, defined a population of hemophiliacs which was monitored for AIDS cases through June 1984. Death reports from the United States Vital Statistics System and from the hemophilia treatment center survey provided mortality trends for 1968-1979 and for 1978-1982, respectively. The results of these investigations demonstrate the following points. 1) The AIDS epidemic is a new and important cause of illness and mortality among hemophiliacs, although a very low incidence of AIDS among hemophiliacs prior to 1982 cannot be ruled out. 2) The AIDS cases who attended the surveyed hemophilia treatment centers were distributed throughout the United States and were older than hemophilia treatment center patients without AIDS. AIDS cases also used more lyophilized clotting-factor concentrate, but only a small number of cases were reported with this information. 3) Improved care for hemophilia, including the use of clotting-factor concentrates, dramatically reduced hemophilia mortality rates during the 1970s. 4) In 1982, hemorrhage was the major cause of death among hemophiliacs. Deaths from non-alcoholic liver disease were also increased. AIDS incidence among hemophilia treatment center attendees was stable at 0.6 cases per 1,000 hemophilia treatment center attendees per year during 1982 and 1983 but increased sharply to 5.4 cases per 1,000 during the first quarter of 1984. PMID:4014173

  14. 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

  15. 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.

  16. Abnormal coagulation factor VIII transcript in a Tennessee Walking Horse colt with hemophilia A.

    PubMed

    Norton, Elaine M; Wooldridge, Anne A; Stewart, Allison J; Cusimano, Layla; Schwartz, Dean D; Johnson, Calvin M; Boudreaux, Mary K; Christopherson, Pete W

    2016-03-01

    Hemophilia A is an X-chromosome-linked disorder caused by a deficiency in factor VIII (FVIII). Although foals have been diagnosed with hemophilia A based on deficiency in FVIII activity, causative gene mutations have not been identified. The genomic DNA and cDNA encoding FVIII of a Tennesee Walking Horse colt affected with hemophilia A and the genomic DNA of his dam and a normal unrelated horse were analyzed with no splice site or coding sequence abnormalities identified in any of the horses. Polymerase chain reactions (PCR) were then performed on hepatic cDNA from the affected colt and an unrelated normal horse, and no product was obtained for the sequence between and including exon 1 and exon 2 in the affected colt. Based on these results, suspected mutations were identified in the noncoding region of FVIII (intron 1), and genomic sequencing of intron 1 in the dam and the affected colt suggested maternal inheritance. PMID:26765501

  17. Cognitive and psychological profiles in treatment compliance: a study in an elderly population with hemophilia

    PubMed Central

    Riva, Silvia; Nobili, Alessandro; Djade, Codjo D; Mancuso, Maria Elisa; Santagostino, Elena; Pravettoni, Gabriella

    2015-01-01

    Elderly patients with hemophilia have to face new challenges linked to concomitant pathologies and concurrent use of different treatments. In order to promote optimal care in the elderly hemophilia population, this study is aimed to analyze treatment compliance in relation to the presence of comorbidities and the role of potential determinants that can affect compliance (positively or negatively), including health-related quality of life, cognitive decline, and sociodemographic parameters (eg, living situation, partnership, presence of caregivers). This will be an observational study of elderly patients with hemophilia (aged >60 years). Patients will be interviewed during their routine medical visits. The data interview will pertaining to several dimension of treatment management. This study will detect more vulnerable patients with special care needs and will highlight psychological factors that should be considered for future psychosocial interventions. PMID:26185433

  18. Immune tolerance induction for patients with severe hemophilia A: a critical literature review.

    PubMed

    Franchini, Massimo; Lippi, Giuseppe

    2011-11-01

    The development of inhibitors that neutralize the function of clotting factor VIII (FVIII) is currently the most challenging complication associated with the treatment of hemophilia A as it increases the disease-related morbidity and mortality. Immune tolerance induction (ITI) is the only documented strategy to eradicate persistent inhibitors in severe hemophilia A patients. Several studies have been conducted so far to identify patient- and treatment-related factors associated with greater ITI success. The currently available literature on ITI in hemophilia A will be critically reviewed in this article. In particular, we will focus on the role of the type of FVIII product on ITI outcome by analyzing the clinical and experimental data. PMID:21818664

  19. [Hepatitis C virus infection in patients with hemophilia].

    PubMed

    Baptista González, Héctor A

    2002-10-01

    After the introduction of second generation ELISA and confirmatory tests clinically available, it was possible to determine that prevalence of infection with HCV was 98% among hemophiliacs exposed to factor VIII concentrates that weren't submitted to viral inactivation. Liver failure is 4.2 times more probable among patients also infected with HIV. The hepatocellular carcinoma studies show similar findings. They report a rate of 1.4 for every 1,000 hemophiliacs, and almost all patients have antibodies for hepatitis C virus. The studies with hemophiliacs exposed to unsafe blood products for HCV showed a significant increase in mortality from different liver diseases, as compared to control subjects. Mortality rate shows an important increase in the hemophiliacs also infected with human immunodeficiency virus. Combination therapy (ribavirin and interferon) doesn't seem to make a difference in the response rate as compared to patients without hemophilia. In spite of the best efforts to improve the safety of factor VIII concentrates, it has been impossible to eliminate the risk of transmission of other infective agents. That's why it seems that recombinant technology will be the answer in obtaining the concentrates. PMID:12712860

  20. A genetic analysis of 23 Chinese patients with hemophilia B

    PubMed Central

    Wang, Qing-Yun; Hu, Bei; Liu, Hui; Tang, Liang; Zeng, Wei; Wu, Ying-Ying; Cheng, Zhi-Peng; Hu, Yu

    2016-01-01

    Hemophilia B (HB) is an X-linked recessive bleeding disorder caused by mutations in the coagulation factor IX (FIX) gene. Genotyping patients with HB is essential for genetic counseling and provides useful information for patient management. In this study, the F9 gene from 23 patients with HB was analyzed by direct sequencing. Nineteen point mutations were identified, including a novel missense variant (c.520G > C, p.Val174Leu) in a patient with severe HB and a previously unreported homozygous missense mutation (c.571C > T, p.Arg191Cys) in a female patient with mild HB. Two large F9 gene deletions with defined breakpoints (g.10413_11363del, g.12163_23369del) were identified in two patients with severe HB using a primer walking strategy followed by sequencing. The flanking regions of the two breakpoints revealed recombination-associated elements (repetitive elements, non-B conformation forming motifs) with a 5-bp microhomology in the breakpoint junction of g.12163_23369del. These findings imply that non-homologous end joining and microhomology-mediated break-induced replication are the putative mechanisms for the deletions of the F9 gene. Because the g.12163_23369del deletion caused exons to be absent without a frameshift mutation occurring, a smaller FIX protein was observed in western blot analyses. PMID:27109384

  1. A genetic analysis of 23 Chinese patients with hemophilia B.

    PubMed

    Wang, Qing-Yun; Hu, Bei; Liu, Hui; Tang, Liang; Zeng, Wei; Wu, Ying-Ying; Cheng, Zhi-Peng; Hu, Yu

    2016-01-01

    Hemophilia B (HB) is an X-linked recessive bleeding disorder caused by mutations in the coagulation factor IX (FIX) gene. Genotyping patients with HB is essential for genetic counseling and provides useful information for patient management. In this study, the F9 gene from 23 patients with HB was analyzed by direct sequencing. Nineteen point mutations were identified, including a novel missense variant (c.520G > C, p.Val174Leu) in a patient with severe HB and a previously unreported homozygous missense mutation (c.571C > T, p.Arg191Cys) in a female patient with mild HB. Two large F9 gene deletions with defined breakpoints (g.10413_11363del, g.12163_23369del) were identified in two patients with severe HB using a primer walking strategy followed by sequencing. The flanking regions of the two breakpoints revealed recombination-associated elements (repetitive elements, non-B conformation forming motifs) with a 5-bp microhomology in the breakpoint junction of g.12163_23369del. These findings imply that non-homologous end joining and microhomology-mediated break-induced replication are the putative mechanisms for the deletions of the F9 gene. Because the g.12163_23369del deletion caused exons to be absent without a frameshift mutation occurring, a smaller FIX protein was observed in western blot analyses. PMID:27109384

  2. [Diagnosis and treatment of hemophilia A acquired during postpartum ].

    PubMed

    Castillo-Cañadas, Ana María; Serrano-Diana, Carolina; López-Del Cerro, Esther; Gómez-García, María Teresa; González De Merlo, Gaspar

    2014-10-01

    Acquired hemophilia A is a truly exceptional hemorrhagic diathesis, that consists of the emergence of polyclonal autoantibodies (inhibitor) IgG-type (subclasses 1 and 4, in most cases) against the coagulant function of the circulating factor VIII, which acts in the domains C2, A2 and A3 of the molecule, thus interfering their interaction with the factor IXa, the phospholipids and the Von Willebrand factor. Its morbidity and mortality are high, but nevertheless its low incidence (1-1.5 cases per million population per year) is the most frequent autoimmune disorder. This paper reports the clinical case of two patients; the first one, 36 years old, who the tenth day of postpartum required re-entry due to a diagnosis of hematoma of the abdominal wall that was surgically drained twice. The patient of case 2 was 39 years old and at six days of postpartum went to the emergency room due to bleeding, she was underwent to curettage and therapeutic transfusion of 3 UCH. Because of the persistence of bleeding, which was not possible to control with medical treatment and conservative measures, therapeutic hysterectomy was performed, with blood transfusion later. Due to the hemorrhagic complications of this condition and the serious clinical consequences derived from them, it is important to establish an early diagnosis; it is therefore critical to know the existence of this very rare disease to be able to avoid its consequences. PMID:25510060

  3. Hemophilia A: an ideal disease to correct in utero

    PubMed Central

    Porada, Christopher D.; Rodman, Christopher; Ignacio, Glicerio; Atala, Anthony; Almeida-Porada, Graça

    2014-01-01

    Hemophilia A (HA) is the most frequent inheritable defect of the coagulation proteins. The current standard of care for patients with HA is prophylactic factor infusion, which is comprised of regular (2–3 times per week) intravenous infusions of recombinant or plasma-derived FVIII to maintain hemostasis. While this treatment has greatly increased the quality of life and lengthened the life expectancy for many HA patients, its high cost, the need for lifelong infusions, and the fact that it is unavailable to roughly 75% of the world's HA patients make this type of treatment far from ideal. In addition, this lifesaving therapy suffers from a high risk of treatment failure due to immune response to the infused FVIII. There is thus a need for novel treatments, such as those using stem cells and/or gene therapy, which have the potential to mediate long-term correction or permanent cure following a single intervention. In the present review, we discuss the clinical feasibility and unique advantages that an in utero approach to treating HA could offer, placing special emphasis on a new sheep model of HA we have developed and on the use of mesenchymal stromal cells (MSC) as cellular vehicles for delivering the FVIII gene. PMID:25566073

  4. New developments in the management of moderate-to-severe hemophilia B.

    PubMed

    Nazeef, Moniba; Sheehan, John P

    2016-01-01

    Hemophilia B is an X-linked genetic deficiency of coagulation factor IX (FIX) activity associated with recurrent deep tissue and joint bleeding that may lead to long-term disability. FIX replacement therapy using plasma-derived protein or recombinant protein has significantly reduced bleeding and disability from hemophilia B, particularly when used in a prophylactic fashion. Although modern factor replacement has excellent efficacy and safety, barriers to the broader use of prophylaxis remain, including the need for intravenous (IV) access, frequent dosing, variability in individual pharmacokinetics, and cost. To overcome the requirement for frequent factor dosing, novel forms of recombinant FIX have been developed that possess extended terminal half-lives. Two of these products (FIXFc and rIX-FP) represent fusion proteins with the immunoglobulin G1 (IgG1) Fc domain and albumin, respectively, resulting in proteins that are recycled in vivo by the neonatal Fc receptor. The third product has undergone site-specific PEGylation on the activation peptide of FIX, similarly resulting in a long-lived FIX form. Clinical trials in previously treated hemophilia B patients have demonstrated excellent efficacy and confirmed less-frequent dosing requirements for the extended half-life forms. However, gaps in knowledge remain with regard to the risk of inhibitor formation and allergic reactions in previously untreated patient populations, safety in elderly patients with hemophilia, effects on in vivo FIX distribution, and cost-effectiveness. Additional strategies designed to rebalance hemostasis in hemophilia patients include monoclonal-antibody-mediated inhibition of tissue factor pathway inhibitor activity and siRNA-mediated reduction in antithrombin expression by the liver. Both of these approaches are long acting and potentially involve subcutaneous administration of the drug. In this review, we will discuss the biology of FIX, the evolution of FIX replacement therapy, the

  5. New developments in the management of moderate-to-severe hemophilia B

    PubMed Central

    Nazeef, Moniba; Sheehan, John P

    2016-01-01

    Hemophilia B is an X-linked genetic deficiency of coagulation factor IX (FIX) activity associated with recurrent deep tissue and joint bleeding that may lead to long-term disability. FIX replacement therapy using plasma-derived protein or recombinant protein has significantly reduced bleeding and disability from hemophilia B, particularly when used in a prophylactic fashion. Although modern factor replacement has excellent efficacy and safety, barriers to the broader use of prophylaxis remain, including the need for intravenous (IV) access, frequent dosing, variability in individual pharmacokinetics, and cost. To overcome the requirement for frequent factor dosing, novel forms of recombinant FIX have been developed that possess extended terminal half-lives. Two of these products (FIXFc and rIX-FP) represent fusion proteins with the immunoglobulin G1 (IgG1) Fc domain and albumin, respectively, resulting in proteins that are recycled in vivo by the neonatal Fc receptor. The third product has undergone site-specific PEGylation on the activation peptide of FIX, similarly resulting in a long-lived FIX form. Clinical trials in previously treated hemophilia B patients have demonstrated excellent efficacy and confirmed less-frequent dosing requirements for the extended half-life forms. However, gaps in knowledge remain with regard to the risk of inhibitor formation and allergic reactions in previously untreated patient populations, safety in elderly patients with hemophilia, effects on in vivo FIX distribution, and cost-effectiveness. Additional strategies designed to rebalance hemostasis in hemophilia patients include monoclonal-antibody-mediated inhibition of tissue factor pathway inhibitor activity and siRNA-mediated reduction in antithrombin expression by the liver. Both of these approaches are long acting and potentially involve subcutaneous administration of the drug. In this review, we will discuss the biology of FIX, the evolution of FIX replacement therapy, the

  6. Identification and Genetic Analysis of a Factor IX Gene Intron 3 Mutation in a Hemophilia B Pedigree in China

    PubMed Central

    Cao, Dong-Hua; Liu, Xiao-Li; Mu, Kai; Ma, Xiang-Wei; Sun, Jing-Li; Bai, Xiao-Zhong; Lin, Chang-Kun; Jin, Chun-Lian

    2014-01-01

    Objective: Hemophilia B is caused by coagulation defects in the factor IX gene located in Xq27.1 on the X chromosome. A wide range of mutations, showing extensive molecular heterogeneity, have been described in hemophilia B patients. Our study was aimed at genetic analysis and prenatal diagnosis of hemophilia B in order to further elucidate the pathogenesis of the hemophilia B pedigree in China. Materials and Methods: Polymerase chain reaction amplification and direct sequencing of all the coding regions was conducted in hemophilia B patients and carriers. Prenatal diagnosis of the proband was conducted at 20 weeks. Results: We identified the novel point mutation 10.389 A>G, located upstream of the intron 3 acceptor site in hemophilia B patients. The fetus of the proband’s cousin was identified as a carrier. Conclusion: Our identification of a novel mutation in the F9 gene associated with hemophilia B provides novel insight into the pathogenesis of this genetically inherited disorder and also represents the basis of prenatal diagnosis. PMID:25330515

  7. Large hemorrhage due to venipuncture in the elbow of a patient with severe hemophilia: A case report and literature review

    PubMed Central

    LYU, JINGTONG; WU, WENJIE; XIANG, ZHOU; HUANG, FUGUO

    2016-01-01

    Hemophilia A, which is the most common form of hemophilia, is caused by a deficiency of clotting factor VIII. The incidence of hemophilia A is 1:10,000 people worldwide. The most common complication associated with hemophilia A is bleeding into joints, predominantly the knees, ankles, and elbows, which may lead to destruction or osteoarthritis of the specific joint. Various degrees of disability may follow these initial or recurrent hemorrhages. Subsequent to improvements in medical management, patients with hemophilia A currently have a life expectancy similar to that of the normal population. However, the management of patients with hemophilia A remains a clinical challenge for various reasons, including the lack of reliable and cost-effective treatment, and the high risk of intra- or post-operative hemorrhages. Large hemorrhages due to the phlebotomizing of young patients are very rare. To the best of our knowledge, the present case is the first report regarding the occurrence of a large hemorrhage due to venipuncture in the elbow of a patient with hemophilia A, and discusses the pathogenesis, clinical manifestation, and the medico-chirurgical treatment of this patient. PMID:26998031

  8. Immunoadsorption for pregnancy-associated severe acquired hemophilia.

    PubMed

    Zeitler, Heike; Ulrich-Merzenich, Gudrun; Marquardt, Natascha; Oldenburg, Johannes; Goldmann, Georg

    2014-02-01

    Postpartum hemorrhage is a common cause of maternal mortality. Acquired hemophilia (AH) is a rare, life-threatening bleeding disorder induced by autoantibodies against coagulation factors (inhibitors). We report about eight patients with postpartum AH (out of 82). Seven AH patients with severe bleeding complications were treated by the "Modified Bonn-Malmö Protocol (MBMP)" which consists of inhibitor elimination via immunoadsorption (IA) in combination with immunosuppression and high-dose Factor VIII substitution. One patient was treated only by immunosuppression. Seven out of eight patients with severe AH and mean inhibitor titers (IT) of 118 BU/mL were referred to our center. They were severe cases with a median delay of diagnosis of 30.5 days (range 7-278 days). After a median of 3 IA sessions (range 3-5 days), no inhibitor was detectable. The factor substitution was discontinued after a median of 13 IA sessions (range 8-24 days) and IA was terminated after a median of 15 sessions (range 9-27 days). One less severe affected patient (IT: 2.1 BU/mL) received prednisolone (1.5 mg/kg BW) for 120 days. Complete remission was achieved in all patients with a median follow-up of 100 months (range 56-126 m). The delayed diagnosis of pregnancy-associated AH leads to a high bleeding risk with bleeding associated complications. Immunoadsorption offers an important treatment option in severe AH, enabling a fast reconstitution of the blood coagulation with a reduced time for the Factor VIII substitution and for immunosuppressive treatment. In cases of postpartum bleeding the diagnosis of AH should be routinely considered. PMID:24499091

  9. Unusual Late Presentation of Hemophilia A in an Active Duty U.S. Marine Following Open Shoulder Surgery.

    PubMed

    Shapiro, Bennett H; Minter, Alex R; McDonald, Lucas S

    2015-12-01

    Hemophilia A is clotting disorder affecting 8:100,000 males in the United States. It is an X-linked recessive genetic disorder, although about one-third of cases occur spontaneously without known family history. Because of the risk of uncontrolled hemorrhage on the battlefield, hemophilia and other bleeding disorders exclude individuals from service in the U.S. military. We report a case of an active duty U.S. Marine whose underlying diagnosis of Hemophilia A was discovered and treated by a multidisciplinary team of orthopedic surgeons and hematologists following recurrent hematomas after open rotator cuff surgery. The patient gave informed consent for publication. PMID:26633674

  10. 78 FR 57868 - Prospective Grant of Exclusive Patent License: Oral Treatment of Hemophilia

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-09-20

    ... administering an effective amount of the appropriate clotting factor, sufficient to induce oral tolerance and supply exogenous clotting factor to the subject. Roughly 20,000 people in the U.S. have hemophilia with... generally involves intravenous infusion of missing clotting factors derived from concentrated...

  11. Uncomplicated abortion with mifepristone and misoprostol in a hemophilia A carrier.

    PubMed

    Hou, Melody Y

    2016-08-01

    Little evidence exists regarding medical abortion for women with inherited bleeding disorders. A 21-year-old primigravid hemophilia A carrier desired a medical abortion. After counseling, she chose medical abortion, which occurred without excess bleeding or surgical intervention. PMID:27085601

  12. Neutralizing antibodies against adeno-associated virus examined prospectively in pediatric patients with hemophilia.

    PubMed

    Li, C; Narkbunnam, N; Samulski, R J; Asokan, A; Hu, G; Jacobson, L J; Manco-Johnson, M J; Monahan, P E

    2012-03-01

    Recombinant adeno-associated virus (rAAV) is a promising gene delivery vector and has recently been used in patients with hemophilia. One limitation of AAV application is that most humans have experienced wild-type AAV serotype 2 exposure, which frequently generates neutralizing antibodies (NAbs) that may inhibit rAAV2 vector transduction. Employing alternative serotypes of rAAV vectors may circumvent this problem. We investigated the development of NAbs in early childhood by examining sera gathered prospectively from 62 children with hemophilia A, participating in a multi-institutional hemophilia clinical trial (the Joint Outcome Study). Clinical applications in hemophilia therapy have been suggested for serotypes AAV2, AAV5 and AAV8, therefore NAbs against these serotypes were serially assayed over a median follow-up of 4 years. NAbs prevalence increased during early childhood for all serotypes. NAbs against AAV2 (43.5%) were observed more frequently and at higher titers compared with both AAV5 (25.8%) and AAV8 (22.6%). NAbs against AAV5 or AAV8 were rarely observed in the absence of co-prevalent and higher titer AAV2 NAbs, suggesting that NAbs to AAV5 and AAV8 were detected following AAV2 exposure due to partial cross-reactivity of AAV2-directed NAbs. The results may guide rational design of clinical trials using alternative AAV serotypes and suggest that younger patients who are given AAV gene therapy will benefit from the lower prevalence of NAbs. PMID:21697954

  13. Spinal Epidural Hematoma Following Cupping Glass Treatment in an Infant With Hemophilia A.

    PubMed

    Fruchtman, Yariv; Dardik, Rima; Barg, Assaf Arie; Livnat, Tami; Feldman, Zeev; Rubinstein, Marina; Grinberg, Gahl; Rosenberg, Nurit; Kenet, Gili

    2016-06-01

    A 6 months old infant, diagnosed with a rare mutation causing severe hemophilia A, presented with spinal epidural hematoma. Parents later admitted the infant had glass cupping therapy performed within 2 weeks of the onset of symptoms. The rare mutation, rare bleeding complication, and the eventual course of therapy applied in this case will be discussed in our case report. PMID:26844816

  14. Knowledge of Oral Hygiene among Hemophilic Patients Referred to Iranian Hemophilia Society

    PubMed Central

    Abrisham, Mohammad; Tabrizizadeh, Mehdi; Ghateh, Alireza

    2009-01-01

    Background and aims Hemophilic patients are faced with poor oral hygiene due to concerns about their dental care. The present study assessed the knowledge of hemophilic patients about oral hygiene and the effect of oral hygiene instruction in patients referred to Iranian Hemophilia Society. Materials and methods This cross-sectional study was carried out on 30 hemophilic patients randomly selected from volunteer patients referred to Iran Hemophilia Center. The study was performed by means of a questionnaire submitted to subjects before and after the instructional brochure submission. The questionnaire included demographic data and items regarding hemophilia and oral hygiene. Data was analyzed with McNemar test and paired t-test. Results The mean age of the patients was 21 years; 27 (90%) were males and 3 ones (10%) were females. They were mostly A hemophilia infected. Most patients enjoyed fair knowledge of oral hygiene. Changes in knowledge after reading the bro-chure were significant regarding the appropriate time to replace the toothbrush (P < 0.01), necessary visits for tooth examina-tions (P < 0.04), adjunctive methods of caries prevention (P < 0.001) and factors related to bleeding (P < 0.01); other factors improved slightly without significant changes. Conclusion The knowledge of hemophilic patients was fair regarding oral hygiene while some relevant factors improved after instructions. However, more instruction is needed in order to attain more improvement in some behaviors. PMID:23230484

  15. Factor VIII gene (F8) mutation and risk of inhibitor development in nonsevere hemophilia A.

    PubMed

    Eckhardt, Corien L; van Velzen, Alice S; Peters, Marjolein; Astermark, Jan; Brons, Paul P; Castaman, Giancarlo; Cnossen, Marjon H; Dors, Natasja; Escuriola-Ettingshausen, Carmen; Hamulyak, Karly; Hart, Daniel P; Hay, Charles R M; Haya, Saturnino; van Heerde, Waander L; Hermans, Cedric; Holmström, Margareta; Jimenez-Yuste, Victor; Keenan, Russell D; Klamroth, Robert; Laros-van Gorkom, Britta A P; Leebeek, Frank W G; Liesner, Ri; Mäkipernaa, Anne; Male, Christoph; Mauser-Bunschoten, Evelien; Mazzucconi, Maria G; McRae, Simon; Meijer, Karina; Mitchell, Michael; Morfini, Massimo; Nijziel, Marten; Oldenburg, Johannes; Peerlinck, Kathelijne; Petrini, Pia; Platokouki, Helena; Reitter-Pfoertner, Sylvia E; Santagostino, Elena; Schinco, Piercarla; Smiers, Frans J; Siegmund, Berthold; Tagliaferri, Annarita; Yee, Thynn T; Kamphuisen, Pieter Willem; van der Bom, Johanna G; Fijnvandraat, Karin

    2013-09-12

    Neutralizing antibodies (inhibitors) toward factor VIII form a severe complication in nonsevere hemophilia A, profoundly aggravating the bleeding pattern. Identification of high-risk patients is hampered by lack of data that take exposure days to therapeutic factor VIII concentrates into account. In the INSIGHT study, we analyzed the association between F8 mutation and inhibitor development in patients with nonsevere hemophilia A (factor VIII 2-40 IU/dL). This analysis included 1112 nonsevere hemophilia A patients from 14 centers in Europe and Australia that had genotyped at least 70% of their patients. Inhibitor risk was calculated as Kaplan-Meier incidence with cumulative number of exposure days as the time variable. During 44 800 exposure days (median, 24 exposure days per patient; interquartile range [IQR], 7-90), 59 of the 1112 patients developed an inhibitor; cumulative incidence of 5.3% (95% confidence interval [CI], 4.0-6.6) after a median of 28 exposure days (IQR, 12-71). The inhibitor risk at 50 exposure days was 6.7% (95% CI, 4.5-8.9) and at 100 exposure days the risk further increased to 13.3% (95% CI, 9.6-17.0). Among a total of 214 different F8 missense mutations 19 were associated with inhibitor development. These results emphasize the importance of F8 genotyping in nonsevere hemophilia A. PMID:23926300

  16. 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. PMID:25675273

  17. 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

  18. [Diagnosis of mild hemophilia A made by massive intraabdominal bleeding in a 13-year-old boy].

    PubMed

    Terao, Yoko; Akiyama, Masaharu; Yokoi, Kentaro; Yamaoka, Masayoshi; Shimizu, Mika; Kato, Yoko; Tanaka, Keiichiro; Baba, Yuji; Kuwashima, Naruo; Ashizuka, Shuichi; Yoshizawa, Jyoji; Motoki, Takanori; Saito, Yoshihiro; Ida, Hiroyuki

    2012-08-01

    We report a 13-year-old boy who had massive intra-abdominal bleeding without a history of bleeding episodes or traumatic cause of bleeding. The patient underwent surgical treatment because bleeding was not controlled after treatment with tranexamic acid and transfusions including fresh-frozen plasma. Bleeding was traced to the lower left lobe of the liver. The mother's side of the family had a history of bleeding episodes in the boy's grandfather, great uncle, and son of a great aunt. A low level of plasma factor VIII coagulant activity (22%) led to a diagnosis of mild hemophilia A. Compared with severe hemophilia, mild hemophilia is more difficult to diagnose because bleeding episodes are less frequent. Most cases are found after incidental trauma or uncontrolled surgery-related bleeding, there is rarely a family history of hemophilia and activated partial thromboplastin time is normal or slightly prolonged. However, bleeding episodes in mild hemophilia may result in excessive, sometimes life-threatening hemorrhage and require early diagnosis and replacement treatment with adequate amounts of factor VIII, as in severe hemophilia. PMID:22975817

  19. Maternal low-level somatic mosaicism of Cys155Tyr of F9 in severe hemophilia B.

    PubMed

    Kim, Hee-Jung; Lee, Ki-O; Yoo, Ki-Young; Kim, Sun-Hee; Kim, Hee-Jin

    2015-12-01

    Hemophilia B is an X-linked bleeding disorder caused by deficient coagulation factor IX from a mutation in the F9 gene. Here, we report a family with two brothers having severe hemophilia B inherited from a mother with low-level somatic mosaicism of a F9 mutation. The proband was a 2-year-old boy with severe hemophilia B from a hemizygous mutation of F9, c.464G>A (p.Cys155Tyr). He was the first child and was considered a sporadic case based on the lack of family history of bleeding diathesis. His mother was tested for carrier status and was determined to be homozygous for wild-type genotypes (noncarrier). Subsequently, however, his brother was born and also had severe hemophilia B from Cys155Tyr. This prompted us to review the chromatogram of the mother, which revealed a small peak corresponding to the mutant genotype. On suspicion of somatic low-level mosaicism in the mother, we further performed allele-specific PCR and thymine and adenine cloning, and confirmed the presence of the mutant allele in the mother. To our knowledge, this is the first case of maternal somatic mosaicism for a cytosine-phosphate-guanine transition mutation in hemophilia B. The acknowledgment of somatic mosaicism and further molecular investigation are important in sporadic hemophilia B to deliver informative genetic counseling and risk assessment. PMID:25402191

  20. How I use bypassing therapy for prophylaxis in patients with hemophilia A and inhibitors.

    PubMed

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

    2015-07-01

    Inhibitor development poses a significant challenge in the management of hemophilia because once an inhibitor is present, bleeding episodes can no longer be treated with standard clotting factor replacement therapy. Consequently, patients with inhibitors are at increased risk for difficult-to-control bleeding and complications, particularly arthropathy and physical disability. Three clinical trials in patients with inhibitors have demonstrated that prophylaxis with a bypassing agent reduces joint and other types of bleeding and improves health-related quality of life compared with on-demand bypassing therapy. In hemophilia patients without inhibitors, the initiation of prophylaxis with factor (F) VIII or FIX prior to the onset of recurrent hemarthroses can prevent the development of joint disease. Whether this is also true for bypassing agent prophylaxis remains to be determined. PMID:25827834

  1. [Mutational Analysis of Hemophilia B in Russia: Molecular-Genetic Study].

    PubMed

    Surin, V L; Demidova, E Yu; Selivanova, D S; Luchinina, Yu A; Salomashkina, V V; Pshenichnikova, O S; Likhacheva, E A

    2016-04-01

    Hemophilia B is a hereditary X-linked coagulation disorder. This pathology is caused by various defects in the factor IX gene, which is, being about 34 kb long and consisting of eight exons, localized in the Xq27 locus of the. X-chromosome long arm. Mutations were revealed in 56 unrelated patients with hemophilia B in this study by using direct sequencing of factor IX gene functionally important fragments. Forty-six mutations were found with prevailing missense mutations (n = 30). The rest of the mutations were nonsense (n = 4) and splicing (n = 4) mutations, large deletions (n = 3), microdeletions (n = 2), microinsertions (n = 2), and promoter mutations (n = 1). Eleven of 46 mutations were previously unknown for human populations. PMID:27529981

  2. [Mild hemophilia A fortuitously discovered during Henoch-Schönlein purpura].

    PubMed

    Joly, B; d'Oiron, R; Desconclois, C; Bendelac, L; Rafowicz, A; Meyzer, C; Labrune, P; Veyradier, A

    2015-11-01

    Henoch-Schönlein purpura is a common form of immunological vasculitis in children. Hemophilia A is a genetic disorder, inherited in a X-linked recessive pattern, and characterized by spontaneous hemorrhage or prolonged bleeding due to factor VIII deficiency. The clinical signs depend on the severity of factor VIII deficiency. We herein report the case of a 4-year-old boy admitted to the emergency room for typical rheumatoid purpura, associated with a lengthening of aPTT, whose exploration had uncovered mild hemophilia A. Laboratory assays should explore lengthening of aPTT: firstly the presence of lupus anticoagulant without bleeding risk, in an inflammatory context; secondly a deficiency of VWF and one of the factors involved in the extrinsic coagulation pathway associated with bleeding risk. PMID:26412326

  3. Emerging issues on comprehensive hemophilia care: preventing, identifying, and monitoring age-related comorbidities.

    PubMed

    Coppola, Antonio; Santoro, Cristina; Franchini, Massimo; Mannucci, Caterina; Mogavero, Selene; Molinari, Angelo Claudio; Schinco, Piercarla; Tagliaferri, Annarita; Santoro, Rita Carlotta

    2013-10-01

    Life expectancy for persons with hemophilia (PWH) has considerably increased in the last decades as a direct result of the availability of modern therapies to control the clotting defect. Because their life expectancy now matches that of the general population, PWH are experiencing age-related comorbidities, such as, cardiovascular diseases, metabolic syndrome, renal diseases, sexuality issues, malignancies, and neurologic problems, that until recently have been rarely seen in this group of patients. In this article, we present a summary of the current knowledge on the aging PWH along with the clinical approaches that may be integrated into the routine comprehensive care of these patients for preventing, diagnosing, and monitoring age-related comorbidities. In general, patients with and without hemophilia should receive similar care, with close collaboration between the physician treating PWH and the specialty expert treating the comorbid disease. PMID:24014070

  4. Prevention of bleeding in hemophilia patients with high-titer inhibitors.

    PubMed

    Leissinger, Cindy A; Konkle, Barbara A; Antunes, Sandra V

    2015-06-01

    Inhibitor development is the most serious adverse event linked to the treatment of hemophilia, as it renders standard hemostatic therapy ineffective. Consequently, inhibitor patients are at increased risk for difficult-to-control bleeding and complications, particularly arthropathy and physical disability. Three randomized clinical trials in patients with inhibitors have demonstrated that compared with on-demand bypassing therapy, prophylaxis with a bypassing agent reduces joint and other types of bleeding and improves health-related quality of life. In hemophilia patients without inhibitors, the initiation of prophylaxis with factor (F) VIII or IX prior to the onset of recurrent hemarthroses can prevent the development of joint disease. Whether this is also true for bypassing agent prophylaxis remains to be determined. PMID:25937074

  5. 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. PMID:27074697

  6. Clinical efficacy and determinants of response to treatment with desmopressin in mild hemophilia a.

    PubMed

    Di Perna, Caterina; Riccardi, Federica; Franchini, Massimo; Rivolta, Gianna Franca; Pattacini, Corrado; Tagliaferri, Annarita

    2013-10-01

    Although desmopressin (DDAVP) is considered as the treatment of choice for many patients with mild hemophilia A, several aspects of DDAVP therapy remain unclear, including the rate and type of response and the molecular determinants of its clinical efficacy. To investigate these issues, we retrospectively studied all patients with mild hemophilia A followed up at the Parma Hemophilia Center. A total of 75 patients were enrolled who underwent a DDAVP test, and out of whom, 76% (57/75) had a complete or partial response. Response to DDAVP was significantly correlated to the patients' age (median age of responders and nonresponders: 24 and 18 y, respectively; p = 0.04) and type of mutation (all the 10 patients with mutations in the promoter region were nonresponders). The median basal factor VIII (FVIII):C level was significantly lower in responders than in nonresponders (0.14 vs. 0.19 IU/mL, respectively; p = 0.01); this was mainly due to nonresponders with promoter region mutations who had higher basal FVIII:C levels. During the 12-year follow-up, 82 of 237 (35%) bleeding episodes occurring in 27 responder patients were treated with 246 DDAVP infusions with complete or partial efficacy in 92% (75/82). Overall, 142 events were managed with 253 prophylactic DDAVP infusions, which were hemostatically effective in 96% of cases. No severe adverse reactions to DDAVP administration were recorded during the study period. These results document the safety and efficacy of DDAVP as a treatment or prevention of bleeding in patients with mild hemophilia A, also in the context of home treatment, and encourage the more widespread use of this product. PMID:24030345

  7. LASER versus electromagnetic field in treatment of hemarthrosis in children with hemophilia.

    PubMed

    Eid, Mohamed A; Aly, Sobhy M

    2015-11-01

    Children with hemophilia usually have recurrent joint bleeding that leads to joint damage, loss of range of motion, and restriction of mobility, therefore affecting the quality of life in these children. The purpose of this study was to compare the effects of low-level laser therapy (LLLT) to that of pulsed electromagnetic field (PEMF) in treatment of hemarthrosis in children with hemophilia. Thirty boys with hemophilia A with ages ranging from 9 to 13 years were selected and assigned randomly, using sealed envelopes, into two equal intervention groups. The study group I received the traditional physical therapy program in addition to LLLT, whereas the study group II received the same physical therapy program given to the study group I in addition to PEMF. Both groups received the treatment sessions three times per week for three successive months. Pain, laboratory investigations, swelling, and range of motion (ROM) of the affected knee joint, in addition to physical fitness were evaluated before, at the end of the sixth week and at 12 weeks of the treatment program. Laser group showed significant improvement in all measured variables after the sixth week of treatment when compared with PEMF. By 12 weeks of treatment, there was a significant improvement in pain, ROM, ESR and leucocytes levels in laser group compared with PEMF, while there was no significant difference in knee circumferences and the 6-min walk test (6MWT) between both groups. Both groups showed significant improvement at 12 weeks of treatment compared with that at 6 weeks. Both LLLT and PEMF are effective modalities in reducing pain, swelling, increasing ROM and improving physical fitness. Twelve weeks of treatment of both modalities demonstrated significant improvement than 6 weeks of treatment. Laser therapy induced significant improvement than electromagnetic therapy in treatment of hemarthrosis-related problems in children with hemophilia. PMID:26306883

  8. US Hemophilia Treatment Center population trends 1990-2010: patient diagnoses, demographics, health services utilization.

    PubMed

    Baker, J R; Riske, B; Drake, J H; Forsberg, A D; Atwood, R; Voutsis, M; Shearer, R

    2013-01-01

    For several decades, US government agencies have partially supported regional networks of Hemophilia Treatment Centers (HTC). HTC multidisciplinary teams provide comprehensive and coordinated diagnosis, treatment, prevention, education, outreach and surveillance services to improve the health of people with genetic bleeding disorders. However, national data are scarce on HTC-patient population trends and services. The aim of the study was to examine national trends over the past 20 years in patient diagnoses, demographics and health services utilization among the Health Resources and Services Administration (HRSA) and Centers for Disease Control and Prevention (CDC)-supported HTC network. Diagnoses, demographics and health services utilization data from 1990 to 2010 were aggregated from all HTCs using the Hemophilia Data Set (HDS). From 1990 to 2010, the HTC population grew 90% from 17 177 to 32 612. HTC patients with von Willebrand's disease increased by 148%, females by 346%, Hispanic patients by 236% and African Americans by 104%. Four thousand and seventy-five deaths were reported. From 2002 to 2010, annual comprehensive evaluations grew 38%, and persons with severe haemophilia on a home intravenous therapy programme rose 37%. In 2010, 46% of patients were less than 18 years vs. 24% for the general US population. The Hemophilia Data Set documents the growth and diversity of the US Hemophilia Treatment Center Network's patient population and services. Despite disproportionate deaths due to HIV, the HTC patient base grew faster than the general US population. The HDS is a vital national public health registry for this rare-disorder population. PMID:22845803

  9. 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

  10. Telehealth Videoconferencing for Children With Hemophilia and Their Families: A Clinical Project.

    PubMed

    Jacobson, Kimberly; Hooke, Mary C

    2016-07-01

    Telehealth is the use of electronic information and telecommunications technologies to support long-distance health care. It supports quality health care that is accessible, and time- and cost-effective. Telehealth videoconferencing may enhance the care for hemophilia patients who are experiencing a bleed by supporting real-time detailed assessment including appearance, range of motion, and ambulation in addition to the traditional phone methods of verbal description of appearance, pain, and function. The aim of this clinical project was to evaluate the feasibility of using telehealth videoconferencing in children with severe hemophilia in the home setting. Twelve patients with severe hemophilia ages 2to 18 years, who had more than 2 breakthrough bleeds in the past year, and had Internet access with a computer camera were included. The incidence of bleeding was low; however, videoconferencing was effective for 3 patients who completed 4 video appointments. Patients and staff reported that videoconferencing improved communication and satisfaction. Telehealth videoconferencing is a feasible tool for managing bleeding disorders in the home setting. PMID:26510644

  11. Hemophilia A due to mutations that create new N-glycosylation sites.

    PubMed Central

    Aly, A M; Higuchi, M; Kasper, C K; Kazazian, H H; Antonarakis, S E; Hoyer, L W

    1992-01-01

    In studying the molecular defects responsible for cross-reacting material-positive hemophilia A, we have identified two patients in whom the nonfunctional factor VIII-like protein has abnormal, slower-moving heavy or light chains on SDS/PAGE. Both patients have severe hemophilia A (less than 1% of normal factor VIII activity) with a normal plasma level of factor VIII antigen. The molecular defects were identified by denaturing gradient gel electrophoresis screening of PCR-amplified products of the factor VIII-coding DNA sequence followed by nucleotide sequencing of the abnormal PCR products. In patient ARC-21, a methionine-to-threonine substitution at position 1772 in the factor VIII light chain creates a potential new N-glycosylation site at asparagine-1770. In patient ARC-22, an isoleucine-to-threonine substitution at position 566 creates a potential new N-glycosylation site at asparagine-564 in the A2 domain of the factor VIII heavy chain. The mobility of these chains on SDS/PAGE was normal after N-Glycanase digestion and procoagulant activity was generated--to a maximum of 23% and 45% of control normal plasma. Abnormal N-glycosylation, blocking factor VIII procoagulant activity, represents a newly recognized mechanism for the pathogenesis of severe hemophilia A. Images PMID:1594597

  12. 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

  13. 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

  14. Expression of von Willebrand factor Normandy: An autosomal mutation that mimics hemophilia A

    SciTech Connect

    Tuley, E.A.; Worrall, N.K.; Sadler, J.E. ); Gaucher, C.; Jorieux, S.; Mazurier, C. )

    1991-07-15

    von Willebrand disease Normandy (vWD Normandy) is a recently described phenotype in which a mutant von Willebrand factor (VWF) appears structurally and functionally normal except that is does not bind to blood coagulation factor VIII. This interaction is required for normal survival of factor VIII in the circulation; consequently, vWD Normandy can present as apparent hemophilia A but with autosomal recessive rather than X chromosome-linked inheritance. AvWF missense mutation, Thr{sup 28} {r arrow} Met, was identified in the propositus in or near the factor VIII binding site. The corresponding mutant recombinant vWF(T28M) formed normal multimers and had normal ristocetin cofactor activity. However, vWF(T28M) exhibited the same defect in factor VIII binding as natural vWF Normandy, confirming that this mutation causes the vWD Normandy phenotype. The distinction between hemophilia A and vWD Normandy is clinically important and should be considered in families affected by apparent mild hemophilia A that fail to show strict X chromosome-linked inheritance and, particularly, in potential female carriers with low factor VIII levels attributed to extreme lyonization.

  15. 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. PMID:27011017

  16. 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

  17. Life-threatening hemorrhage from acquired hemophilia A as a presenting manifestation of prostate cancer.

    PubMed

    Sheth, Chirag; Gill, Amandeep; Sekhon, Sumeet

    2016-01-01

    Acquired factor VIII deficiency (acquired hemophilia A) is a rare condition characterized by the acquisition of autoantibodies that affect the clotting activity of factor VIII (fVIII). The most common manifestation in affected patients is a hemorrhagic diathesis. This disorder is associated with autoimmune diseases, pregnancy, postpartum period, drugs, and malignancy. Management of this condition begins with attempts to arrest an acute bleed based on the site and severity of bleeding and inhibitor titer. The next priority is eradication of the fVIII antibodies using immunosuppressive therapies. We report the case of a 66-year-old male who presented with spontaneous right thigh hematoma with prolonged activated partial prothrombin time and normal prothrombin time. Mixing studies confirmed the presence of an inhibitor. Further investigation for the underlying etiology of acquired hemophilia A leads to diagnosis of prostate cancer. Treatment consisted of bypassing agents including activated factor VII and activated prothrombin plasma concentrate to arrest the bleeding. Steroids and cyclophosphamide were added to suppress the fVIII inhibitors. Concomitant treatment of locally advanced prostate cancer with chemotherapy confirmed the eradication of the inhibitors. To our knowledge, this is the first reported case of prostate cancer diagnosed and treated simultaneously with acquired hemophilia A resulting in favorable patient outcome. PMID:27609734

  18. 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. PMID:21764831

  19. The Association Between HLA Class II Alleles and the Occurrence of Factor VIII Inhibitor in Thai Patients with Hemophilia A

    PubMed Central

    Nathalang, Oytip; Sriwanitchrak, Pramote; Sasanakul, Werasak; Chuansumrit, Ampaiwan

    2012-01-01

    Objective: This study aimed to investigate the association between HLA class II alleles and the occurrence of FVIIIinhibitor in Thai hemophilia A patients. Material and Methods: The distribution of HLA-DRB1 alleles and DQB1 alleles in 57 Thai hemophilia A patientsand 36 blood donors as controls was determined using the PCR sequence-specific primer (PCR-SSP) method, and theassociation between the occurrence of factor VIII (FVIII) inhibitor and the presence of certain HLA class II alleles wasinvestigated. Results: The frequency of HLA-DRB1*15 was higher in the hemophilia A patients with and without FVIII inhibitor,whereas that of DRB1*14, DRB1*07, and DQB1*02 was lower in the hemophilia A patients with FVIII inhibitor, ascompared to controls. Interestingly, only the frequency of DRB1*15 was significantly higher in the patients with inhibitorthan in the controls (P = 0.021). Moreover, the frequency of DRB1*15 in the patients with inhibitor was higher than inthose without inhibitor (P = 0.198). Conclusion: The study’s findings show that the DRB1*15 allele might have contributed to the occurrence of inhibitorin the Thai hemophilia A patients; however, additional research using larger samples and high-resolution DRB1 typingis warranted. PMID:24744621

  20. Life-threatening bleeding in a patient with mild hemophilia A and heterozygosity for von Willebrand disease Type 2N.

    PubMed

    Allan, John N; Friedman, Kenneth D; DeSancho, Maria T

    2014-12-01

    Hemophilia A and von Willebrand disease (VWD) are distinct bleeding disorders with a spectrum of clinical phenotypes. They are characterized by mutations in either factor VIII (F8) or von Willebrand factor (VWF) genes, respectively. The pattern of inheritance and appropriate laboratory evaluation differentiates these diseases, and treatment strategies for both are different. Here, we report a male patient with hemophilia A and VWD Type 2 Normandy (N) mutations who presented with life-threatening bleeding. We document his medical history, clinical course, management, and diagnostic work up. PMID:25212677

  1. [Gene mutation analysis of coagulation factor VIII from a female patient with hemophilia A].

    PubMed

    Zhou, Jing; Yan, Nai-hong; Jia, Yong-qian; Lu, Yi-lu; Yu, Jiang; Cao, Gui-qun; Chen, Qing-ying; Wang, Ling; Zhang, Fa-qiang; Xia, Oing-jie

    2006-05-01

    Hemophilia A affects male, whereas females are carriers and generally spared from this disease. However, we here reported a 65-year-old female with Hemophilia A while screening the gene mutation of coagulation factor VIII. The female went to hospital because of tripping to lead her right chest to be injured with subcutaneous hematoma. She had historically a hemorrhagic diathesis. The physical examination discovered her hip limited to bend and move, but no discrepancy length between her two legs. The initial laboratory tests showed that the activated partial thromboplastin time (APTT) was 61. 3 seconds (20-40 seconds), and the APTT corrected by mixing with normal plasma was 41.3 s, but the levels of PT, FIB and TT were normal. The plain radiographs revealed the hip joints to suffer from the acetabular dysplasia and osteoarthritis. The level of FVIII:C was 2%, F IX:C 200%, vWF:Ag 120%, vWF:Rcof 100%, vWF:CBA 128%, and the F VIII binding assay to vWF was normal. The primers for exon 14 of F VIII gene were designed according to the NM - 000132 gene sequence. DNA was abstracted from the patient blood. PCR were carried out and the DNA sequence was followed. A new mutation of 4111A-->C was discovered, which caused the amino acid sequence changed (T 1314 P). The mutation of T 1314 P may be the cause of this female patient to get the hemophilia A. This mutation was a novel one which has never been reported before. PMID:16761442

  2. Characterization of genetic defects of hemophilia A in patients of Chinese origin

    SciTech Connect

    Lin, Shu-Wha; Lin, Shu-Rung; Shen, Ming-Ching )

    1993-12-01

    The molecular characterization of hemophilia A of Chinese origin was carried out by the polymerase chain reaction (PCR) and direct sequencing of patient's factor VIII genes. Single-strand conformation polymorphism (SSCP) and dideoxy fingerprinting (ddF) were used as screening methods to detect mutated DNAs. A total of 102 individuals from 87 different families, including 10 patients (10 families) with mild-to-moderate and 92 patients (77 families) with severe hemophilia A, were analyzed by PCR-SSCP and PCR-ddF. Of the 87 independent cases, 40 revealed a single mutation in the coding regions of their factor VIII genes. These mutations include 21 with single base changes resulting in 8 nonsense and 13 missense codons, 16 with deletion or insertion of 1-11 nucleotides, and 3 with deletion of large DNA fragments. The frequency of 8 of the identified factor VIII polymorphisms or silent mutations was also determined among Chinese. The frequencies for codons 1241, 1269, and 2223 (the numbering system follows J. Gitschier et al., 1984, Nature 312: 326-330) were found to be different from those reported for other populations. As for the 47 severe cases whose mutational events were not readily detected by PCR-SSCP and PCR-ddF, the reverse transcriptase PCR method was applied. In 24 such cases analyzed, 17 were found to be of the [open quotes]intron 22 mutations[close quotes] as described by Naylor et al. (1992, The Lancet, 342: 1066-1067), accounting for 39% of Chinese patients with hemophilia A. 31 refs., 2 figs., 6 tabs.

  3. Safety and prolonged activity of recombinant factor VIII Fc fusion protein in hemophilia A patients

    PubMed Central

    Josephson, Neil C.; Quon, Doris; Ragni, Margaret V.; Cheng, Gregory; Li, Ella; Jiang, Haiyan; Li, Lian; Dumont, Jennifer A.; Goyal, Jaya; Zhang, Xin; Sommer, Jurg; McCue, Justin; Barbetti, Margaret; Luk, Alvin

    2012-01-01

    Current factor VIII (FVIII) products display a half-life (t1/2) of ∼ 8-12 hours, requiring frequent intravenous injections for prophylaxis and treatment of patients with hemophilia A. rFVIIIFc is a recombinant fusion protein composed of a single molecule of FVIII covalently linked to the Fc domain of human IgG1 to extend circulating rFVIII t1/2. This first-in-human study in previously treated subjects with severe hemophilia A investigated safety and pharmacokinetics of rFVIIIFc. Sixteen subjects received a single dose of rFVIII at 25 or 65 IU/kg followed by an equal dose of rFVIIIFc. Most adverse events were unrelated to study drug. None of the study subjects developed anti-rFVIIIFc antibodies or inhibitors. Across dose levels, compared with rFVIII, rFVIIIFc showed 1.54- to 1.70-fold longer elimination t1/2, 1.49- to 1.56-fold lower clearance, and 1.48- to 1.56-fold higher total systemic exposure. rFVIII and rFVIIIFc had comparable dose-dependent peak plasma concentrations and recoveries. Time to 1% FVIII activity above baseline was ∼ 1.53- to 1.68-fold longer than rFVIII across dose levels. Each subject showed prolonged exposure to rFVIIIFc relative to rFVIII. Thus, rFVIIIFc may offer a viable therapeutic approach to achieve prolonged hemostatic protection and less frequent dosing in patients with hemophilia A. This trial was registered at www.clinicaltrials.gov as NCT01027377. PMID:22223821

  4. Direct detection of common and rare inversion mutations in the genetic diagnosis of severe hemophilia A

    SciTech Connect

    Windsor, A.S.; Lillicrap, D.P.; Taylor, S.A.M.

    1994-09-01

    Approximately 50% of the cases of severe hemophilia A (factor VIII:C < 0.01 units/ml) may be due to gross rearrangements of the factor VIII gene. The mutation involves homologous sequences upstream of the factor VIII locus and within intron 22 in an intrachromosomal recombination, inversion, event. The rearrangements can readily be detected on a Southern blot using a probe that is complementary to sequences from within intron 22. We describe here the analysis of this mutation in 71 severe hemophilia A patients. Thirty two of the patients (45%) showed evidence of a rearrangement. Five different patterns of rearrangements were seen, two of which have previously been described and account for the majority of cases (pattern 1, 70% and pattern 2, 16%). Three other abnormal patterns were observed. The inversion mechanism does not usually result in the loss or gain of any genetic material, but in one patient, in whom a unique rearrangement pattern was observed (pattern 3), we have previously documented a gross deletion which removes exons 1-22 of the factor VII gene as well as sequences 5{prime} to the gene. In another individual a fourth pattern in which an extra 19.0 kb band is present was detected. In this case it is unclear as to whether the rearrangement is responsible for the disease or is simply coincident normal variation. A fifth pattern, in which an extra 16.0 kb band was detected, was observed in a family with a new mutation causing hemophilia A. The affected individual and his mother inherited a de novo rearrangement of the factor VIII gene from his unaffected grandfather, implicating it as the cause of the disease. In conclusion, testing for the factor VIII inversion mutation was positive in approximately 45% of severe hemophiliacs, 72% of whom were isolated cases, and as such should constitute the initial stage in the genetic testing protocol for these patients` families.

  5. Potential role of a new PEGylated recombinant factor VIII for hemophilia A

    PubMed Central

    Wynn, Tung Thanh; Gumuscu, Burak

    2016-01-01

    Hemophilia A, a deficiency in the activity of coagulation factor (F) VIII, is an X-linked bleeding disorder with an approximate incidence of one in 5,000 male infants. Bleeding-related complications often result in greater severity of disease, poor quality of life, surgical interventions for severe joint destruction, and shortened life span. With the availability of plasma-derived and recombinant FVIII products, the benefits of primary prophylaxis were demonstrated and is now the standard of care for patients with severe factor deficiencies. Current hemophilia research is focusing on the creation of new factor replacement therapies with longer half-lives; accessing alternative mechanisms to achieve desired hemostasis and enhance bypassing activity; and limiting the immunogenicity of the protein. PEGylation involves the covalent attachment of polyethylene glycol (PEG) to a protein, peptide, or a small molecule drug. PEG effectively increases the molecular weight and size of the protein by creating a hydrophilic cloud around the molecule. This molecular change may reduce susceptibility of the molecule to proteolytic activity and degradation. It is also believed that PEGylation changes the surface charge of the protein that ultimately interferes with some receptor-mediated clearance processes. The half-life of PEGylated factor is more prolonged when compared to non-PEGylated full-length recombinant FVIII. The dawn of a new era in the care of hemophilia patients is upon us with the release of recombinant FVIII products with extended half-lives, and products with even more extended half-life will become available in a very short time. With all the promise of these new agents, many questions still remain. PMID:27382347

  6. [Surgical aortic valve replacement for acute Streptococcus viridans endocarditis with simultaneous moderate hemophilia A].

    PubMed

    Krawietz, W; Loracher, C; Struck, E; Schlimok, G; Falk, H

    1988-07-01

    This is a report of a 25-year-old patient with known aortic valve stenosis since early youth and hemophilia A, showing recurrent joint bleeding. Acute Streptococcus endocarditis induced aortic valve insufficiency resulting in cardiac failure. Aortic valve replacement was performed after substitution of factor VIII, during which intra- and postoperative bleeding was prolonged by pericardial adhesions. Heparin was administered during cardiopulmonary-bypass as usual, but usual postoperative cumarin therapy was not initiated due to prolonged PTT time. One year postoperatively, the patient was in an excellent condition and fully rehabilitated. PMID:3145652

  7. 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. PMID:25485786

  8. 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; Borrego, Salud; 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

  9. 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.…

  10. AAV-based Neonatal Gene Therapy for Hemophilia A: Long-Term Correction and Avoidance of Immune Responses in Mice

    PubMed Central

    Hu, Chuhong; Lipshutz, Gerald S.

    2012-01-01

    Hemophilia A gene therapy has been hampered by immune responses to vector-associated antigens and by neutralizing antibodies or inhibitors to the factor VIII (FVIII) protein; these ‘inhibitors’ more commonly effect hemophilia A patients than those with hemophilia B. A gene replacement strategy beginning in the neonatal period may avoid the development of these immune responses and lead to prolonged expression with correction of phenotype thereby avoiding long-term consequences. Serotype rh10 AAV was developed splitting the FVIII coding sequence into heavy and light chains with the chicken β-actin promoter/CMV enhancer for dual recombinant AAV vector delivery. Coinjection of virions of each FVIII chain intravenously to mice on the second day of life was performed. Mice express sustained FVIII antigen levels of ≥5% to 22 months of life without the development of antibodies to FVIII. Phenotypic correction was manifest in all AAV-FVIII-treated mice as demonstrated by functional assay and reduction in bleeding time. This study demonstrates the use of AAV in a gene replacement strategy in neonatal mice that establishes both long-term phenotypic correction of hemophilia A and lack of antibody development to FVIII in this disease model where AAV is administered shortly after birth. These studies support consideration of gene replacement therapy for diseases that are diagnosed in utero or in the early neonatal period. PMID:22241178

  11. 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

    2016-01-01

    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. PMID:26964564

  12. The Future of Hemophilia Treatment: Longer-Acting Factor Concentrates versus Gene Therapy.

    PubMed

    Giangrande, Paul

    2016-07-01

    Gene therapy is the only novel technology that currently offers the prospect of a lasting cure for hemophilia and freedom from the burden of repeated injections. Recent data from a handful of patients who have undergone gene therapy for hemophilia B are very encouraging with a sustained factor IX (FIX) level of 0.05 IU/mL maintained for over 4 years. While this level is above the current usual target trough levels, it falls well short of the level that patients on prophylaxis with longer-acting products can expect. Prophylaxis is also associated with high peak levels, which permits patients to maintain an active lifestyle. A major barrier to widespread adoption of gene therapy is a high seroprevalence of antibodies to adeno-associated virus (AAV) vectors in the general population. Young children would be the best candidates for gene therapy in view of much lower seroprevalence to AAV in infants. A stable level of FIX early in life would prevent the onset of joint bleeds and the development of arthropathy. The recent experience with apolipoprotein tiparvovec (Glybera; uniQure, Amsterdam, the Netherlands) indicates that gene therapy is unlikely to prove to be a cheap therapeutic option. It is also quite possible that other new technologies that do not require viral vectors (such as stem cell therapy) may overtake gene therapy during development and make it redundant. PMID:27148842

  13. Ex vivo expanded autologous polyclonal regulatory T cells suppress inhibitor formation in hemophilia

    PubMed Central

    Sarkar, Debalina; Biswas, Moanaro; Liao, Gongxian; Seay, Howard R; Perrin, George Q; Markusic, David M; Hoffman, Brad E; Brusko, Todd M; Terhorst, Cox; Herzog, Roland W

    2014-01-01

    Adoptive cell therapy utilizing ex vivo expanded polyclonal CD4+CD25+FOXP3+ regulatory T cells (Treg) is in use in clinical trials for the treatment of type 1 diabetes and prevention of graft versus host disease in bone marrow transplantation. Here, we seek to evaluate this approach in the treatment of inherited protein deficiencies, i.e., hemophilia, which is often complicated by antibody formation against the therapeutic protein. Treg from mice that express green fluorescent protein–marked FoxP3 were highly purified by two-step magnetic/flow sorting and ex vivo expanded 50- to 100-fold over a 2-week culture period upon stimulation with antibody-coated microbeads. FoxP3 expression was maintained in >80% of expanded Treg, which also expressed high levels of CD62L and CTLA-4. Transplanted Treg suppressed inhibitory antibody formation against coagulation factors VIII and IX in protein and gene therapies in strain-matched hemophilia A and B mice, including in mice with pre-existing antibodies. Although transplanted Treg became undetectable within 2 weeks, suppression persisted for >2 months. Additional studies suggested that antigen-specific suppression emerged due to induction of endogenous Treg. The outcomes of these studies support the concept that cell therapy with ex vivo expanded autologous Treg can be used successfully to minimize immune responses in gene and protein replacement therapies. PMID:25364772

  14. Acquired hemophilia possibly induced by etanercept in a patient with rheumatoid arthritis.

    PubMed

    Banse, Christopher; Benhamou, Ygal; Lequerré, Thierry; Le Cam-Duchez, Véronique; Lévesque, Hervé; Vittecoq, Olivier

    2015-05-01

    A 47-year-old woman with rheumatoid arthritis (RA) treated successively with infliximab, abatacept, and etanercept spontaneously developed subcutaneous bruises and a noncompressive hematoma 11 months after starting etanercept therapy (50mg/week). Her prothrombin time was normal but her activated partial thromboplastin time was increased to 2.48 (normal range, 0.85-1.17). She had a circulating anticoagulant (Rosner index, 45; normal,<13) due to an anti-factor VIII antibody in a titer of 45 Bethesda units. Her factor VIII level was less than 1% (normal range, 55-150). The etanercept and leflunomide were stopped and prednisone was given in a daily dosage of 1mg/kg, in combination with rituximab, two 1-g doses at an interval of 2 weeks. After 5 months, persistence of the anti-factor VIII antibody prompted the initiation of azathioprine therapy, 2mg/kg/d. A remission was achieved 9 months after the diagnosis of acquired hemophilia and was sustained at last follow-up after 3 years. This new case of acquired hemophilia in a patient with RA may reflect a simple association or an inducing role of etanercept. PMID:25617259

  15. IDO1 suppresses inhibitor development in hemophilia A treated with factor VIII

    PubMed Central

    Matino, Davide; Gargaro, Marco; Santagostino, Elena; Di Minno, Matteo N.D.; Castaman, Giancarlo; Morfini, Massimo; Rocino, Angiola; Mancuso, Maria E.; Di Minno, Giovanni; Coppola, Antonio; Talesa, Vincenzo N.; Volpi, Claudia; Vacca, Carmine; Orabona, Ciriana; Iannitti, Rossana; Mazzucconi, Maria G.; Santoro, Cristina; Tosti, Antonella; Chiappalupi, Sara; Sorci, Guglielmo; Tagariello, Giuseppe; Belvini, Donata; Radossi, Paolo; Landolfi, Raffaele; Fuchs, Dietmar; Boon, Louis; Pirro, Matteo; Marchesini, Emanuela; Grohmann, Ursula; Puccetti, Paolo; Iorio, Alfonso; Fallarino, Francesca

    2015-01-01

    The development of inhibitory antibodies to factor VIII (FVIII) is a major obstacle in using this clotting factor to treat individuals with hemophilia A. Patients with a congenital absence of FVIII do not develop central tolerance to FVIII, and therefore, any control of their FVIII-reactive lymphocytes relies upon peripheral tolerance mechanisms. Indoleamine 2,3-dioxygenase 1 (IDO1) is a key regulatory enzyme that supports Treg function and peripheral tolerance in adult life. Here, we investigated the association between IDO1 competence and inhibitor status by evaluating hemophilia A patients harboring F8-null mutations that were either inhibitor negative (n = 50) or positive (n = 50). We analyzed IDO1 induction, expression, and function for any relationship with inhibitor occurrence by multivariable logistic regression and determined that defective TLR9-mediated activation of IDO1 induction is associated with an inhibitor-positive status. Evaluation of experimental hemophilic mouse models with or without functional IDO1 revealed that tryptophan metabolites, which result from IDO1 activity, prevent generation of anti-FVIII antibodies. Moreover, treatment of hemophilic animals with a TLR9 agonist suppressed FVIII-specific B cells by a mechanism that involves IDO1-dependent induction of Tregs. Together, these findings indicate that strategies aimed at improving IDO1 function should be further explored for preventing or eradicating inhibitors to therapeutically administered FVIII protein. PMID:26426076

  16. Tailoring hemostatic therapies to lower inhibitor development in previously untreated patients with severe hemophilia A.

    PubMed

    Mannucci, P M; Mancuso, M E; Franchini, M

    2016-07-01

    After technological progress provided safer therapeutic products for patients with hemophilia A, the development of alloantibodies (inhibitors) neutralizing the coagulant activity of infused factor VIII (FVIII) remains the most serious complication of replacement therapy, predisposing patients to greater morbidity and causing higher treatment costs. The pathogenesis of inhibitors, which develop at a high rate in previously untreated children with severe hemophilia A, is multifactorial, resulting from complex interactions between genetic and environmental factors. Among non-genetic determinants, a key role is played by treatment-related factors, including the source of FVIII product (i.e., plasma derived or recombinant) and the mode of replacement therapy delivery (i.e., intensity, prophylaxis vs. on demand). We review the potential interventions on these modifiable factors that may help to lower the rate of inhibitor development. In addition, interest is currently directed toward the potential for lesser immunogenicity of novel hemostatic agents designed to decrease the dosing frequency or avoid/delay the need of FVIII replacement therapy. PMID:27155314

  17. Severe hemophilia in a girl infant with mosaic Turner syndrome and persistent hyperplastic primary vitreous.

    PubMed

    Shahriari, Mahdi; Bazrafshan, Asghar; Moghadam, Mohamad; Karimi, Mehran

    2016-04-01

    A 6-month-old girl was referred by an ophthalmologist because of postoperative bleeding. She was scheduled for operation because of persistent hyperplastic primary vitreous. Workups were done and prolonged partial thromboplastin time with normal platelet count, normal bleeding time, and prothrombin time were detected. There was negative family history of bleeding tendency in both maternal and paternal family, so at the first step, Factor XI assay was requested which was normal. Then, von Willebrand factor and factor VIII were assayed which was 127% and less than 1%, respectively. Severe factor VIII deficiency was not suspected in a girl unless in siblings of a hemophilic patient who gets married with her carrier cousin. Chromosomal study and genetic testing were requested and mosaic Turner syndrome (45 XO) with ring X (p22, 2q13) along with inversion 22 (hemizygote) was detected. Abdominal and pelvic sonography showed absence of both ovaries with presence of infantile uterus. Maternal genetic study was in favor of carrier of hemophilia (heterozygote inversion 22). To the best of our knowledge, this is the first case of association of Turner syndrome with severe hemophilia A and persistent hyperplastic primary vitreous. PMID:26484646

  18. IDO1 suppresses inhibitor development in hemophilia A treated with factor VIII.

    PubMed

    Matino, Davide; Gargaro, Marco; Santagostino, Elena; Di Minno, Matteo N D; Castaman, Giancarlo; Morfini, Massimo; Rocino, Angiola; Mancuso, Maria E; Di Minno, Giovanni; Coppola, Antonio; Talesa, Vincenzo N; Volpi, Claudia; Vacca, Carmine; Orabona, Ciriana; Iannitti, Rossana; Mazzucconi, Maria G; Santoro, Cristina; Tosti, Antonella; Chiappalupi, Sara; Sorci, Guglielmo; Tagariello, Giuseppe; Belvini, Donata; Radossi, Paolo; Landolfi, Raffaele; Fuchs, Dietmar; Boon, Louis; Pirro, Matteo; Marchesini, Emanuela; Grohmann, Ursula; Puccetti, Paolo; Iorio, Alfonso; Fallarino, Francesca

    2015-10-01

    The development of inhibitory antibodies to factor VIII (FVIII) is a major obstacle in using this clotting factor to treat individuals with hemophilia A. Patients with a congenital absence of FVIII do not develop central tolerance to FVIII, and therefore, any control of their FVIII-reactive lymphocytes relies upon peripheral tolerance mechanisms. Indoleamine 2,3-dioxygenase 1 (IDO1) is a key regulatory enzyme that supports Treg function and peripheral tolerance in adult life. Here, we investigated the association between IDO1 competence and inhibitor status by evaluating hemophilia A patients harboring F8-null mutations that were either inhibitor negative (n = 50) or positive (n = 50). We analyzed IDO1 induction, expression, and function for any relationship with inhibitor occurrence by multivariable logistic regression and determined that defective TLR9-mediated activation of IDO1 induction is associated with an inhibitor-positive status. Evaluation of experimental hemophilic mouse models with or without functional IDO1 revealed that tryptophan metabolites, which result from IDO1 activity, prevent generation of anti-FVIII antibodies. Moreover, treatment of hemophilic animals with a TLR9 agonist suppressed FVIII-specific B cells by a mechanism that involves IDO1-dependent induction of Tregs. Together, these findings indicate that strategies aimed at improving IDO1 function should be further explored for preventing or eradicating inhibitors to therapeutically administered FVIII protein. PMID:26426076

  19. Joining the patient on the path to customized prophylaxis: one hemophilia team explores the tools of engagement

    PubMed Central

    Gue, Deborah; Squire, Sandra; McIntosh, Kam; Bartholomew, Claude; Summers, Nicole; Sun, Haowei; Yang, Ming; Jackson, Shannon

    2015-01-01

    Background The relationship between hemophilia team interventions and achievement of optimal clinical outcomes remains to be elucidated. The British Columbia Hemophilia Adult Team has previously reported results of a comprehensive approach to individualize prophylaxis that has resulted in substantially reduced bleeding rates. In order to facilitate knowledge exchange and potential replication, it was important to gain a thorough understanding of the team’s approach. Methods A focus group of the British Columbia Hemophilia Adult Team was conducted to identify specific roles and processes that might be contributing to the prophylaxis regimen outcomes in this clinic. The focus group consisted of two workshops; one to describe the individual and collective roles of the clinic team in providing clinical care and guiding patients toward individualized prophylaxis; and the other to describe the patient journey from initial contact through reaching a successful engagement with the clinic. Results Analysis of the results revealed team roles and processes that underpinned a shared decision-making relationship with the patient with a particular focus on supporting the patient’s autonomy. Within this relationship, team focus shifts away from “adherence” toward the process whereby patients design and implement prophylaxis regimens resulting in reduction or elimination of bleeding episodes. Limitations Using the current methodology, it is not possible to demonstrate a causal link between specific team processes and improved bleeding rates in patients. Conclusion Through the active support of patient autonomy in all aspects of decisions related to hemophilia management, the British Columbia Hemophilia Adult Team approach de-emphasizes “adherence” as the primary goal, and focuses on a prophylaxis plan that is customized by the patient and aligned with his priorities. Adoption of this comprehensive team approach facilitates shared goals between the patient and the team

  20. Marker and real-time quantitative analyses to confirm hemophilia B carrier diagnosis of a complete deletion of the F9 gene.

    PubMed

    Venceslá, Adoración; Barceló, María Jesús; Baena, Manel; Quintana, Manuel; Baiget, Montserrat; Tizzano, Eduardo F

    2007-11-01

    Approximately 3% of hemophilia B patients have major deletions in the F9 gene, half of which are complete. Marker and quantitative PCR analyses were employed for carrier diagnosis in a family of a mentally retarded hemophilia B patient with a total deletion of the F9 gene and neighbor genes. Both methodologies allowed the confirmation of carrier or non-carrier status. PMID:18024414

  1. Analysis of factor VIII gene inversions in 164 unrelated hemophilia A families

    SciTech Connect

    Vnencak-Jones, L.; Phillips, J.A. III; Janco, R.L.

    1994-09-01

    Hemophilia A is an X-linked recessive disease with variable phenotype and both heterogeneous and wide spread mutations in the factor VIII (F8) gene. As a result, diagnostic carrier or prenatal testing often relies upon laborious DNA linkage analysis. Recently, inversion mutations resulting from an intrachromosomal recombination between DNA sequences in one of two A genes {approximately}500 kb upstream from the F8 gene and a homologous A gene in intron 22 of the F8 gene were identified and found in 45% of severe hemophiliacs. We have analyzed banked DNA collected since 1986 from affected males or obligate carrier females representing 164 unrelated hemophilia A families. The disease was sporadic in 37%, familial in 54% and in 10% of families incomplete information was given. A unique deletion was identified in 1/164, a normal pattern was observed in 110/164 (67%), and 53/164 (32%) families had inversion mutations with 43/53 (81%) involving the distal A gene (R3 pattern) and 10/53 (19%) involving the proximal A gene (R2 pattern). While 19% of all rearrangements were R2, in 35 families with severe disease (< 1% VIII:C activity) all 16 rearrangements seen were R3. In 18 families with the R3 pattern and known activities, 16 (89%) had levels < 1%, with the remaining 2 families having {le} 2.4% activity. Further, 18 referrals specifically noted the production of inhibitors and 8/18 (45%) had the R3 pattern. Our findings demonstrate that the R3 inversion mutation patterns is (1) only seen with VIII:C activity levels of {le} 2.4%, (2) seen in 46% of families with severe hemophilia, (3) seen in 45% of hemophiliacs known to have inhibitors, (4) not correlated with sporadic or familial disease and (5) not in disequilibrium with the Bcl I or Taq I intron 18 or ST14 polymorphisms. Finally, in families positive for an inversion mutation, direct testing offers a highly accurate and less expensive alternative to DNA linkage analysis.

  2. Perceptions of Men With Moderate to Severe Hemophilia Regarding the Management of Their Chronic Disorder and Utilization of Community-Based Support.

    PubMed

    Rolstad, Erik B

    2015-11-01

    Hemophilia is a genetic bleeding disorder that almost exclusively affects men. There is a nationwide network of nonprofit organizations providing support to men with hemophilia, which are affiliated with localized agencies that serve affected individuals within specific regions of the country. This community-based study was implemented in response to a local Utah agency's concern that men with hemophilia may be disengaged from and underserved by their local support network. The goal of the study was to gain a better understanding of the (a) unique challenges, (b) adaptations, and (c) physical, financial, psychological, and social needs of adult men with moderate to severe hemophilia from the local community. Over a period of 9 months, verbal qualitative interviews were conducted with 10 affected individuals, and written interviews were obtained from 3 additional participants. Using a grounded-theory approach, six themes were identified, based on men's commentary from interviews, across a spectrum of physical, social, communal, personal, medical, and vocational dimensions. Resilience theory, which explores internal resources that assist in coping with adverse situations, was used as a framework for interpreting research results. Findings indicate that men value the array of educational, social, and medical services that are available to them but choose to manage their hemophilia independently from the community and access support according to their individual needs. Understanding this dynamic may be helpful in developing services that are more specifically tailored to the physical and psychosocial needs of adult men with hemophilia and, potentially, men with other chronic health disorders. PMID:25294868

  3. Anti-inflammatory/regulatory cytokine microenvironment mediated by IL-4 and IL-10 coordinates the immune response in hemophilia A patients infected chronically with hepatitis C virus.

    PubMed

    Pimentel, João Paulo; Chaves, Daniel Gonçalves; Araújo, Ana Ruth Silva; de Araújo, Erbênia Maria Martins; da Silva Fraporti, Liziara; Neves, Walter Luiz Lima; Tarragô, Andrea Monteiro; Torres, Katia Luz; Gentz, Solange Henschke Lima; Teixeira-Carvalho, Andréa; Martins-Filho, Olindo Assis; Malheiro, Adriana

    2013-06-01

    In the past decades patients with hemophilia were infected commonly by hepatitis C virus (HCV) and a significant number of patients are infected chronically. Focusing on the role of the immune system for controlling and or maintaining HCV infection, the leukocyte and cytokine profiles of peripheral blood from hemophilia A patients and other patients with and without HCV infection were studied. The results demonstrated that hemophilia A is characterized by a general state of circulating leukocytes activation along with an overall increase in the frequency of IL-6 and IL-10 with decrease of IL-8 and IL-12. HCV infection of patients with hemophilia A does not influence further the activation state of circulating leukocytes but is accompanied by lower levels of alanine transaminase (ALT) and a prominent anti-inflammatory/regulatory serum cytokine pattern, mediated by IL-4 and IL-10. Additionally, the results demonstrated that hemophilia A patients infected with HCV displaying No/Low antibody response to C33c and C22 have significant lower viral load and higher serum levels of IL-12 and IL-4. This finding suggests that the differential RIBA reactivity to C33c/C22 HCV core proteins may have a putative value as a prognostic biomarker for the infection in hemophilia A patients. PMID:23591975

  4. Half-life extended factor VIII for the treatment of hemophilia A.

    PubMed

    Tiede, A

    2015-06-01

    Prophylactic infusion of factor VIII (FVIII) prevents joint bleeding and other hemorrhages in patients with hemophilia A. Conventional FVIII concentrates have a short half-life, with an average of about 12 h in adults, ranging in individual patients between 6 and 24 h, and even shorter in younger children. Therefore, effective prophylaxis requires frequent intravenous injection, usually three times per week or every other day. Several technologies are currently under investigation to extend the half-life of FVIII, including Fc fusion (Eloctate, Elocta, efmoroctocog alfa), addition of polyethylene glycol (turoctocog alfa pegol [N8-GP], BAY 94-9027, BAX 855), and a single-chain construct (CSL627). This review summarizes characteristics of products in clinical development and discusses their potential benefits. PMID:26149020

  5. Intraosseous Delivery of Lentiviral Vectors Targeting Factor VIII Expression in Platelets Corrects Murine Hemophilia A

    PubMed Central

    Wang, Xuefeng; Shin, Simon C; Chiang, Andy F J; Khan, Iram; Pan, Dao; Rawlings, David J; Miao, Carol H

    2015-01-01

    Intraosseous (IO) infusion of lentiviral vectors (LVs) for in situ gene transfer into bone marrow may avoid specific challenges posed by ex vivo gene delivery, including, in particular, the requirement of preconditioning. We utilized IO delivery of LVs encoding a GFP or factor VIII (FVIII) transgene directed by ubiquitous promoters (a MND or EF-1α-short element; M-GFP-LV, E-F8-LV) or a platelet-specific, glycoprotein-1bα promoter (G-GFP-LV, G-F8-LV). A single IO infusion of M-GFP-LV or G-GFP-LV achieved long-term and efficient GFP expression in Lineage-Sca1+c-Kit+ hematopoietic stem cells and platelets, respectively. While E-F8-LV produced initially high-level FVIII expression, robust anti-FVIII immune responses eliminated functional FVIII in circulation. In contrast, IO delivery of G-F8-LV achieved long-term platelet-specific expression of FVIII, resulting in partial correction of hemophilia A. Furthermore, similar clinical benefit with G-F8-LV was achieved in animals with pre-existing anti-FVIII inhibitors. These findings further support platelets as an ideal FVIII delivery vehicle, as FVIII, stored in α-granules, is protected from neutralizing antibodies and, during bleeding, activated platelets locally excrete FVIII to promote clot formation. Overall, a single IO infusion of G-F8-LV was sufficient to correct hemophilia phenotype for long term, indicating that this approach may provide an effective means to permanently treat FVIII deficiency. PMID:25655313

  6. Prophylactic efficacy of BeneFIX vs Alprolix in hemophilia B mice.

    PubMed

    Cooley, Brian; Funkhouser, William; Monroe, Dougald; Ezzell, Ashley; Mann, David M; Lin, Feng-Chang; Monahan, Paul E; Stafford, Darrel W

    2016-07-14

    FIX binds tightly to collagen IV. Furthermore, a FIX mutant, FIXK5R, which binds better than wild-type FIX to collagen IV, provides better hemostasis than wild-type FIX, long after both are undetectable in the plasma. There is also credible evidence of extravascular FIX. Here, we use the saphenous vein bleeding model to compare the efficacy of recombinant FIXFc (Alprolix) and wild-type FIX (BeneFIX) in hemophilia B mice 7 days postinfusion. Although the terminal half-life of Alprolix is significantly longer than that of BeneFIX, at equal doses Alprolix is not better at controlling bleeding 7 days postinfusion, presumably because of the extravascular FIX. Both BeneFIX and Alprolix exhibit a linear response in clotting efficacy up to 150 IU/kg, where they appear to saturate an extravascular compartment, because there is no additional prophylactic benefit from higher doses. A robust pool of extravascular FIX is clearly observed surrounding blood vessels, localized to the same region as collagen IV, in 2 representative human tissues: liver and skeletal muscle. We see no increased risk for thrombosis at 250 IU/kg FIX at 6 hours postinfusion. In summary, 7 days postinfusion into hemophilia B mice, BeneFIX and Alprolix are hemostatically indistinguishable despite the latter's increased half-life. We predict that doses of FIX ∼3 times higher than the currently recommended 40 to 50 IU/kg will, because of FIX's large extravascular compartment, efficiently prolong prophylactic hemostasis without thrombotic risk. PMID:27106122

  7. MicroRNA-15b Modulates Molecular Mediators of Blood Induced Arthropathy in Hemophilia Mice

    PubMed Central

    Sen, Dwaipayan; Jayandharan, Giridhara R.

    2016-01-01

    The development of arthropathy is a major co-morbidity in patients with hemophilia. The present study was designed to study the role of a microRNA biomarker (miR-15b) in the development of joint disease. To investigate the expression profile of miR-15b during the development of arthropathy, we first isolated and studied small RNA from the acute and chronic hemarthrosis model of hemophilia A mice. We observed that miR-15b was consistently repressed (~1- to 4-fold) from the onset of joint bleeding (1, 3, 7 and 24 h) until six bleeding episodes (up to 90 days). To test if reconstitution of miR-15b modulates biomarkers of joint damage in a chronic hemarthrosis model, we administered an adeno-associated virus (AAV) 5-miR-15b vector intra-articularly alone or in combination with systemic administration of AAV2-factor VIII. miR-15b overexpression downregulated markers of angiogenesis and hypoxia (vascular epithelial growth factor α (VEGF-α) and hypoxia inducing factor 2α (HIF-2α), ~70% and ~34%, respectively) in the affected joints. In addition, the co-administration of miR-15b and factor VIII vectors reduced the levels of the chondrodegenerative matrix-metalloproteinases (MMPs) 1, 3, 9 and 14 (~14% to 60%) in the injured joints. These data demonstrate for the first time the role of a miR-15b in the development of hemophilic arthropathy and has implications in development of miR based therapies for joint disease. PMID:27070581

  8. Analysis of inversions in the factor VIII gene in Spanish hemophilia A patients and families

    SciTech Connect

    Domenech, M.; Tizzano, E.; Baiget, M.; Altisent, C.

    1994-09-01

    Intron 22 is the largest intron of the factor VIII gene and contains a CpG island from which two additional transcripts originate. One of these transcripts corresponds to the F8A gene which have telomeric extragenic copies in the X chromosome. An inversion involving homologous recombination between the intragenic and the distal or proximal copies of the F8A gene has been recently described as a common cause of severe hemophilia A (HA). We analyzed intron 22 rearrangements in 195 HA patients (123 familial and 72 sporadic cases). According to factor VIII levels, our sample was classified as severe in 114 cases, moderate in 29 cases and mild in 52 cases. An intron 22 (F8A) probe was hybridized to Southern blots of BcII digested DNA obtained from peripheral blood. A clear pattern of altered bands identifies distal or proximal inversions. We detected an abnormal pattern identifying an inversion in 49 (25%) of the analyzed cases. 43% of severe HA patients (49 cases) showed an inversion. As expected, no inversion was found in the moderate and mild group of patients. We found a high proportion (78%) of the distal rearrangement. From 49 identified inversions, 33 were found in familial cases (27%), while the remaining 15 were detected in sporadic patients (22%) in support that this mutational event occurs with a similar frequency in familial or sporadic cases. In addition, we detected a significant tendency of distal inversion to occur more frequently in familial cases than in sporadic cases. Inhibitor development to factor VIII was documented in approximately 1/3 of the patients with inversion. The identification of such a frequent molecular event in severe hemophilia A patients has been applied in our families to carrier and prenatal diagnosis, to determine the origin of the mutation in the sporadic cases and to detect the presence of germinal mosaicism.

  9. Spectrum of mutations in CRM-positive and CRM-reduced hemophilia A

    SciTech Connect

    McGinniss, M.J.; Kazazian, H.H. Jr.; Bi, L.; Antonarakis, S.E. ); Hoyer, L.W. ); Inaba, H. )

    1993-02-01

    Hemophilia A is due to the functional deficiency of factor VIII (FVIII, gene locus F8C). Although half the patients have no detectable FVIII protein in their plasma, the more rare patients ([approximately]5%) have normal levels of a dysfunctional FVIII and are termed cross-reacting material (CRM)-positive. More commonly ([approximately]45%), patients have plasma FVIII protein reduced to an extent roughly comparable to the level of FVIII activity and are designated CRM-reduced. We used denaturing gradient gel electrophoresis to screen for mutations within the F8C gene of 11 patients (6CRM-positive, 5 CRM-reduced) and identified 9 different mutations in 9 patients after analyses of all 26 exons, the promoter region, and the polyadenylation site. Six mutations have not been described previously. Five weree missense (Ser289Leu, Ser558Phe, Val634Ala, Val634Met, Asn1441Lys), and the sixth was a 3-bp deletion ([Delta]Phe652). A review of the literature and the assay of FVIII antigen in 5 hemophilia A patients with previously identified missense mutations from this laboratory yielded a total of 20 other unique CRM-reduced and CRM-positive mutations. Almost all CRM-positive/reduced mutations (24/26) were missense, and many (12/26) occurred at CpG dinucleotides. We examined 19 missense mutation for evolutionary conservation using the portions of the porcine and murine F8C sequences that are known, and 18/19 amino acid residue altered by mutation in these patients wer conserved. Almost 50% of mutations (11/26) clustered in the A2 domain, suggesting that this region is critical for the function of FVIII. The results indicate a nonrandom distribution of mutations and suggest that mutations in a limited number of FVIII regions may cause CRM-positive and CRM-reduced heomphilia A. 48 refs., 1 fig., 1 tab.

  10. Sclerotherapy Of Esophageal Varices In Severe Hemophilia A Patient And High Titer Inhibitor--Case Report.

    PubMed

    Szczepanik, Andrzej B; Dąbrowski, Wojciech P; Szczepanik, Anna M; Pielaciński, Konrad; Jaśkowiak, Wojciech

    2015-09-01

    In cirrhotic hemophilia patients bleeding from esophageal varices is a serious clinical condition due to congenital deficiency of clotting factors VIII or IX, decreased prothrombin synthesis and hypersplenic thrombocytopenia. In hemophiliac with high-titer inhibitor bypassing therapy is required with activated prothrombin complex concentrates (aPCC) or recombinant activated coagulation factor VII (rFVIIa). Doses and duration treatment with these agents following endoscopic treatment of esophageal varices have not been yet established. Authors report the first case of a severe hemophilia A patient with high titer inhibitor (40 BU) treated with repeated injection sclerotherapy. The patient was admitted with symptoms of massive esophageal variceal hemorrhage ceased with emergency sclerotherapy. Bypassing therapy was administered with aPCC at initial dose of 72.5 U/kg and then with average daily dose of 162 U/kg through 5 days. To achieved a total eradication of esophageal varices the patient was then subjected to four elective sclerotherapy procedures. Two were covered by aPCC with daily dose of 120 U/kg and 145 U/kg for 4 and 3 days respectively and the following two procedures were covered by rFVIIa with the initial dose of 116 µg/kg and the next doses of 87 µg/kg administered every 3 hours in procedure day and every 4 hours on the next two days. During all procedures excellent hemostasis was achieved and no hemorrhagic or thromboembolic complications were observed. Bypassing regimen therapy with aPCC and rFVIIa we applied have been shown to be safe and effective in this patient subjected to sclerotherapy procedures. PMID:26812842

  11. Recombinant B domain deleted porcine factor VIII for the treatment of bleeding episodes in adults with acquired hemophilia A.

    PubMed

    Gomperts, Edward

    2015-08-01

    Hemophilia A is an inherited deficiency of clotting factor VIII (FVIII) often complicated by inhibitor development (CHAWI) in which neutralizing antibodies block the therapeutic benefit of replacement therapy. Inhibitors to FVIII can also be seen in an auto-immune disease known as acquired hemophilia A (AHA). 'Bypassing' therapies have been shown to provide hemostasis but dosing must be done empirically because current assays cannot measure objective markers of treatment efficacy and safety. A recombinant porcine sequence factor VIII (r-pFVIII) has been developed for the management of AHA. Preclinical, Phase I and Phase II clinical research studies in CHAWI subjects showed therapeutic potential and safety of this agent. A Phase II/III study in AHA with serious bleeding episodes shows a positive response in all subjects after administration. Based on current preclinical and clinical trial data, r-pFVIII should become the first line of treatment in the management of hemorrhage in patients with AHA. PMID:25927594

  12. Recombinant Factor IX Fc Fusion Protein Maintains Full Procoagulant Properties and Exhibits Prolonged Efficacy in Hemophilia B Mice

    PubMed Central

    Toby, Garabet G.; Liu, Tongyao; Buyue, Yang; Zhang, Xin; Bitonti, Alan J.; Pierce, Glenn F.; Sommer, Jurg M.; Jiang, Haiyan; Peters, Robert T.

    2016-01-01

    Introduction Hemophilia B is an inherited X chromosome–linked disorder characterized by impaired blood clotting owing to the absence of functional coagulation factor IX. Due to the relatively short half-life of factor IX, patients with hemophilia B require frequent factor IX infusions to maintain prophylaxis. We have developed a recombinant factor IX (rFIX) fused to the Fc region of IgG (rFIXFc) with an extended half-life in animals and humans. Materials and Methods Procoagulant properties of rFIXFc and rFIX (BENEFIX®) were compared to determine the effect of the Fc region on rFIXFc hemostatic function. Specifically, we assessed rFIXFc activation, intermolecular interactions within the Xase complex, inactivation by antithrombin III (AT) and thrombin generation potential compared with rFIX. We also assessed the acute and prophylactic efficacy profiles of rFIXFc and rFIX in vivo in hemophilia B mouse bleeding models. Results and Conclusions The activation by factor XIa or factor VIIa/tissue factor, inhibition by AT, interaction profiles with phospholipids, affinities for factor VIIIa within the context of the Xase complex, and thrombin generation profiles were similar for rFIXFc and rFIX. Xase complexes formed with either molecule exhibited similar kinetic profiles for factor Xa generation. In acute efficacy models, mice infused with rFIXFc or rFIX were equally protected from bleeding. However, in prophylactic efficacy models, protection from bleeding was maintained approximately three times longer in rFIXFc-dosed mice than in those given rFIX; this prolonged efficacy correlates with the previously observed half-life extension. We conclude that rFIXFc retains critical FIX procoagulant attributes and that the extension in rFIXFc half-life translates into prolonged efficacy in hemophilia B mice. PMID:26840952

  13. Hemophilia B

    MedlinePlus

    ... PA: Elsevier Saunders; 2013:chap 137. Scott JP, Flood VH. Hereditary clotting factor deficiencies (bleeding disorders). In: ... writing by ADAM Health Solutions. About MedlinePlus Site Map FAQs Contact Us Get email updates Subscribe to ...

  14. Hemophilia B

    MedlinePlus

    ... tract bleeding Nosebleeds Prolonged bleeding from cuts, tooth extraction, and surgery Bleeding that starts without cause ... chap 476. Srivastava A, Brewer AK, Mauser-Bunschoten EP, et al. Treatment Guidelines Working Group on Behalf ...

  15. Acquired hemophilia A as a cause of recurrent bleeding into the pleural cavity - case report and literature review.

    PubMed

    Wojtyś, Małgorzata; Żuk, Ewa; Alchimowicz, Jacek; Grodzki, Tomasz

    2014-09-01

    Acquired hemophilia A is a coagulation disorder caused by autoantibodies against blood coagulation factor VIII. The first sign of this disease is often massive bleeding, which can affect patients after routine procedures. The parameter which indicates the presence of this condition is isolated prolonged activated partial thromboplastin time (APTT). The present article describes a case of a 32-year-old man with acute interstitial pneumonia and pleural effusion, in whom a massive hemothorax appeared after thoracocentesis; active bleeding was observed after the introduction of a chest tube. The patient was operated on, and no pinpoint bleeding was discovered during the procedure. Active bleeding was still taking place postoperatively. The patient underwent another operation after 6 days. Once more, no pinpoint bleeding was found. Prolonged APTT was observed. The activity of blood coagulation factor VIII was 3.04%. The presence of antibodies against factor VIII was confirmed, and acquired hemophilia was diagnosed. The article also includes an analysis of the literature on acquired hemophilia. PMID:26336444

  16. Perioperative management of hemophilia patients receiving total hip and knee arthroplasty: a complication report of two cases

    PubMed Central

    Tateiwa, Toshiyuki; Takahashi, Yasuhito; Ishida, Tsunehito; Kubo, Kosuke; Masaoka, Toshinori; Shishido, Takaaki; Sano, Keiji; Yamamoto, Kengo

    2015-01-01

    It has been recognized that perioperative hemostasis management after joint-replacement surgery for hemophilia patients is complicated and cumbersome, due to the necessity of rigorous monitoring for clotting-factor levels throughout the infusion. Between 2005 and 2014, we examined seven patients with hemophilia A (ten joints: six hips and four knees) receiving total hip or knee arthroplasty (THA or TKA) for hemophilic arthropathy. One male patient (31 years old) showed an intra-articular hematoma formation after THA (case 1). In another male patient (46 years old) receiving TKA, the postoperative trough factor VIII level became lower significantly than reference levels (80%–100% for the 5–10 postoperative days) recommended by the guidelines from the Japanese Society on Thrombosis and Hemostasis, despite sufficient coagulant based on the guidelines being administered (case 2). In the latter patient, deep infection and hematoma formation were observed postoperatively. In this article, we provide a detailed clinical report regarding these two complication cases at the early postoperative periods, and the management of bleeding control for hemophilia patients is discussed. PMID:26396523

  17. [A quick and efficient method to generate hemophilia B mouse models by the CRISPR/Cas system].

    PubMed

    Qihan, Wang; Cong, Huai; Ruilin, Sun; Hua, Zhuang; Hongyan, Chen; Jian, Fei; Daru, Lu

    2015-11-01

    Hemophilia B, or the Christmas disease, is a common human disease caused by coagulation factor Ⅸ (FⅨ) deficiency. It is an X-linked recessive hereditary disease. Here we obtained FⅨ-knockout mouse strains with phenotype of hemophilia B with the CRISPR/Cas system efficiently. We chose the 8th exon as the target locus, and co-injected codon-optimized Cas9 mRNA with sgRNA of FⅨ into C57BL/6 mice zygotes. We obtained 60 mice in total and genotyped them by high resolution melting (HRM) and sequencing. The results showed the mutation rate was 85.0% in total, and 79.5% and 95.2% in males and females, respectively. No off-targets were detected in the similar locus by HRM. We future measured the FⅨ activity of each mice. The FⅨ: C of mutant mice were significantly below the normal level and reduced to 6.82% of wild-type mice. The activity assay demonstrated that all the mutant mice were lack of FⅨ. In summary, we have generated hemophilia B model mice with extreme efficiency, using the RNA-guided Cas9 nuclease gene editing system. PMID:26582528

  18. Highly effective peginterferon α-2a plus ribavirin combination therapy for chronic hepatitis C in hemophilia in Korea

    PubMed Central

    Yang, Suh Yoon; Lee, Hyun Woong; Lee, Youn Jae; Park, Sung Jae; Yoo, Ki Young

    2015-01-01

    Background/Aims Chronic hepatitis C (CHC) is a major comorbidity in patients with hemophilia. However, there are no published data on the efficacy of antiviral therapy in Korea. We assessed the safety and efficacy of combination therapy with peginterferon α-2a plus ribavirin for CHC in hemophilia. Methods Patients (n=115) were enrolled between March 2007 and December 2008. Seventy-seven patients were genotype 1 or 6, and 38 patients were genotype 2 or 3. We evaluated rapid virologic responses (RVRs), early virologic response (EVRs), end-of-treatment response (ETRs), sustained virologic response (SVRs), and relapses. Safety evaluations included adverse events and laboratory tests. Results Eleven patients were excluded from the study because they had been treated previously. Among the remaining 104 treatment-naïve patients, RVR was achieved in 64 (60.6%), ETR was achieved in 95 (91.3%), and SVR was achieved in 89 (85.6%). Relapse occurred in eight patients (8.9%). Common adverse events were hair loss (56.7%) and headache (51.0%). Common hematologic adverse events were neutropenia (22.1%), anemia (27.9%), and thrombocytopenia (3.8%). However, there were no serious adverse events such as bleeding. RVR was the only predictor of SVR in multivariate analysis. Conclusions Peginterferon α-2a plus ribavirin combination treatment produced a favorable response rate in CHC patients with hemophilia without serious adverse events. PMID:26157749

  19. Issues in assessing products for the treatment of hemophilia – the intersection between efficacy, economics, and ethics

    PubMed Central

    Farrugia, Albert; Noone, Declan; Schlenkrich, Uwe; Schlenkrich, Steffen; O’Mahony, Brian; Cassar, Josephine

    2015-01-01

    Following the obviation of the pathogen safety threats posed by previous generations of clotting factor concentrates for the treatment of hemophilia, the principal issue facing the patient community is timely access to adequate supplies of continuously improving therapies. The application of evidence-based medicine has enhanced the basis of hemophilia therapy, while resulting in some challenges to patient care. Increasingly, the criteria used for the approval and payment of treatment products by regulatory and reimbursement agencies, respectively, are becoming inflexible and unrealistic. This is occurring particularly in the requirements for demonstrating product efficacy. Concurrently, emerging evidence of the interpatient variability in the clinical response to therapy has led to the proposed personalization of therapeutic regimens. Possible impediments to optimal care include competitive tensions among suppliers who seek to gain label claims for reimbursement purposes, which result in clinical trial designs of, arguably, unethical design, carried out in poor countries. We synthesize these converging developments to suggest some changes to the current hemophilia treatment paradigm, which should make it more patient-centric and enable speedier access to new therapies. PMID:26124687

  20. 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.

  1. Mutation spectrum of 122 hemophilia A families from Taiwanese population by LD-PCR, DHPLC, multiplex PCR and evaluating the clinical application of HRM

    PubMed Central

    Lin, Shin-Yu; Su, Yi-Ning; Hung, Chia-Cheng; Tsay, Woei; Chiou, Shyh-Shin; Chang, Chieh-Ting; Ho, Hong-Nerng; Lee, Chien-Nan

    2008-01-01

    Background Hemophilia A represents the most common and severe inherited hemorrhagic disorder. It is caused by mutations in the F8 gene, which leads to a deficiency or dysfunctional factor VIII protein, an essential cofactor in the factor X activation complex. Methods We used long-distance polymerase chain reaction and denaturing high performance liquid chromatography for mutation scanning of the F8 gene. We designed the competitive multiplex PCR to identify the carrier with exonal deletions. In order to facilitate throughput and minimize the cost of mutation scanning, we also evaluated a new mutation scanning technique, high resolution melting analysis (HRM), as an alternative screening method. Results We presented the results of detailed screening of 122 Taiwanese families with hemophilia A and reported twenty-nine novel mutations. There was one family identified with whole exons deletion, and the carriers were successfully recognized by multiplex PCR. By HRM, the different melting curve patterns were easily identified in 25 out of 28 cases (89%) and 15 out of 15 (100%) carriers. The sensitivity was 93 % (40/43). The overall mutation detection rate of hemophilia A was 100% in this study. Conclusion We proposed a diagnostic strategy for hemophilia A genetic diagnosis. We consider HRM as a powerful screening tool that would provide us with a more cost-effective protocol for hemophilia A mutation identification. PMID:18565236

  2. Molecular characterization of severe hemophilia A suggests that about half the mutations are not within the coding regions and splice junctions of the factor VIII gene

    SciTech Connect

    Higuchi, Miyoko; Kazazian, H.H. Jr.; Kasch, L.; Warren, T.C.; McGinniss, M.J.; Antonarakis, S.E. ); Phillips, J.A. III; Janco, R. ); Kasper, C. )

    1991-08-15

    Hemophilia A is an X chromosome-linked disorder resulting from deficiency of factor VIII, an important protein in blood coagulation. A large number of disease-producing mutations have been reported in the factor VIII gene. However, a comprehensive analysis of the mutations has been difficult because of the larger gene size, its many scattered exons, and the high frequency of de novo mutations. Recently, the authors have shown that nearly all mutations resulting in mild-to-moderate hemophilia A can be detected by PCR and denaturing gradient gel electrophoresis (DGGE). In this study, they attempted to discover the mutations causing severe hemophilia A by analyzing 47 unselected patients, 30 of whom had severe hemophilia and 17 of whom had mild-to-moderate disease. Using DGGE as a screening method, they analyzed 99% of the coding region, 94% of the splice junctions, the promoter region, and the polyadenylylation site of the gene. They found the mutation in 16 of 17 (94%) patients with mild-to-moderate disease but in only 16 of 30 (53%) patients with severe hemophilia A.

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

    SciTech Connect

    Kickuth, Ralph Anderson, Suzanne; Peter-Salonen, Kristiina; Laemmle, Bernhard; Eggli, Stefan; Triller, Juergen

    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 angiography 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.

  4. Human von Willebrand factor/factor VIII concentrates in the management of pediatric patients with von Willebrand disease/hemophilia A

    PubMed Central

    Castaman, Giancarlo; Linari, Silvia

    2016-01-01

    Several plasma-derived intermediate and high-purity concentrates containing von Willebrand factor (VWF) and factor VIII (FVIII) are currently available. The main role of these products in the management of the pediatric population is represented by the replacement therapy in patients with severe or intermediate forms of von Willebrand disease, in whom other treatments are ineffective or contraindicated. Another important role of VWF/FVIII concentrates in children may be their use in immune tolerance induction (ITI) protocols. ITI is particularly recommended for hemophilia A children who have developed an inhibitor against FVIII, currently the most serious complication of substitutive treatment in hemophilia. Although recombinant concentrates may represent the preferred option in children with hemophilia A, VWF/FVIII concentrates may offer an advantage in rescuing patients who failed previous ITI. PMID:27445481

  5. Human von Willebrand factor/factor VIII concentrates in the management of pediatric patients with von Willebrand disease/hemophilia A.

    PubMed

    Castaman, Giancarlo; Linari, Silvia

    2016-01-01

    Several plasma-derived intermediate and high-purity concentrates containing von Willebrand factor (VWF) and factor VIII (FVIII) are currently available. The main role of these products in the management of the pediatric population is represented by the replacement therapy in patients with severe or intermediate forms of von Willebrand disease, in whom other treatments are ineffective or contraindicated. Another important role of VWF/FVIII concentrates in children may be their use in immune tolerance induction (ITI) protocols. ITI is particularly recommended for hemophilia A children who have developed an inhibitor against FVIII, currently the most serious complication of substitutive treatment in hemophilia. Although recombinant concentrates may represent the preferred option in children with hemophilia A, VWF/FVIII concentrates may offer an advantage in rescuing patients who failed previous ITI. PMID:27445481

  6. Orthopedic disorders of the knee in hemophilia: A current concept review

    PubMed Central

    Rodriguez-Merchan, E Carlos; Valentino, Leonard A

    2016-01-01

    The knee is frequently affected by severe orthopedic changes known as hemophilic arthropathy (HA) in patients with deficiency of coagulation factor VIII or IX and thus this manuscript seeks to present a current perspective of the role of the orthopedic surgeon in the management of these problems. Lifelong factor replacement therapy (FRT) is optimal to prevent HA, however adherence to this regerous treatment is challenging leading to breakthrough bleeding. In patients with chronic hemophilic synovitis, the prelude to HA, radiosynovectomy (RS) is the optimal to ameliorate bleeding. Surgery in people with hemophilia (PWH) is associated with a high risk of bleeding and infection, and must be performed with FRT. A coordinated effort including orthopedic surgeons, hematologists, physical medicine and rehabilitation physicians, physiotherapists and other team members is key to optimal outcomes. Ideally, orthopedic procedures should be performed in specialized hospitals with experienced teams. Until we are able to prevent orthopedic problems of the knee in PWH will have to continue performing orthopedic procedures (arthrocentesis, RS, arthroscopic synovectomy, hamstring release, arthroscopic debridement, alignment osteotomy, and total knee arthroplasty). By using the aforementioned procedures, the quality of life of PWH will be improved. PMID:27335812

  7. Phenotypic correction of hemophilia A in sheep by postnatal intraperitoneal transplantation of FVIII-expressing MSC.

    PubMed

    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

    2011-12-01

    We recently re-established a line of sheep that accurately mimics the clinical symptoms and genetics of severe hemophilia A (HA). Here, we tested a novel, nonablative transplantation therapy in two 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 human FVIII 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. Postmortem 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, nonablative MSC transplantation was straightforward, safe, and converted life-threatening, debilitating HA to a moderate phenotype in a large animal model. PMID:21906573

  8. Principles of genetic variations and molecular diseases: applications in hemophilia A.

    PubMed

    Lannoy, N; Hermans, C

    2016-08-01

    DNA structure alterations are the ultimate source of genetic variations. Without them, evolution would be impossible. While they are essential for DNA diversity, defects in DNA synthesis can lead to numerous genetic diseases. Due to increasingly innovative technologies, our knowledge of the human genome and genetic diseases has grown considerably over the last few years, allowing us to detect another class of variants affecting the chromosomal structure. DNA sequence can be altered in multiple ways: DNA sequence changes by substitution, deletion, or duplication of some nucleotides; chromosomal structure alterations by deletion, duplication, translocation, and inversion, ranging in size from kilobases to mega bases; changes in the cell's genome size. If the alteration is located within a gene and sufficiently deleterious, it can cause genetic disorders. Due to the F8 gene's high rate of new small mutations and its location at the tip of X chromosome, containing high repetitive sequences, a wide variety of genetic variants has been described as the cause of hemophilia A (HA). In addition to the F8 intron 22 repeat inversion, HA can also result from point mutations, other inversions, complex rearrangements, such as duplications or deletions, and transposon insertions causing phenotypes of variable severity characterized by complete or partial deficiency of circulating FVIII. This review aims to present the origins, mechanisms, and consequences of F8 alterations. A sound understanding of the multiple genetic mechanisms responsible for HA is essential to determine the appropriate strategy for molecular diagnosis and detected each type of genetic variant. PMID:27296059

  9. Orthopedic disorders of the knee in hemophilia: A current concept review.

    PubMed

    Rodriguez-Merchan, E Carlos; Valentino, Leonard A

    2016-06-18

    The knee is frequently affected by severe orthopedic changes known as hemophilic arthropathy (HA) in patients with deficiency of coagulation factor VIII or IX and thus this manuscript seeks to present a current perspective of the role of the orthopedic surgeon in the management of these problems. Lifelong factor replacement therapy (FRT) is optimal to prevent HA, however adherence to this regerous treatment is challenging leading to breakthrough bleeding. In patients with chronic hemophilic synovitis, the prelude to HA, radiosynovectomy (RS) is the optimal to ameliorate bleeding. Surgery in people with hemophilia (PWH) is associated with a high risk of bleeding and infection, and must be performed with FRT. A coordinated effort including orthopedic surgeons, hematologists, physical medicine and rehabilitation physicians, physiotherapists and other team members is key to optimal outcomes. Ideally, orthopedic procedures should be performed in specialized hospitals with experienced teams. Until we are able to prevent orthopedic problems of the knee in PWH will have to continue performing orthopedic procedures (arthrocentesis, RS, arthroscopic synovectomy, hamstring release, arthroscopic debridement, alignment osteotomy, and total knee arthroplasty). By using the aforementioned procedures, the quality of life of PWH will be improved. PMID:27335812

  10. Engineering protein processing of the mammary gland to produce abundant hemophilia B therapy in milk

    PubMed Central

    Zhao, Jianguo; Xu, Weijie; Ross, Jason W.; Walters, Eric M.; Butler, Stephen P.; Whyte, Jeff J.; Kelso, Lindsey; Fatemi, Mostafa; Vanderslice, Nicholas C.; Giroux, Keith; Spate, Lee D.; Samuel, Melissa S.; Murphy, Cliff N.; Wells, Kevin D.; Masiello, Nick C.; Prather, Randall S.; Velander, William H.

    2015-01-01

    Both the low animal cell density of bioreactors and their ability to post-translationally process recombinant factor IX (rFIX) limit hemophilia B therapy to <20% of the world’s population. We used transgenic pigs to make rFIX in milk at about 3,000-fold higher output than provided by industrial bioreactors. However, this resulted in incomplete γ-carboxylation and propeptide cleavage where both processes are transmembrane mediated. We then bioengineered the co-expression of truncated, soluble human furin (rFurin) with pro-rFIX at a favorable enzyme to substrate ratio. This resulted in the complete conversion of pro-rFIX to rFIX while yielding a normal lactation. Importantly, these high levels of propeptide processing by soluble rFurin did not preempt γ-carboxylation in the ER and therefore was compartmentalized to the Trans-Golgi Network (TGN) and also to milk. The Golgi specific engineering demonstrated here segues the ER targeted enhancement of γ-carboxylation needed to biomanufacture coagulation proteins like rFIX using transgenic livestock. PMID:26387706

  11. Engineering protein processing of the mammary gland to produce abundant hemophilia B therapy in milk.

    PubMed

    Zhao, Jianguo; Xu, Weijie; Ross, Jason W; Walters, Eric M; Butler, Stephen P; Whyte, Jeff J; Kelso, Lindsey; Fatemi, Mostafa; Vanderslice, Nicholas C; Giroux, Keith; Spate, Lee D; Samuel, Melissa S; Murphy, Cliff N; Wells, Kevin D; Masiello, Nick C; Prather, Randall S; Velander, William H

    2015-01-01

    Both the low animal cell density of bioreactors and their ability to post-translationally process recombinant factor IX (rFIX) limit hemophilia B therapy to <20% of the world's population. We used transgenic pigs to make rFIX in milk at about 3,000-fold higher output than provided by industrial bioreactors. However, this resulted in incomplete γ-carboxylation and propeptide cleavage where both processes are transmembrane mediated. We then bioengineered the co-expression of truncated, soluble human furin (rFurin) with pro-rFIX at a favorable enzyme to substrate ratio. This resulted in the complete conversion of pro-rFIX to rFIX while yielding a normal lactation. Importantly, these high levels of propeptide processing by soluble rFurin did not preempt γ-carboxylation in the ER and therefore was compartmentalized to the Trans-Golgi Network (TGN) and also to milk. The Golgi specific engineering demonstrated here segues the ER targeted enhancement of γ-carboxylation needed to biomanufacture coagulation proteins like rFIX using transgenic livestock. PMID:26387706

  12. Associations of quality of life, pain, and self-reported arthritis with age, employment, bleed rate, and utilization of hemophilia treatment center and health care provider services: results in adults with hemophilia in the HERO study

    PubMed Central

    Forsyth, Angela L; Witkop, Michelle; Lambing, Angela; Garrido, Cesar; Dunn, Spencer; Cooper, David L; Nugent, Diane J

    2015-01-01

    Introduction Severe hemophilia and subsequent hemophilic arthropathy result in joint pain and impaired health-related quality of life (HRQoL). Assessment of HRQoL in persons with hemophilia (PWH), including underlying factors that drive HRQoL differences, is important in determining health care resource allocation and in making individualized clinical decisions. Aim To examine potential associations between HRQoL, pain interference, and self-reported arthritis and age, employment, activity, bleed frequency, and hemophilia treatment center and health care professional utilization. Methods PWH (age ≥18 years) from ten countries completed a 5-point Likert scale on pain interference over the previous 4 weeks, the EQ-5D-3L scale (mobility, usual activities, self-care, pain/discomfort, anxiety/depression) including a health-related visual analog scale (0–100, coded as an 11-point categorical response). Results Pain interference (extreme/a lot) was higher in PWH aged >40 years (31%) compared to those aged 31–40 years (27%) or ≤30 years (21%). In an analysis of eight countries with home treatment, PWH who reported EQ-5D mobility issues were less likely to be employed (53% vs 79%, with no mobility issues). Median annual bleed frequency increased with worsening EQ-5D pain or discomfort. The percentage of PWH with inhibitors reporting visual analog scale scores of 80–90–100 was lower (20%) than those without inhibitors (34%). Median bleed frequency increased with pain. Globally, nurse and social worker involvement increased with disability and pain; physiotherapist utilization was moderate regardless of the extent of disability or pain. Conclusion Increased disability and pain were associated with increased age, lower employment, higher reported bleed frequency, and lower HRQoL. PMID:26604708

  13. 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. PMID:25523881

  14. 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

  15. 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

  16. Long-term course of anti-factor VIII antibody in patients with hemophilia A at a single center

    PubMed Central

    Joo, Sang Chun; Choi, Yong Mook

    2016-01-01

    Background Immune tolerance induction (ITI) can reduce inhibitors against factor VIII concentrates by 70-80%. In this study, we elucidated the characteristics of inhibitors and attempted to determine the proper indications and timing for ITI. Methods Subjects included hemophilia A patients registered at the Korea Hemophilia Foundation from 1991 through 2014. Inhibitors were classified as persistent and transient. Patients were classified into groups according to peak inhibitor titer: low (<2 BU/mL), moderate (2 to <5 BU/mL), high (5 to <10 BU/mL), and very high titer (≥10 BU/mL). Results Overall, 350 (21.4%) of 1,634 hemophilia A patients developed inhibitors at least once. Of these, 100 (6.1%) and 250 (15.3%) patients developed persistent and transient inhibitors, respectively. For transient inhibitors, the median peak titer was 1.0 BU/mL, persistent for median of 11.0 months (10.0, 8.0, 13.0, and 19.0 months in the low, moderate, high, and very high titer transient inhibitor groups, respectively). Overall, 95.8% (215), 72.2% (17), 52.4% (21), and 21.7% (97) of patients in the low, moderate, high, and very high titer groups became inhibitor-negative spontaneously, without ITI. Conclusion Given the spontaneous disappearance of inhibitors and high cost of ITI, it is worthwhile to postpone ITI for 11 months unless the peak inhibitor titer is greater than 10 BU/mL. PMID:27104190

  17. Whole-exome sequencing to identify genetic risk variants underlying inhibitor development in severe hemophilia A patients.

    PubMed

    Gorski, Marcin M; Blighe, Kevin; Lotta, Luca A; Pappalardo, Emanuela; Garagiola, Isabella; Mancini, Ilaria; Mancuso, Maria Elisa; Fasulo, Maria Rosaria; Santagostino, Elena; Peyvandi, Flora

    2016-06-01

    The development of neutralizing antibodies (inhibitors) against coagulation factor VIII (FVIII) is the most problematic and costly complication of FVIII replacement therapy that affects up to 30% of previously untreated patients with severe hemophilia A. The development of inhibitors is a multifactorial complication involving environmental and genetic factors. Among the latter, F8 gene mutations, ethnicity, family history of inhibitors, and polymorphisms affecting genes involved in the immune response have been previously investigated. To identify novel genetic elements underling the risk of inhibitor development in patients with severe hemophilia A, we applied whole-exome sequencing (WES) and data analysis in a selected group of 26 Italian patients with (n = 17) and without (n = 9) inhibitors. WES revealed several rare, damaging variants in immunoregulatory genes as novel candidate mutations. A case-control association analysis using Cochran-Armitage and Fisher's exact statistical tests identified 1364 statistically significant variants. Hierarchical clustering of these genetic variants showed 2 distinct patterns of homozygous variants with a protective or harmful role in inhibitor development. When looking solely at coding variants, a total of 28 nonsynonymous variants were identified and replicated in 53 inhibitor-positive and 174 inhibitor-negative Italian severe hemophilia A patients using a TaqMan genotyping assay. The genotyping results revealed 10 variants showing estimated odds ratios in the same direction as in the discovery phase and confirmed the association of the rs3754689 missense variant (OR 0.58; 95% CI 0.36-0.94; P = .028) in a highly conserved haplotype region surrounding the LCT locus on chromosome 2q21 with inhibitor development. PMID:27060170

  18. Factor VIII (F8) inversions in severe hemophilia A: Male germ cell origin and diagnosis with RT-PCR

    SciTech Connect

    Antonarakis, S.E. |; Rossiter, J.P.; Young, M.

    1994-09-01

    The Factor VIII (F8) gene, which is defective in hemophilia A, is located in the most telomeric megabase of Xq. Inversions due to intrachromosomal homologous recombination between mispaired copies of gene A located within intron 22 of the gene and about 500 kb telomeric to it account for nearly half of the cases of severe hemophilia A. We hypothesized that pairing of Xq with its homolog inhibits the inversion process, and that therefore the event originates predominantly in male germ cells. In all 21 informative cases in which the inversion originated in a maternal grandparent, DNA polymorphism analysis using markers within or very closely linked to F8, determined that it occurred in the male germline. In addition, all but one of 56 mothers of sporadic cases due to inversions were carriers. The data indicate that the F8 gene inversions leading to severe hemophilia A occur almost exclusively in male germ cells. The mean age of maternal grandfathers at the birth of their carrier daughters was 29.9 years (13 cases), i.e. not different from the mean paternal age in the general population, supporting the hypothesis that the inversions occur in meiosis. The inversions can be diagnosed by Southern blot analysis. For more rapid diagnosis we have used RT-PCR of RNA ectopically expressed in blood. Oligonucleotides were used to PCR amplify, after the initial RT reaction of RNA samples using random hexamers, either the normal transcript (F8 exons 21 to 24;312 bp product) or the novel abnormal transcript that is generated after the inversion. Both type 1 and 2 inversions can be recognized in affecteds and carriers by the presence of the diagnostic PcR product of 248 bp. Correct diagnoses were made in samples from 6 patients and 2 carriers with type 1 inversions, 2 patients and 2 carriers with type 2 inversions and 5 normal controls.

  19. Consanguineous Marital Union Resulting in a Progeny of Whistling-face Syndrome and Hemophilia: A Case Report.

    PubMed

    Gurjar, Vivek; Gurjar, Minal

    2015-04-01

    Many different types of genetic disorders are noted to be prevalent among consanguineous progeny. Although the most common type of consanguineous union in all major societies is between first cousins, the importance of customary influences is apparent from variations in the specific types of first-cousin marriages contracted. Epidemiological data for the prevalence of whistling-face syndrome (WFS) are not available, but less than a hundred cases reported in the literature are noted. We are presenting a case where a consanguineous marriage resulted in two of their children presenting with WFS and one with hemophilia. PMID:25954077

  20. Concurrent influenza vaccination reduces anti-FVIII antibody responses in murine hemophilia A.

    PubMed

    Lai, Jesse D; Moorehead, Paul C; Sponagle, Kate; Steinitz, Katharina N; Reipert, Birgit M; Hough, Christine; Lillicrap, David

    2016-06-30

    Inflammatory signals such as pathogen- and danger-associated molecular patterns have been hypothesized as risk factors for the initiation of the anti-factor VIII (FVIII) immune response seen in 25% to 30% of patients with severe hemophilia A (HA). In these young patients, vaccines may be coincidentally administered in close proximity with initial exposure to FVIII, thereby providing a source of such stimuli. Here, we investigated the effects of 3 vaccines commonly used in pediatric patients on FVIII immunogenicity in a humanized HA murine model with variable tolerance to recombinant human FVIII (rhFVIII). Mice vaccinated intramuscularly against the influenza vaccine prior to multiple infusions of rhFVIII exhibited a decreased incidence of rhFVIII-specific neutralizing and nonneutralizing antibodies. Similar findings were observed with the addition of an adjuvant. Upon exposure to media from influenza- or FVIII-stimulated lymph node or splenic lymphocytes, naïve CD4(+) lymphocytes preferentially migrated toward media from influenza-stimulated cells, indicating that antigen competition, by means of lymphocyte recruitment to the immunization site, is a potential mechanism for the observed decrease in FVIII immunogenicity. We also observed no differences in incidence or titer of rhFVIII-specific antibodies and inhibitors in mice exposed to the live-attenuated measles-mumps-rubella vaccine regardless of route of administration. Together, our results suggest that concomitant FVIII exposure and vaccination against influenza does not increase the risk of inhibitor formation and may in fact decrease anti-FVIII immune responses. PMID:27034428

  1. 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

  2. Fc-fusion technology and recombinant FVIII and FIX in the management of the hemophilias

    PubMed Central

    Mancuso, Maria Elisa; Mannucci, Pier Mannuccio

    2014-01-01

    Prophylaxis with regular infusions of factor VIII (FVIII)- or factor IX (FIX)- containing products is the mainstay of modern hemophilia care. However, this therapeutic regimen is inconvenient, requiring repeated intravenous injections from childhood. Approaches meant to prolong the half-life of FVIII and FIX in plasma have been developed in order to improve the feasibility and acceptability of replacement therapy, extending protection from bleeding, reducing infusion frequency and hence the need for venous access devices in young children. Several strategies have been implemented to enhance the pharmacokinetics of clotting factors, including conjugation with polyethylene glycol and the production by genetic engineering of fusion proteins containing the coagulation factors linked to a long-lived plasma protein such as albumin or the Fc fragment of immunoglobulin (Ig)G. The latter technology is one of the most promising, since the prolongation of FVIII and FIX half-life is obtained by exploiting the physiological binding of the Fc domain to the neonatal Fc receptor. Fc fusion monomers have been obtained with both recombinant FVIII (rFVIIIFc) and FIX (rFIXFc), and data from preclinical and clinical studies showed improved pharmacokinetics for both factors, which are produced in human embryonic kidney (HEK) 293 cells, thus ensuring full human post-translational modifications. In Phase I/IIa studies, rFVIIIFc and rFIXFc showed 1.5–1.7 fold and 3.0–4.0 fold longer elimination half-life, respectively. Similar data have been obtained in the Phase III clinical studies with rFVIIIFc and rFIX-Fc published recently. Both drugs were satisfactorily safe, particularly with respect to immunogenicity, and no serious adverse event was observed. PMID:24729686

  3. Early eradication of factor VIII inhibitor in patients with congenital hemophilia A by immune tolerance induction with a high dose of immunoglobulin.

    PubMed

    Mizoguchi, Yoko; Furue, Aya; Kagawa, Reiko; Chijimatsu, Ikue; Tomioka, Keita; Shimomura, Maiko; Imanaka, Yusuke; Nishimura, Shiho; Saito, Satoshi; Miki, Mizuka; Ono, Atsushi; Konishi, Nakao; Kawaguchi, Hiroshi; Kobayashi, Masao

    2016-04-01

    The production of factor VIII (FVIII) inhibitory antibodies is a serious problem in patients with hemophilia A. Immune tolerance induction (ITI) is the only strategy proven to eradicate persistent inhibitors and has been shown to be successful in 70 % of patients with hemophilia A. However, a minority of hemophilia patients present life-long inhibitors. To eliminate such inhibitors, we designed an intravenous immunoglobulin (IVIG) strategy in combination with high dose recombinant FVIII for ITI in hemophilia A children with inhibitors. Four previously untreated patients produced inhibitors within 16 exposures to FVIII. The peak inhibitor titers in these patients ranged from 3 to 14 BU/mL. The patients received ITI combined with IVIG within 1.5 months after the inhibitors were detected. All patients showed a negative titer for inhibitors by 28 days, with no anamnestic responses. The recovery of FVIII in the plasma concentration was normalized within three months after initiation of ITI. An additional course of IVIG administration led to induction of complete tolerance by 20 months after initiation of ITI therapy in all patients. ITI treatment with high-dose FVIII combined with IVIG may be effective for the early elimination of inhibitors. PMID:26830966

  4. Expression of human factor IX in rat capillary endothelial cells: Toward somatic gene therapy for hemophilia B

    SciTech Connect

    Shounan Yao; Wilson, J.M.; Nabel, E.G.; Kurachi, Sumiko; Hachiya, H.L.; Kurachi, Kotoku )

    1991-09-15

    In aiming to develop a gene therapy approach for hemophilia B, the authors expressed and characterized human factor IX in rat capillary endothelial cells (CECs). Moloney murine leukemia virus-derived retrovirus vectors that contain human factor IX cDNA linked to heterologous promoters and the neomycin-resistant gene were constructed and employed to prepare recombinant retroviruses. Rat CECs and NIH 3T3 cells infected with these viruses were selected with the neomycin analogue, G418 sulfate, and tested for expression of factor IX. A construct with the factor IX cDNA under direct control by long terminal repeat gave the highest level of expression as quantitated by immunoassays as well as clotting activity assays. A single RNA transcript of 4.4 kilobases predicted by the construct and a recombinant factor IX were found. The recombinant human factor IX produced showed full clotting activity, demonstrating that CECs have an efficient mechanism for posttranslational modifications, including {gamma}-carboxylation, essential for its biological activity. These results, in addition to other properties of the endothelium, including large number of cells, accessibility, and direct contact with the circulating blood, suggest that CECs can serve as an efficient drug delivery vehicle producing factor IX in a somatic gene therapy for hemophilia B.

  5. Phosphatidylserine containing liposomes reduce immunogenicity of recombinant human factor VIII (rFVIII) in a murine model of hemophilia A.

    PubMed

    Ramani, Karthik; Miclea, Razvan D; Purohit, Vivek S; Mager, Donald E; Straubinger, Robert M; Balu-Iyer, Sathy V

    2008-04-01

    Factor VIII (FVIII) is a multidomain protein that is deficient in hemophilia A, a clinically important bleeding disorder. Replacement therapy using recombinant human FVIII (rFVIII) is the main therapy. However, approximately 15-30% of patients develop inhibitory antibodies that neutralize rFVIII activity. Antibodies to epitopes in C2 domain, which is involved in FVIII binding to phospholipids, are highly prevalent. Here, we investigated the effect of phosphatidylserine (PS)-containing liposomes, which bind to C2 domain with high affinity and specificity, upon the immunogenicity of rFVIII. Circular dichroism studies showed that PS-containing liposomes interfered with aggregation of rFVIII. Immunogenicity of free- versus liposomal-rFVIII was evaluated in a murine model of hemophilia A. Animals treated with s.c. injections of liposomal-rFVIII had lower total- and inhibitory titers, compared to animals treated with rFVIII alone. Antigen processing by proteolytic enzymes was reduced in the presence of liposomes. Animals treated with s.c. injections of liposomal-rFVIII showed a significant increase in rFVIII plasma concentration compared to animals that received rFVIII alone. Based on these studies, we hypothesize that specific molecular interactions between PS-containing bilayers and rFVIII may provide a basis for designing lipidic complexes that improve the stability, reduce the immunogenicity of rFVIII formulations, and permit administration by s.c. route. PMID:17705286

  6. Recombinant factor VIII Fc (rFVIIIFc) fusion protein reduces immunogenicity and induces tolerance in hemophilia A mice.

    PubMed

    Krishnamoorthy, Sriram; Liu, Tongyao; Drager, Douglas; Patarroyo-White, Susannah; Chhabra, Ekta Seth; Peters, Robert; Josephson, Neil; Lillicrap, David; Blumberg, Richard S; Pierce, Glenn F; Jiang, Haiyan

    2016-03-01

    Anti-factor VIII (FVIII) antibodies is a major complication of FVIII replacement therapy for hemophilia A. We investigated the immune response to recombinant human factor VIII Fc (rFVIIIFc) in comparison to BDD-rFVIII and full-length rFVIII (FL-rFVIII) in hemophilia A mice. Repeated administration of therapeutically relevant doses of rFVIIIFc in these mice resulted in significantly lower antibody responses to rFVIII compared to BDD-rFVIII and FL-rFVIII and reduced antibody production upon subsequent challenge with high doses of rFVIIIFc. The induction of a tolerogenic response by rFVIIIFc was associated with higher percentage of regulatory T-cells, a lower percentage of pro-inflammatory splenic T-cells, and up-regulation of tolerogenic cytokines and markers. Disruption of Fc interactions with either FcRn or Fcγ receptors diminished tolerance induction, suggesting the involvement of these pathways. These results indicate that rFVIIIFc reduces immunogenicity and imparts tolerance to rFVIII demonstrating that recombinant therapeutic proteins may be modified to influence immunogenicity and facilitate tolerance. PMID:26775174

  7. An improved method for prenatal diagnosis of genetic diseases by analysis of amplified DNA sequences. Application to hemophilia A.

    PubMed

    Kogan, S C; Doherty, M; Gitschier, J

    1987-10-15

    We report the development of a rapid nonradioactive technique for the genetic prediction of human disease and its diagnostic application to hemophilia A. This method is based on enzymatic amplification of short segments of human genes associated with inherited disorders. A novel feature of the procedure is the use of a heat-stable DNA polymerase, which allows the repeated rounds of DNA synthesis to proceed at 63 degrees C. The high sequence specificity of the amplification reaction at this elevated temperature permits restriction-site polymorphisms, contained in the amplified samples, to be analyzed by visual inspection of their digestion products on polyacrylamide gels. By means of this method, we have performed carrier detection and prenatal diagnosis of hemophilia in two families with use of the factor VIII intragenic polymorphisms identified by the restriction enzymes BclI and XbaI. Predictions can be made directly from chorionic villi, without previous DNA extraction, and fetal sex can be determined by amplification of sequences specific for the Y chromosome. Specific amplification of genomic sequences with heat-stable DNA polymerase is applicable to the diagnosis of a wide variety of inherited disorders. These include diseases diagnosed by restriction-site variation, such as Duchenne's muscular dystrophy and sickle cell anemia, those due to a collection of known mutations, such as beta-thalassemia, and those due to gene deletion, such as alpha-thalassemia. PMID:3657865

  8. Correction of the coagulation defect in hemophilia using a factor Xa variant with novel engineered protease function

    PubMed Central

    Ivanciu, Lacramioara; Toso, Raffaella; Margaritis, Paris; Pavani, Giulia; Kim, Haein; Schlachterman, Alexander; Liu, Jian-Hua; Clerin, Valerie; Pittman, Debra D.; Rose-Miranda, Rosalind; Shields, Kathleen M.; Erbe, David V.; Tobin, James F.; Arruda, Valder R.; Camire, Rodney M.

    2011-01-01

    Effective therapies are needed to control excessive bleeding in a range of clinical conditions. We describe a surprisingly useful approach to improve hemostasis in vivo using a variant of coagulation factor Xa (FXaI16L). This conformationally pliant derivative is partially inactive due to a defect in transitioning from zymogen to protease 1,2. Using mouse models of hemophilia, we show that FXaI16L has a prolonged half-life, relative to wild-type FXa and does not cause excessive activation of coagulation. Once clotting mechanisms are activated to produce its cofactor FVa, FXaI16L is driven to the protease state and restores hemostasis in hemophilic animals upon vascular injury. Moreover, using human or murine analogs, we show that FXaI16L is more efficacious than FVIIa which is used to treat bleeding in hemophilia inhibitor patients3. Because of its underlying mechanism of action, FXaI16L may provide an effective strategy to enhance blood clot formation and act as a rapid pan-hemostatic agent for the treatment of bleeding conditions. PMID:22020385

  9. Partial correction of a severe molecular defect in hemophilia A, because of errors during expression of the factor VIII gene

    SciTech Connect

    Young, M.; Antonarakis, S.E.; Inaba, Hiroshi

    1997-03-01

    Although the molecular defect in patients in a Japanese family with mild to moderately severe hemophilia A was a deletion of a single nucleotide T within an A{sub 8}TA{sub 2} sequence of exon 14 of the factor VIII gene, the severity of the clinical phenotype did not correspond to that expected of a frameshift mutation. A small amount of functional factor VIII protein was detected in the patient`s plasma. Analysis of DNA and RNA molecules from normal and affected individuals and in vitro transcription/translation suggested a partial correction of the molecular defect, because of the following: (i) DNA replication/RNA transcription errors resulting in restoration of the reading frame and/or (ii) {open_quotes}ribosomal frameshifting{close_quotes} resulting in the production of normal factor VIII polypeptide and, thus, in a milder than expected hemophilia A. All of these mechanisms probably were promoted by the longer run of adenines, A{sub 10} instead of A{sub 8}TA{sub 2}, after the delT. Errors in the complex steps of gene expression therefore may partially correct a severe frameshift defect and ameliorate an expected severe phenotype. 36 refs., 6 figs.

  10. Somatic mosaicism and female-to-female transmission in a kindred with hemophilia B (factor IX deficiency)

    SciTech Connect

    Taylor, S.A.M.; Deugau, K.V.; Lillicrap, D.P. )

    1991-01-01

    Studies have shown that hemophilia B (Christmas disease; factor IX deficiency) results from many different mutations in the factor IX gene, of which {gt}95% are single nulceotide substitutions. This study has identified a previously unreported form of hemophilia B in a patient who was a somatic mosaic for a guanine-to-cytosine transversion at nucleotide 31,170 in the factor IX gene. This point mutation changes the codon for residue 350 in the catalytic domain of factor IX from a cysteine to a serine. The authors used differential termination of primer extension to confirm and measure the degree of mosaicism. The study shows that a varying proportion of cells from hepatic, renal, smooth muscle, and hematopoietic populations possessed normal as well as mutant factor IX sequences. These results indicate that the mutation in this patient occurred either as an uncorrected half-chromatid mutation in the female gamete or as a replication or postreplication error in the initial mitotic divisions of the zygote preceding implantation. In addition, this kindred also contains two females in successive generations who have moderately severe factor IX deficiency. The molecular pathogenesis of this latter phenomenon has been studied and seems to relate to the unaccompanied expression of the mutant factor IX gene consequent upon a second, as yet undefined, genetic event that has prevented inactivation of sequences including the mutant factor IX gene on the X chromosome inherited from the affected male.

  11. Recombinant factor VIII Fc (rFVIIIFc) fusion protein reduces immunogenicity and induces tolerance in hemophilia A mice

    PubMed Central

    Krishnamoorthy, Sriram; Liu, Tongyao; Drager, Douglas; Patarroyo-White, Susannah; Chhabra, Ekta Seth; Peters, Robert; Josephson, Neil; Lillicrap, David; Blumberg, Richard S.; Pierce, Glenn F.; Jiang, Haiyan

    2016-01-01

    Anti-factor VIII (FVIII) antibodies is a major complication of FVIII replacement therapy for hemophilia A. We investigated the immune response to recombinant human factor VIII Fc (rFVIIIFc) in comparison to BDD-rFVIII and full-length rFVIII (FL-rFVIII) in hemophilia A mice. Repeated administration of therapeutically relevant doses of rFVIIIFc in these mice resulted in significantly lower antibody responses to rFVIII compared to BDD-rFVIII and FL-rFVIII and reduced antibody production upon subsequent challenge with high doses of rFVIIIFc. The induction of a tolerogenic response by rFVIIIFc was associated with higher percentage of regulatory T-cells, a lower percentage of pro-inflammatory splenic T-cells, and up-regulation of tolerogenic cytokines and markers. Disruption of Fc interactions with either FcRn or Fcγ receptors diminished tolerance induction, suggesting the involvement of these pathways. These results indicate that rFVIIIFc reduces immunogenicity and imparts tolerance to rFVIII demonstrating that recombinant therapeutic proteins may be modified to influence immunogenicity and facilitate tolerance. PMID:26775174

  12. 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. PMID:26302233

  13. Neonatal helper-dependent adenoviral vector gene therapy mediates correction of hemophilia A and tolerance to human factor VIII

    PubMed Central

    Cela, Racel G.; Suzuki, Masataka; Lee, Brendan; Lipshutz, Gerald S.

    2011-01-01

    Neonatal gene therapy is a promising strategy for treating a number of congenital diseases diagnosed shortly after birth as expression of therapeutic proteins during postnatal life may limit the pathologic consequences and result in a potential “cure.” Hemophilia A is often complicated by the development of antibodies to recombinant protein resulting in treatment failure. Neonatal administration of vectors may avoid inhibitory antibody formation to factor VIII (FVIII) by taking advantage of immune immaturity. A helper-dependent adenoviral vector expressing human factor VIII was administered i.v. to neonatal hemophilia A knockout mice. Three days later, mice produced high levels of FVIII. Levels declined rapidly with animal growth to 5 wk of age with stable factor VIII expression thereafter to >1 y of age. Decline in factor VIII expression was not related to cell-mediated or humoral responses with lack of development of antibodies to capsid or human factor VIII proteins. Subsequent readministration and augmentation of expression was possible as operational tolerance was established to factor VIII without development of inhibitors; however, protective immunity to adenovirus remained. PMID:21245323

  14. The role of plasma-derived factor VIII/von Willebrand factor concentrates in the treatment of hemophilia A patients.

    PubMed

    Auerswald, Günter; Spranger, Torsten; Brackmann, Hans-Hermann

    2003-06-01

    Besides preventing bleeding episodes, common goals of the treatment of hemophilia include integrating of patients into a normal social life and optimizing their quality of life. Sufficient amounts of factor VIII (FVIII) concentrates, whether recombinant or plasma-derived, are continuously needed. Guidelines for quality assurance of treatment will be a cornerstone to maintain optimal clinical management of patients especially considering financial aspects. Advances in manufacturing technologies have made possible general availability of modern concentrates for the management of hemophilia A patients. Safety, cost and continuous supply of concentrates must be considered when deciding on a product for replacement therapy. As todays' products have reached an excellent margin of safety with regard to virus transmission, the development and treatment of inhibitors is currently the main concern for physicians and patients. The incidence of inhibitors is influenced by various patient-related factors such as mutation type or severity of the disease. Plasma-derived FVIII concentrates containing von Willebrand factor (VWF) may have clinical advantages over pure FVIII concentrates with regard to inhibitor development and inhibitor eradication. Clinical trials comparing FVIII/VWF concentrates with pure FVIII concentrates are lacking, thus a lower inhibitor incidence has not yet been proven. Data from Germany on immune tolerance induction with FVIII/VWF concentrates indicate higher success rates with these than with pure FVIII concentrates. In addition FVIII/VWF concentrates are the therapy of choice when immune tolerance therapy with pure FVIII products is not successful. PMID:12826531

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

    PubMed

    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; Jiang, Haiyan

    2012-03-29

    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

  16. Cohort profile: UK Millennium Cohort Study (MCS).

    PubMed

    Connelly, Roxanne; Platt, Lucinda

    2014-12-01

    The UK Millennium Cohort Study (MCS) is an observational, multidisciplinary cohort study that was set up to follow the lives of children born at the turn of the new century. The MCS is nationally representative and 18 552 families (18 827 children) were recruited to the cohort in the first sweep. There have currently been five main sweeps of data collection, at ages 9 months and 3, 5, 7 and 11 years. A further sweep of data collection is planned for age 14 years. A range of health-related data have been collected as well as measures concerning child development, cognitive ability and educational attainment. The data also include a wealth of information describing the social, economic and demographic characteristics of the cohort members and their families. In addition, the MCS data have been linked to administrative data resources including health records. The MCS provides a unique and valuable resource for the analysis of health outcomes and health inequalities. The MCS data are freely available to bona fide researchers under standard access conditions via the UK Data Service (http://ukdataservice.ac.uk) and the MCS website provides detailed information on the study (http://www.cls.ioe.ac.uk/mcs). PMID:24550246

  17. Molecular characterization of severe hemophilia A suggests that about half the mutations are not within the coding regions and splice junctions of the factor VIII gene.

    PubMed Central

    Higuchi, M; Kazazian, H H; Kasch, L; Warren, T C; McGinniss, M J; Phillips, J A; Kasper, C; Janco, R; Antonarakis, S E

    1991-01-01

    Hemophilia A is an X chromosome-linked disorder resulting from deficiency of factor VIII, an important protein in blood coagulation. A large number of disease-producing mutations have been reported in the factor VIII gene. However, a comprehensive analysis of the mutations has been difficult because of the large gene size, its many scattered exons, and the high frequency of de novo mutations. Recently, we have shown that nearly all mutations resulting in mild-to-moderate hemophilia A can be detected by PCR and denaturing gradient gel electrophoresis (DGGE). In this study, we attempted to discover the mutations causing severe hemophilia A by analyzing 47 unselected patients, 30 of whom had severe hemophilia and 17 of whom had mild-to-moderate disease. Using DGGE as a screening method, we analyzed 99% of the coding region, 94% of the splice junctions, the promoter region, and the polyadenylylation site of the gene. We found the mutation in 16 of 17 (94%) patients with mild-to-moderate disease but in only 16 of 30 (53%) patients with severe hemophilia A. Since DGGE after computer analysis appears to detect all mutations in a given fragment, the lower-than-expected yield of mutations in patients with severe disease is likely not due to failure of the detection method; it is probably due to the presence of mutations in DNA sequences outside the regions studied. Such sequences may include locus-controlling regions, other sequences within introns or outside the gene that are important for its expression, or another gene involved in factor VIII expression that is very closely linked to the factor VIII gene. Images PMID:1908096

  18. Cancer Epidemiology Cohorts

    Cancer.gov

    Cohort studies are fundamental for epidemiological research by helping researchers better understand the etiology of cancer and provide insights into the key determinants of this disease and its outcomes.

  19. Physical activity recommendations for children with specific chronic health conditions: Juvenile idiopathic arthritis, hemophilia, asthma and cystic fibrosis.

    PubMed

    Philpott, J; Houghton, K; Luke, A

    2010-04-01

    As a group, children with a chronic disease or disability are less active than their healthy peers. There are many reasons for suboptimal physical activity, including biological, psychological and social factors. Furthermore, the lack of specific guidelines for 'safe' physical activity participation poses a barrier to increasing activity. Physical activity provides significant general health benefits and may improve disease outcomes. Each child with a chronic illness should be evaluated by an experienced physician for activity counselling and for identifing any contraindications to participation. The present statement reviews the benefits and risks of participation in sport and exercise for children with juvenile arthritis, hemophilia, asthma and cystic fibrosis. Guidelines for participation are included. PMID:21455465

  20. Physical activity recommendations for children with specific chronic health conditions: juvenile idiopathic arthritis, hemophilia, asthma, and cystic fibrosis.

    PubMed

    Philpott, John F; Houghton, Kristin; Luke, Anthony

    2010-05-01

    As a group, children with a chronic disease or disability are less active than their healthy peers. There are many reasons for suboptimal physical activity, including biological, psychological, and social factors. Furthermore, the lack of specific guidelines for 'safe' physical activity participation poses a barrier to increasing activity. Physical activity provides significant general health benefits and may improve disease outcomes. Each child with a chronic illness should be evaluated by an experienced physician for activity counselling and for identifying any contraindications to participation. The present statement reviews the benefits and risks of participation in sport and exercise for children with juvenile arthritis, hemophilia, asthma, and cystic fibrosis. Guidelines for participation are included. PMID:20445355

  1. Severe hemophilia A in a female by cryptic translocation: Order and orientation of factor VIII within Xq28

    SciTech Connect

    Migeon, B.R.; McGinniss, M.J.; Antonarakis, S.E.; Axelman, J.; Stasiowski, B.A.; Youssoufian, H.; Kearns, W.G.; Chung, A.; Pearson, P.L.; Kazazian, H.H. Jr. ); Muneer, R.S. )

    1993-04-01

    The authors report studies of a female with severe hemophilia A resulting from a complex de novo translocation of chromosomes X and 17 (46,X,t(X; 17)). Somatic cell hybrids containing the normal X, the der(X), or the der(17) were analyzed for coagulation factor VIII (F8C) sequences using Southern blots and polymerase chain reaction. The normal X, always late replicating, contains a normal F8C gene, whereas the der(X) has no F8C sequences. The der(17) chromosome containing Xq24-Xq28 carries a functional G6PD locus and a deleted F8C allele that lacks exons 1--15. Also, it lacks the DXYS64-X locus, situated between the F8C locus and the Xq telomere. These results indicate that a cryptic breakpoint within Xq28 deleted the 5[prime] end of F8C, but left the more proximal G6PD locus intact on the der(17)chromosome. As the deleted segment includes the 5[prime] half of F8C as well as the subtelomeric DXYS64 locus, F8C must be oriented on the chromosome with its 5[prime] region closest to the telomere. Therefore, the order of these loci is Xcen-G6PD-3[prime]F8C-5[prime]F8C-DXYS64-Xqtel. The analysis of somatic cell hybrids has elucidated the true nature of the F8C mutation in the pro-band, revealing a more complex rearrangement (three chromosomes involved) than that expected from cytogenetic analysis, chromosome painting, and Southern blots. A 900-kb segment within Xq28 has been translocated to another autosome. Hemophilia A in this heterozygous female is due to the decapitation of the F8C gene on the der(17) and inactivation of the intact allele on the normal X. 27 refs., 5 figs., 1 tab.

  2. Extrahepatic sources of factor VIII potentially contribute to the coagulation cascade correcting the bleeding phenotype of mice with hemophilia A

    PubMed Central

    Zanolini, Diego; Merlin, Simone; Feola, Maria; Ranaldo, Gabriella; Amoruso, Angela; Gaidano, Gianluca; Zaffaroni, Mauro; Ferrero, Alessandro; Brunelleschi, Sandra; Valente, Guido; Gupta, Sanjeev; Prat, Maria; Follenzi, Antonia

    2015-01-01

    A large fraction of factor VIII in blood originates from liver sinusoidal endothelial cells although extrahepatic sources also contribute to plasma factor VIII levels. Identification of cell-types other than endothelial cells with the capacity to synthesize and release factor VIII will be helpful for therapeutic approaches in hemophilia A. Recent cell therapy and bone marrow transplantation studies indicated that Küpffer cells, monocytes and mesenchymal stromal cells could synthesize factor VIII in sufficient amount to ameliorate the bleeding phenotype in hemophilic mice. To further establish the role of blood cells in expressing factor VIII, we studied various types of mouse and human hematopoietic cells. We identified factor VIII in cells isolated from peripheral and cord blood, as well as bone marrow. Co-staining for cell type-specific markers verified that factor VIII was expressed in monocytes, macrophages and megakaryocytes. We additionally verified that factor VIII was expressed in liver sinusoidal endothelial cells and endothelial cells elsewhere, e.g., in the spleen, lungs and kidneys. Factor VIII was well expressed in sinusoidal endothelial cells and Küpffer cells isolated from human liver, whereas by comparison isolated human hepatocytes expressed factor VIII at very low levels. After transplantation of CD34+ human cord blood cells into NOD/SCIDγNull-hemophilia A mice, fluorescence activated cell sorting of peripheral blood showed >40% donor cells engrafted in the majority of mice. In these animals, plasma factor VIII activity 12 weeks after cell transplantation was up to 5% and nine of 12 mice survived after a tail clip-assay. In conclusion, hematopoietic cells, in addition to endothelial cells, express and secrete factor VIII: this information should offer further opportunities for understanding mechanisms of factor VIII synthesis and replenishment. PMID:25911555

  3. Expression and Characterization of Gly-317 Variants of Factor IX Causing Variable Bleeding in Hemophilia B Patients.

    PubMed

    Lu, Qiuya; Yang, Likui; Manithody, Chandrashekhara; Wang, Xuefeng; Rezaie, Alireza R

    2015-06-23

    We recently identified two hemophilia B patients who carried Gly-317 to Arg (FIX-G317R) or Gly-317 to Glu (FIX-G317E) substitutions in their FIX gene. The former mutation caused severe and the latter moderate bleeding in afflicted patients. To understand the molecular basis for the variable clinical manifestation of Gly-317 mutations, we prepared recombinant G317R and G317E derivatives of FIX and compared their kinetic properties to those of recombinant wild-type FIX in appropriate assay systems. Both physiological activators, factor XIa and extrinsic Tenase (factor VIIa-tissue factor), activated both zymogen variants with an ∼1.5-fold elevated K(m); however, extrinsic Tenase activated FIX-G317E with an ∼2-fold improved k(cat). By contrast to zymogen activation, the catalytic activities of both FIXa-G317R and FIXa-G317E enzymes toward the natural substrate, factor X, were dramatically (>4 orders of magnitude) impaired, but their apparent affinity for interaction with factor VIIIa was only slightly (<2-fold) decreased. Further studies revealed that the reactivity of FIXa-G317R and FIXa-G317E with antithrombin has been impaired 10- and 13-fold, respectively, in the absence and 166- and 500-fold, respectively, in the presence of pentasaccharide. As expected, the clotting activities of FIX variants could not be measured by the aPTT assay. These results implicate a critical role for Gly-317 in maintaining normal catalytic function for FIX/FIXa in the clotting cascade. The results further suggest that improved k(cat) of FIX-G317E activation in the extrinsic pathway together with dramatically impaired reactivity of FIXa-G317E with antithrombin may account for the less severe bleeding phenotype of a hemophilia B patient carrying the FIX-G317E mutation. PMID:26023895

  4. Occupational Cohort Time Scales

    PubMed Central

    Roth, H. Daniel

    2015-01-01

    Purpose: This study explores how highly correlated time variables (occupational cohort time scales) contribute to confounding and ambiguity of interpretation. Methods: Occupational cohort time scales were identified and organized through simple equations of three time scales (relational triads) and the connections between these triads (time scale web). The behavior of the time scales was examined when constraints were imposed on variable ranges and interrelationships. Results: Constraints on a time scale in a triad create high correlations between the other two time scales. These correlations combine with the connections between relational triads to produce association paths. High correlation between time scales leads to ambiguity of interpretation. Conclusions: Understanding the properties of occupational cohort time scales, their relational triads, and the time scale web is helpful in understanding the origins of otherwise obscure confounding bias and ambiguity of interpretation. PMID:25647318

  5. Minimizing the Risk of Perioperative Bleeding in a Child with Hemophilia A during Dental Rehabilitation under General Anesthesia: A Case Report

    PubMed Central

    Yehia El Batawi, Hisham

    2013-01-01

    ABSTRACT Hemophilia, among other bleeding disorders, raises concerns for dental service providers who routinely use sharp hand and rotary instruments, address highly vascular soft tissue and provide dental extractions. In pediatric dentistry, dealing with fearful or irritable children increases the possibility of trauma and subsequent bleeding risks in hemophilic pediatric dental patients. In the current report, we discuss how anesthetic, pediatric and dental management may contribute to the delivery of safe and complete dental treatment for such children. This report describes the safe performance of dental treatments, including multiple extractions under general anesthesia, in a hemophilic child. How to cite this article: El Batawi HY. Minimizing the Risk of Perioperative Bleeding in a Child with Hemophilia A during Dental Rehabilitation under General Anesthesia: A Case Report. Int J Clin Pediatr Dent 2013;6(3):217-222. PMID:25206227

  6. Regional intravascular delivery of AAV-2-F.IX to skeletal muscle achieves long-term correction of hemophilia B in a large animal model.

    PubMed

    Arruda, Valder R; Stedman, Hansell H; Nichols, Timothy C; Haskins, Mark E; Nicholson, Matthew; Herzog, Roland W; Couto, Linda B; High, Katherine A

    2005-05-01

    In earlier work, we showed that adeno-associated virus-mediated delivery of a Factor IX gene to skeletal muscle by direct intramuscular injection resulted in therapeutic levels of circulating Factor IX in mice. However, achievement of target doses in humans proved impractical because of the large number of injections required. We used a novel intravascular delivery technique to achieve successful transduction of extensive areas of skeletal muscle in a large animal with hemophilia. We provide here the first report of long-term (> 3 years, with observation ongoing), robust Factor IX expression (circulating levels of 4%-14%) by muscle-directed gene transfer in a large animal, resulting in essentially complete correction of the bleeding disorder in hemophilic dogs. The results of this translational study establish an experimental basis for clinical studies of this delivery method in humans with hemophilia B. These findings also have immediate relevance for gene transfer in patients with muscular dystrophy. PMID:15479726

  7. Interprosthetic humeral fracture revision using a tibial allograft total elbow prosthetic composite in a patient with hemophilia A : a case report

    PubMed Central

    2012-01-01

    Introduction Interprosthetic fractures of the humerus are rare. Revisions of total elbow arthroplasty components in these cases are difficult. We report the first case of a patient with hemophilia who underwent a revision with a tibial allograft prosthetic composite without the need for hardware augmentation. Case presentation A 43-year-old Caucasian man with a history of hemophilia and transfusion-related human immunodeficiency virus and hepatitis B and C presented with an interprosthetic fracture of his humerus after months of pain between his total elbow and total shoulder arthroplasties. Because of the poor remaining bone stock available in his distal humerus, a revision using a barrel-staved tibial allograft prosthetic composite was performed. Our patients’ factor VIII level was optimized before the operation and he suffered no major long-term complications at 28 months. His only complication was an incomplete radial nerve palsy that ultimately recovered and left him with some numbness on the dorsum of his hand. Conclusion Careful use of an allograft prosthetic composite is a very reasonable option when a patient experiences an interprosthetic fracture. We have successfully performed revision total elbow arthroplasty for a patient with hemophilia with an interprosthetic fracture using a tibial allograft and no additional fixation, which resulted in his return to full activities of daily living, minimal pain and full incorporation of the allograft to host bone. PMID:23009283

  8. NCI Cohort Consortium

    Cancer.gov

    The NCI Cohort Consortium is an extramural-intramural partnership formed by the National Cancer Institute to address the need for large-scale collaborations to pool the large quantity of data and biospecimens necessary to conduct a wide range of cancer studies.

  9. 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

  10. Increasing hepatitis C virus RNA levels in hemophiliacs: relationship to human immunodeficiency virus infection and liver disease. Multicenter Hemophilia Cohort Study.

    PubMed

    Eyster, M E; Fried, M W; Di Bisceglie, A M; Goedert, J J

    1994-08-15

    We have previously observed an increased frequency of liver failure in human immunodeficiency virus (HIV)-infected hemophiliacs. The purpose of this study was to quantitate hepatitis C virus (HCV) RNA levels in serial samples from HIV-seropositive (HIV+) and HIV-seronegative (HIV-) hemophiliacs before and after HIV seroconversion, and to examine the relationship of HCV RNA levels to CD4 cell counts and to hepatic dysfunction over time. HCV RNA levels were measured on serial samples of serum stored frozen from 17 HCV+/HIV+ and 17 HCV+/HIV- subjects matched within 5 years of their birth dates. All were HCV+ before study entry. HCV RNA levels were quantitated by a branched DNA-enhanced label amplification (bDNA) assay. For samples less than the cut off, HCV RNA was measured by the nested polymerase chain reaction. Individual changes over time, clinical groups, and mean values within predetermined time windows were compared with Wilcoxon rank sum tests. Mean HCV RNA levels increased from 2.76 (standard error [SE] 1.33) x 10(5) to 2.84 (SE 1.39) x 10(6) eq/mL during the first 2 years after HIV seroconversion (P = .006). Baseline HCV RNA levels in the pre-HIV seroconversion group were not significantly different from the baseline levels in those who remained HIV (P = .79). Over the entire period of study, HCV RNA levels increased nearly threefold in those who remained HIV- (mean 9.47 [SE 4.78] x 10(5) to 2.81 [SE 1.13] x 10(6)/mL; P = .02). Among those who became HIV+, HCV RNA levels increased 58-fold (mean 2.85 [SE 1.26] x 10(5) to 1.66 [SE 0.57] x 10(7) eq/mL; P = .0001). The rate of increase in HCV RNA levels was eightfold faster for HIV+ subjects than for subjects who remained HIV- (P = .009). HCV RNA levels increased twofold higher in 5 subjects who developed liver failure compared with the 12 who did not (P = .43). HCV RNA levels correlated significantly with CD4 counts (R = -.33, P = .01) and serum aspartate aminotransferase levels (AST) (R = .36, P = .007). We conclude that HCV RNA levels are significantly higher in HIV+ than in HIV- multitransfused hemophiliacs. HCV load increases over time, is enhanced by HIV, and further increases as immune deficiency progresses. HCV RNA levels are directly associated with high AST levels. These findings suggest that HIV-induced immune deficiency may promote increased HCV replication. PMID:8049420

  11. Cohort Profile: Mysore Parthenon Birth Cohort

    PubMed Central

    Krishnaveni, Ghattu V; Veena, Sargoor R; Hill, Jacqueline C; Karat, Samuel C; Fall, Caroline HD

    2015-01-01

    The Mysore Parthenon Birth Cohort was established to examine the long-term effects of maternal glucose tolerance and nutritional status on cardiovascular disease risk factors in the offspring. During 1997–98, 830 of 1233 women recruited from the antenatal clinics of the Holdsworth Memorial Hospital (HMH), Mysore, India, underwent an oral glucose tolerance test. Of these, 667 women delivered live babies at HMH. Four babies with major congenital anomalies were excluded, and the remaining 663 were included for further follow-up. The babies had detailed anthropometry at birth and at 6–12-monthly intervals subsequently. Detailed cardiovascular investigations were done at ages 5, 9.5 and 13.5 years in the children, and in the parents at the 5-year and 9.5-year follow-ups. This ongoing study provides extensive data on serial anthropometry and body composition, physiological and biochemical measures, dietary intake, nutritional status, physical activity measures, stress reactivity measures and cognitive function, and socio-demographic parameters for the offspring. Data on anthropometry, cardiovascular risk factors and nutritional status are available for mothers during pregnancy. Anthropometry and risk factor measures are available for both parents at follow-up. PMID:24609067

  12. Cohort profile: Mysore parthenon birth cohort.

    PubMed

    Krishnaveni, Ghattu V; Veena, Sargoor R; Hill, Jacqueline C; Karat, Samuel C; Fall, Caroline H D

    2015-02-01

    The Mysore Parthenon Birth Cohort was established to examine the long-term effects of maternal glucose tolerance and nutritional status on cardiovascular disease risk factors in the offspring. During 1997-98, 830 of 1233 women recruited from the antenatal clinics of the Holdsworth Memorial Hospital (HMH), Mysore, India, underwent an oral glucose tolerance test. Of these, 667 women delivered live babies at HMH. Four babies with major congenital anomalies were excluded, and the remaining 663 were included for further follow-up. The babies had detailed anthropometry at birth and at 6-12-monthly intervals subsequently. Detailed cardiovascular investigations were done at ages 5, 9.5 and 13.5 years in the children, and in the parents at the 5-year and 9.5-year follow-ups. This ongoing study provides extensive data on serial anthropometry and body composition, physiological and biochemical measures, dietary intake, nutritional status, physical activity measures, stress reactivity measures and cognitive function, and socio-demographic parameters for the offspring. Data on anthropometry, cardiovascular risk factors and nutritional status are available for mothers during pregnancy. Anthropometry and risk factor measures are available for both parents at follow-up. PMID:24609067

  13. Factor eight inhibitor bypass activity (FEIBA) in the management of bleeds in hemophilia patients with high-titer inhibitors

    PubMed Central

    Tjønnfjord, Geir E; Andre Holme, Pål

    2007-01-01

    The development of high-titer inhibitors to FVIII and less often to other coagulation factors are the most serious complication of hemophilia therapy and makes treatment of bleeds very challenging. At present, bypassing agents, such as factor eight inhibitor bypass activity (FEIBA) and activated recombinant factor VII (rFVIIa) are the only coagulation factor concentrates available for the treatment of bleeds in inhibitor patients. Both products are effective and safe, and their efficacy has been found to be comparable (approximately 80%) in a recent prospective study. A significant number of patients report a better effect of one or the other of the products, and in a minority of the patients none of the products are particularly effective. The hemostatic efficacy of bypassing agents is not considered equal to that of coagulation factor replacement in patients without inhibitors by most physicians. An improvement in hemostatic efficacy may be achieved by optimizing the dosing of by passing agents. However, the lack of standardized and validated laboratory assays reflecting the hemostatic efficacy of the bypassing agents is an obstacle to this achievement. PMID:17969383

  14. 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

  15. 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

    2016-01-01

    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

  16. New and Emerging Agents for the Treatment of Hemophilia: Focus on Extended Half-Life Recombinant Clotting Proteins.

    PubMed

    Ragni, Margaret V

    2015-09-01

    Hemophilia A and B are X-linked disorders caused by deficient or defective clotting factor VIII (FVIII) or IX factor (FIX) proteins, and characterized by spontaneous or traumatic bleeding into joints and muscles. Previous use of plasma and plasma-derived clotting factors that lacked appropriate viral inactivation steps in manufacturing led to significant morbidity associated with transfusion-transmitted HIV and hepatitis C virus (HCV). The development of recombinant proteins revolutionized their treatment, and, with no new HIV or HCV infection via clotting proteins for nearly 30 years, greatly improved their lifespan, which now approaches that of the general population, and with the same risks for aging complications. Novel long-acting factor proteins are being licensed to extend FVIII and FIX half-life, thereby reducing infusion frequency and potentially bleed frequency and associated morbidity. Further, novel therapeutics which take advantage of new technologies, including siRNA, monoclonal antibody, and small peptide inhibition technologies, have the potential to simplify treatment and improve outcomes for those with inhibitors. PMID:26310188

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

    SciTech Connect

    Kuppuswamy, M.N.; Hoffmann, J.W.; Spitzer, S.G.; Groce, S.L.; Bajaj, S.P. ); Kasper, C.K. )

    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 to 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.

  18. 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

  19. Systematic review of the role of FVIII concentrates in inhibitor development in previously untreated patients with severe hemophilia a: a 2013 update.

    PubMed

    Franchini, Massimo; Coppola, Antonio; Rocino, Angiola; Santagostino, Elena; Tagliaferri, Annarita; Zanon, Ezio; Morfini, Massimo

    2013-10-01

    Nowadays, patients with hemophilia A receive a high standard of care; therefore, the most challenging complication of factor VIII (FVIII) replacement therapy has become the development of FVIII inhibitors, which render the concentrate infusion ineffective and expose patients to an increased risk of morbidity and mortality. Among environmental risk factors influencing inhibitor development, the type of FVIII products has always drawn the attention of investigators. Conflicting results are reported in the literature concerning rates of inhibitor development after either plasma-derived or recombinant FVIII concentrates. To help elucidate this controversial issue, we have performed a systematic review and meta-analysis of prospective studies evaluating the incidence of inhibitors in previously untreated patients with severe hemophilia A receiving plasma-derived or recombinant FVIII products. The quality of the studies was assessed using the Newcastle-Ottawa Scale (NOS), the STrenghtening the Reporting of OBservational studies in Epidemiology and an ad hoc quality score. Overall, 28 prospective studies, including 1,421 patients with hemophilia A, fulfilled our selection criteria and were included in the systematic review. No statistically significant differences were observed in the inhibitor incidence between plasma-derived and recombinant FVIII concentrates considering all (weighted means: 23%, 95% CI: 15-33% vs. 29%, 95% CI: 26-32%) and high titer (16%, 95% CI: 10-26% vs. 18%, 95% CI: 15-21%) inhibitors. Similarly, no significant differences were found in the inhibitor incidence among the different classes of recombinant products. In conclusion, the results of our meta-analysis show that the different types of FVIII products are not associated with different risks of inhibitor development. PMID:24022806

  20. Gene therapy for hemophilia B with liver-specific element mediated by Rep-RBE site-specific integration system.

    PubMed

    Xu, Zhengxin; Ye, Juan; Zhang, Amin; Xie, Linjun; Shen, Qi; Xue, Jinglun; Chen, Jinzhong

    2015-02-01

    Adeno-associated virus (AAV) is a nonpathogenic virus capable of targeting human chromosome 19 for integration at AAVS1 site, and a 16 bp Rep binding element (RBE) sequence of AAV was sufficient for mediating this specific integration in the presence of AAV regulation proteins (Rep). Previously, we cotransduced 2 plasmids, pRBE-CMV-hFIX and pRC, into the AAVS1 transgenic mice by hydrodynamic injection, and a long-term expression of human coagulation Factor IX (hFIX) was observed. The corresponding AAVS1 locus site-specific integrations were verified by nested polymerase chain reaction. In this study, we established a novel hFIX expression plasmid, pRBE-HCR-hAAT-hFIX, driven by a liver-specific promoter by replacing the CMV promoter of pRBE-CMV-hFIX with a humanized promoter consisting of HCR-hAAT. The expression of hFIX in vitro was almost the same in transient transfection of pRBE-CMV-hFIX or pRBE-HCR-hAAT-hFIX. AAVS1-specific integrations were identified both in mice transfected with pRC/pRBE-CMV-hFIX cocktail and pRC/pRBE-HCR-hAAT-hFIX cocktail. However, the expression of hFIX of pRBE-HCR-hAAT-hFIX mice was higher and persisted longer. It achieved more than 1% of normal plasma hFIX concentration and maintained for 240 days. The result suggested that RBE-HCR-hAAT element could improve the expression of hFIX and present potential usage of Rep-RBE site-specific integration in gene therapy for hemophilia B. PMID:25295466

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

    PubMed

    Wang, Q; Dong, B; Firrman, J; Wu, W; Roberts, S; Moore, A R; Liu, L S; Chin, M P S; Diao, Y; Kost, J; Xiao, W

    2016-07-01

    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, different biological properties between cFVIII and human FVIII (hFVIII) indicated that the development of novel HA treatment may require careful characterization of non-human FVIII. To investigate whether the data obtained using cFVIII can translate to HA treatment in human, we analyzed the differential biological properties of canine heavy chain (cHC) and light chain (cLC) by comparing with human heavy chain (hHC) and light chain (hLC). The secretion of cHC was 5-30-fold higher than hHC, with or without light chains (LCs). cHC+hLC group exhibited ~18-fold increase in coagulation activity compared with hHC+hLC delivery by recombinant adeno-associated viral vectors. Unlike hHC, the secretion of cHC was independent of LCs. cLC improves the specific activity of FVIII by two- to threefold compared with hLC. Moreover, the cLC, but not cHC, contributes to the higher stability of cFVIII. Our results suggested that the cFVIII expression results in the canine model should be interpreted with caution as the cHC secreted more efficiently than hHC and cLC exhibited a more active and stable phenotype than hLC. PMID:27064790

  2. Extracorporeal Treatment for the Acute und Long-Term Outcome of Patients with Life-Threatening Acquired Hemophilia.

    PubMed

    Zeitler, Heike; Ulrich-Merzenich, Gudrun; Panek, Darius; Goldmann, Georg; Vidovic, Natascha; Brackmann, Hans-Hermann; Oldenburg, Johannes

    2012-08-01

    OBJECTIVES: In acquired hemophilia (AH), autoantibodies (inhibitors) impede blood coagulation factors leading to severe bleedings. Cornerstones of a successful treatment are the control of bleeding and an eradication of autoantibodies. The present study is an update of our previous documentation of the treatment of high-titer AH patients with severe life-threatening bleeding undergoing the modified Bonn-Malmö-Protocol (MBMP). METHODS: 64 AH patients were treated by a standard combination protocol (MBMP) consisting of antibody depletion through immunoadsorption, i.v. immunoglobulin, immunosuppression, and high-dose FVIII substitution. They underwent a long-term follow-up. RESULTS: Primary study endpoints loss of detection of the activity of the inhibitor and FVIII recovery ? 5% were reached in a median time of 3 days (95% CI: 2.6-3.4 days), the median time of FVIII substitution was 13 days (95% CI 10.6-15.3 days), and the median time of immunoadsorption was 16 days (95% CI 13-18.9 days). In 5 patients the AH occurred as paraneoplastic syndrome, and partial remission was achieved. Relapses without bleeding event occurred only in second-line MBMP. Those responded excellently to short time treatment. Overall patients remained in remission over a median follow-up time of 8 years. Conclusion: Except for paraneoplastic AH, MBMP-treated patients have a remarkable prognosis which is confirmed by long-term follow-up with a complete response rate of 93% (53/57) in the first year post MBMP and 100% during long-term follow-up. These outcome in life-threatening AH is unique and until now not achievable via other treatment schedules. In life-threatening bleedings physicians should take into account MBMP as a first line treatment. PMID:22969696

  3. Advances in bypassing agent therapy for hemophilia patients with inhibitors to close care gaps and improve outcomes.

    PubMed

    Shapiro, Amy D; Hedner, Ulla

    2011-10-01

    In the past, patients with hemophilia and inhibitors have had less-than-optimal treatment and have experienced more orthopedic complications than patients without inhibitors. Bypassing agents offer the potential to close treatment gaps between inhibitor and noninhibitor patients by helping the former better attain key treatment goals, including: facilitating early initiation of treatment and hemostatic control in hemarthroses; providing effective treatment in serious hemorrhagic episodes; and performance of major surgery. Effective treatment with a bypassing agent minimizes joint and/or muscle damage and potentially can serve as an effective prophylactic agent to minimize the number of hemarthroses experienced per year, thereby mitigating the development of arthropathy. The reported efficacy of the currently available bypassing agents ranges from approximately 50-80% (50-64% in controlled studies) for plasma-derived activated prothrombin complex concentrate (pd-aPCC) and 81-91% (in controlled studies) for recombinant activated factor VII (rFVIIa), including use in major orthopedic surgery. Both bypassing agents have undergone key improvements in their formulation and/or properties in recent years. The nanofiltered, vapor-heated formulation of pd-aPCC has diminished the risk of acquiring blood-borne viral infections and the room temperature stable formulation of rFVIIa allows more convenient storage, increased ease to dissolve and inject, and smaller volumes, thereby increasing overall ease of administration. Use of recommended dosing has been demonstrated to provide effective hemostasis with a minimal number of injections for both agents. In this paper, we review the individual characteristics of pd-aPCC and rFVIIa and discuss clinical data from studies conducted in inhibitor patients that demonstrate the potential benefits of these bypassing agents in this difficult-to-treat population, and underscore the potential opportunities to close the gap in care between

  4. Evaluation of factor VIII polymorphic short tandem repeat markers in linkage analysis for carrier diagnosis of hemophilia A

    PubMed Central

    Shrestha, Sabina; Dong, Sufang; Li, Zuhua; Huang, Zhuliang; Zheng, Fang

    2016-01-01

    Hemophilia A (HA) is the most common inherited X-linked recessive bleeding disorder caused by heterogeneous mutations in the factor VIII gene (FVIII). Diagnosis of the carrier is critical for preventing the birth of children affected by this coagulation disorder, which ultimately facilitates its management. Due to the heterogeneous nature of mutations, the large inversions and the complexity of the FVIII gene, direct recognition of the disease-associated mutation in HA is complex. Indirect linkage analysis using highly informative heterozygous polymorphic markers is an alternative method for determining the co-segregation of the mutant gene within a family for carrier detection of HA. The aim of the present study was to perform carrier diagnosis in a family with HA. Rapid multifluorescent polymerase chain reaction (PCR) was performed with six extragenic short tandem repeats (STRs), DXS1073, DXS15, DXS8091, DXS1227, DXS991, DXS993 and one intragenic marker, STR22 for linkage analysis in the HA family. All the STR markers employed in the present study were informative for linkages of pathogenic and healthy haplotypes among family members, particularly STR22, DXS1073 and DXS15. The STR marker, STR22, is within the FVIII gene while the DXS1073 and DXS15 markers are very close to the FVIII gene, where the chances of recombination are comparatively low, and provided the most accurate interpretation analysis, indicating that the proband's sister may have been the HA carrier. Rapid multifluorescent PCR using STR markers and linkage analysis was identified to be a simple method for performing HA carrier diagnosis. PMID:27446547

  5. Somatic mosaicism in families with hemophilia B: 11% of germline mutations originate within a few cell divisions post-fertilization

    SciTech Connect

    Knoell, A.; Ketterling, R.P.; Vielhaber, E.

    1994-09-01

    Previous molecular estimates of mosaicism in the dystrophin and other genes generally have focused on the transmission of the mutated allele to two or more children by an individual without the mutation in leukocyte DNA. We have analyzed 414 families with hemophilia B by direct genomic sequencing and haplotype analysis, and have deduced the origin of mutation in 56 families. There was no origin individual who transmitted a mutant allele to more than one child. However, somatic mosaicism was detected by sequence analysis of four origin individuals (3{female} and 1{male}). The sensitivity of this analysis is typically one part in ten. In one additional female who had close to a 50:50 ratio of mutant to normal alleles, three of four noncarrier daughters inherited the haplotype associated with the mutant allele. This highlights a caveat in molecular analysis: a presumptive carrier in a family with sporadic disease does not necessarily have a 50% probability of transmitting the mutant allele to her offspring. After eliminating those families in which mosaicism could not be detected because of a total gene deletion or absence of DNA from a deduced origin individual, 5 of 43 origin individuals exhibited somatic mosaicism at a level that reflects a mutation within the first few cell divisions after fertilization. In one patient, analysis of cervical scrapings and buccal mucosa confirm the generalized distribution of somatic mutation. Are the first few cell divisions post-fertilization highly mutagenic, or do mutations at later divisions also give rise to somatic mosaicism? To address this question, DNA from origin individuals are being analyzed to detect somatic mosaicism at a sensitivity of 1:1000. Single nucleotide primer extension (SNuPE) has been utilized in eight families to date and no mosaicism has been detected. When the remaining 30 samples are analyzed, it will be possible to compare the frequency of somatic mosaicism at 0.1-10% with that of {ge}10%.

  6. Germ-line origins of mutation in families with hemophilia B: The sex ratio varies with the type of mutation

    SciTech Connect

    Ketterling, R.P.; Vielhaber, E.; Bottema, C.D.K.; Schaid, D.J.; Sommer, S.S. ); Cohen, M.P. ); Sexauer, C.L. )

    1993-01-01

    Previous epidemiological and biochemical studies have generated conflicting estimates of the sex ratio of mutation. Direct genomic sequencing in combination with haplotype analysis extends previous analyses by allowing the precise mutation to be determined in a given family. From analysis of the factor IX gene of 260 consecutive families with hemophilia B, the authors report the germ-line origin of mutation in 25 families. When combined with 14 origins of mutation reported by others and with 4 origins previously reported by them, a total of 25 occur in the female germ line, and 18 occur in the male germ line. The excess of germ-line origins in females does not imply an overall excess mutation rate per base pair in the female germ line. Bayesian analysis of the data indicates that the sex ratio varies with the type of mutation. The aggregate of single-base substitutions shows a male predominance of germ-line mutations (P < .002). The maximum-likelihood estimate of the male predominance is 3.5-fold. Of the single-base substitutions, deletions display a sex ratio of unity. Analysis of the parental age at transmission of a new mutation suggests that germ-line mutations are associated with a small increase in parental age in females but little, if any, increase in males. Although direct genomic sequencing offers a general method for defining the origin of mutation in specific families, accurate estimates of the sex ratios of different mutational classes require large sample sizes and careful correction for multiple biases of ascertainment. The biases in the present data result in an underestimate of the enhancement of mutation in males. 62 refs., 1 fig., 5 tabs.

  7. Cohort Size Effects and Migration.

    ERIC Educational Resources Information Center

    Wilson, Franklin D.

    1983-01-01

    Explores whether changes in the size of cohorts entering the labor force affected the propensity within the U.S. labor force to migrate and socioeconomic circumstances of migrants at destination within 1965-76. Suggests that a significant reduction in the volume of migration among members of the baby boom cohort was the primary adjustment…

  8. Expression of human factor IX in rabbit hepatocytes by retrovirus-mediated gene transfer: Potential for gene therapy of hemophilia B

    SciTech Connect

    Thompson, A.R. Puget Sound Blood Center, Seattle, WA ); Darlington, G. ); Armentano, D.; Woo, S.L.C.

    1990-08-01

    Hemophilia B (Christmas disease) is a chromosome X-linked blood clotting disorder which results when factor IX is deficient or functionally defective. The enzyme is synthesized in the liver, and the existence of animal models for this genetic disease will permit the development of somatic gene therapy protocols aimed at transfer of the functional gene into the liver. The authors report the construction of an N2-based recombinant retroviral vector, NCMVFIX, for efficient transfer and expression of human factor IX cDNA in primary rabbit hepatocytes. In this construct the human cytomegalovirus immediate early promoter directs the expression of factor IX. Hepatocytes were isolated from 3-week-old New Zealand White rabbits, infected with the recombinant virus, and analyzed for secretion of active factor IX. The infected rabbit hepatocytes produced human factor IX that is indistinguishable from enzyme derived from normal human plasma. The recombinant protein is sufficiently {gamma}-carboxylated and is functionally active in clotting assays. These results establish the feasibility of using infected hepatocytes for the expression of this protein and are a step toward the goal of correcting hemophilia B by hepatic gene transfer.

  9. Molecular characterization of mild-to-moderate hemophilia A: detection of the mutation in 25 of 29 patients by denaturing gradient gel electrophoresis.

    PubMed Central

    Higuchi, M; Antonarakis, S E; Kasch, L; Oldenburg, J; Economou-Petersen, E; Olek, K; Arai, M; Inaba, H; Kazazian, H H

    1991-01-01

    To date it has been difficult to characterize completely a genetic disorder, such as hemophilia A, in which the involved gene is large and unrelated affected individuals have different mutations, most of which are point mutations. Toward this end, we analyzed the DNA of 29 patients with mild-to-moderate hemophilia A in which the causative mutation is likely to be a missense mutation. Using computer analysis, we determined the melting properties of factor VIII gene sequences to design primer sets for PCR amplification and subsequent denaturing gradient gel electrophoresis (DGGE). A total of 45 primer sets was chosen to amplify 99% of the coding region of the gene and 41 of 50 splice junctions. To facilitate detection of point mutations, we mixed DNA from two male patients, and both homoduplexes and heteroduplexes were analyzed. With these 45 primer sets, 26 DNAs containing previously identified point mutations in the factor VIII gene were studied, and all 26 mutations were easily distinguishable from normal. After analyzing the 29 patients with unknown mutations, we identified the disease-producing mutation in 25 (86%). Two polymorphisms and two rare normal variants were also found. Therefore, DGGE after computer analysis is a powerful method for nearly complete characterization of disease-producing mutations and polymorphisms in large genes such as that for factor VIII. Images PMID:1924291

  10. Surgical Treatment of an Infected Nonunion of the Middle Third of the Femur Associated with Femoral Shortening in a Hemophilia Patient

    PubMed Central

    Salduz, Ahmet; Kaya, Özcan; Balci, Halil İbrahim; Akgul, Turgut; Dikici, Fatih; Zülfikar, Bülent; Kocaoğlu, Mehmet

    2016-01-01

    The management of nonunion and limb length discrepancy has remained a constant challenge in hemophilic patients. In this study, we aimed to present the treatment of femur infected nonunion and limb length discrepancy in a twenty-seven-year-old patient with hemophilia type A. A 27-year-old male patient with hemophilia type A referred to our institution for the treatment of right femur infected nonunion and 10 cm shortness of the femur. Resection of the nonunion site and bone-to-bone fixation with autologous bone grafting were performed. Compression to the pseudoarthrosis site and distraction from new osteotomy site were applied with the unilateral external fixator. Union was achieved, and 6 cm lengthening was obtained according to the initial length. Patient was followed up for 7 years. After this treatment, the patient is able to walk with full weight bearing on the affected extremity with 4 cm shortening which is compensated by the heel lift. The results of this case indicate that limb lengthening and treatment of nonunion with the external fixation could be reliable and effective method for hemophilic patients. PMID:27073706

  11. Functions of AAV-CMV-F.IX And AAV-EF1alpha-F.IX in gene therapy for hemophilia B.

    PubMed

    Wiwanitkit, Viroj

    2007-02-01

    There has been substantial progress in using gene therapy to treat animals with hemophilia. Adeno-associated viral (AAV) gene transfer of coagulation factor IX to skeletal muscle and liver of murine and canine models of hemophilia has resulted in sustained systemic expression and, in several studies, in complete cure of the bleeding disorder. Two AAV vectors widely used at present are AAV-CMV-F.IX and AAV-EF1alpha-F.IX. This work compares the predicted molecular functions of AAV-CMV-F.IX and AAV-EF1alpha -F.IX by sequence docking and gene ontology. It is shown that both AAV-CMV-F.IX and AAV-EF1alpha -F.IX induce coagulation factor IXa activity; however, AAV-CMV-F.IX administration also yields coagulation factor XIa activity and AAV-EF1alpha -F.IX treatment results in coagulation factor Xa activity. Therefore, AAV-CMV-F.IX might be useful for factor XI deficiency. AAV-CMV-F.IX has several additional molecular functions and processes compared with AAV-CMV-F.IX. PMID:17266422

  12. Integration-deficient Lentiviral Vectors Expressing Codon-optimized R338L Human FIX Restore Normal Hemostasis in Hemophilia B Mice

    PubMed Central

    Suwanmanee, Thipparat; Hu, Genlin; Gui, Tong; Bartholomae, Cynthia C; Kutschera, Ina; von Kalle, Christof; Schmidt, Manfred; Monahan, Paul E; Kafri, Tal

    2014-01-01

    Integration-deficient lentiviral vectors (IDLVs) have been shown to transduce a wide spectrum of target cells and organs in vitro and in vivo and to maintain long-term transgene expression in nondividing cells. However, epigenetic silencing of episomal vector genomes reduces IDLV transgene expression levels and renders these safe vectors less efficient. In this article, we describe for the first time a complete correction of factor IX (FIX) deficiency in hemophilia B mice by IDLVs carrying a novel, highly potent human FIX cDNA. A 50-fold increase in human FIX cDNA potency was achieved by combining two mechanistically independent yet synergistic strategies: (i) optimization of the human FIX cDNA codon usage to increase human FIX protein production per vector genome and (ii) generation of a highly catalytic mutant human FIX protein in which the arginine residue at position 338 was substituted with leucine. The enhanced human FIX activity was not associated with liver damage or with the formation of human FIX-directed inhibitory antibodies and rendered IDLV-treated FIX-knockout mice resistant to a challenging tail-clipping assay. A novel S1 nuclease-based B1-quantitative polymerase chain reaction assay showed low levels of IDLV integration in mouse liver. Overall, this study demonstrates that IDLVs carrying an improved human FIX cDNA safely and efficiently cure hemophilia B in a mouse model. PMID:23941813

  13. Molecular characterization of mild-to-moderate hemophilia A: Detection of the mutation in 25 of 29 patients by denaturing gradient gel electrophoresis

    SciTech Connect

    Higuchi, Miyoko; Antonarakis, S.E.; Kasch, L. Economou-Petersen, E.; Kazazian, H.H. Jr. ); Oldenburg, J.; Olek, K. ); Arai, Morio; Inaba, Hiroshi )

    1991-10-01

    To date it has been difficult to characterize completely a genetic disorder, such as hemophilia A, in which the involved gene is large and unrelated affected individuals have different mutations, most of which are point mutations. Toward this end, the authors analyzed the DNA of 29 patients with mild-to-moderate hemophilia A in which the causative mutation is likely to be a missense mutation. Using computer analysis, they determined the melting properties of factor VIII gene sequences to design primer sets for PCR amplification and subsequent denaturing gradient gel electrophoresis (DGGE). A total of 45 primer sets was chosen to amplify 99% of the coding region of the gene and 41 of 50 splice junctions. To facilitate detection of point mutations, they mixed DNA from two male patients, and both homoduplexes and heteroduplexes were analyzed. With these 45 primer sets, 26 DNAs containing previously identified point mutations were easily distinguishable from normal. After analyzing the 29 patient with unknown mutations, they identified the disease-producing mutation in 25 (86%). Two polymorphisms and two rare normal variants were also found. Therefore, DGGE after computer analysis is a powerful method for nearly complete characterization of disease-producing mutations and polymorphisms in large genes such as that for factor VIII.

  14. F8 gene mutation profile in Indian hemophilia A patients: Identification of 23 novel mutations and factor VIII inhibitor risk association.

    PubMed

    Pinto, Patricia; Ghosh, Kanjaksha; Shetty, Shrimati

    2016-04-01

    'FVIII inhibitors', especially in severe hemophilia A (HA) patients, is a serious adverse effect that complicates their clinical management. Many genetic and non-genetic risk factors have been proposed for FVIII inhibitor development, diverse in different population groups. This is the first study in Indian hemophiliacs that analyzes inhibitor risk in relation to the complete F8 mutation profile, in a case-control study that included 145 Indian severe HA patients, i.e. 69 inhibitor positive (with 18 inhibitor concordant/discordant family members), and 58 inhibitor negative patients, after informed consent. While 53.54% (68/127) index cases were positive for intron 22 or intron 1 inversions, 55 causative F8 mutations were detected in the 59 inversion negative patients, of which 23 were novel mutations (in 24 patients) and 32 were reported earlier (in 35 patients). A higher incidence of mutations, in the C1 and C2 domains in inhibitor positive patients, and in the A1 domain in inhibitor negative patients was observed, though not significantly different. The study suggests that large F8 rearrangements (significantly higher in the inhibitor positive patients) pose the highest risk, while missense mutations (significantly higher in the inhibitor negative patients) pose the lowest risk of inhibitor development in Indian hemophilia A patients. PMID:26897466

  15. Plant-based oral tolerance to hemophilia therapy employs a complex immune regulatory response including LAP+CD4+ T cells.

    PubMed

    Wang, Xiaomei; Su, Jin; Sherman, Alexandra; Rogers, Geoffrey L; Liao, Gongxian; Hoffman, Brad E; Leong, Kam W; Terhorst, Cox; Daniell, Henry; Herzog, Roland W

    2015-04-01

    Coagulation factor replacement therapy for the X-linked bleeding disorder hemophilia is severely complicated by antibody ("inhibitor") formation. We previously found that oral delivery to hemophilic mice of cholera toxin B subunit-coagulation factor fusion proteins expressed in chloroplasts of transgenic plants suppressed inhibitor formation directed against factors VIII and IX and anaphylaxis against factor IX (FIX). This observation and the relatively high concentration of antigen in the chloroplasts prompted us to evaluate the underlying tolerance mechanisms. The combination of oral delivery of bioencapsulated FIX and intravenous replacement therapy induced a complex, interleukin-10 (IL-10)-dependent, antigen-specific systemic immune suppression of pathogenic antibody formation (immunoglobulin [Ig] 1/inhibitors, IgE) in hemophilia B mice. Tolerance induction was also successful in preimmune mice but required prolonged oral delivery once replacement therapy was resumed. Orally delivered antigen, initially targeted to epithelial cells, was taken up by dendritic cells throughout the small intestine and additionally by F4/80(+) cells in the duodenum. Consistent with the immunomodulatory responses, frequencies of tolerogenic CD103(+) and plasmacytoid dendritic cells were increased. Ultimately, latency-associated peptide expressing CD4(+) regulatory T cells (CD4(+)CD25(-)LAP(+) cells with upregulated IL-10 and transforming growth factor-β (TGF-β) expression) as well as conventional CD4(+)CD25(+) regulatory T cells systemically suppressed anti-FIX responses. PMID:25700434

  16. Transforming the treatment for hemophilia B patients: update on the clinical development of recombinant fusion protein linking recombinant coagulation factor IX with recombinant albumin (rIX-FP).

    PubMed

    Santagostino, Elena

    2016-05-01

    Recombinant fusion protein linking recombinant coagulation factor IX with recombinant albumin (rIX-FP; Idelvion®(†)) is an innovative new treatment designed to extend the half-life of factor IX (FIX) and ease the burden of care for hemophilia B patients. The rIX-FP clinical development program - PROLONG-9FP - is in its advanced phases, with pivotal studies in previously treated adults, adolescents, and pediatrics now completed. Across all age groups studied, rIX-FP has demonstrated a markedly improved pharmacokinetic profile compared with plasma-derived and recombinant FIX treatments, with a 30-40% higher incremental recovery, an approximately 5-fold longer half-life, a lower clearance, and a greater area under the curve. rIX-FP has been very well tolerated with an excellent safety profile. In the pivotal studies, there have been no reports of FIX inhibitors or antidrug antibodies, and few treatment-related adverse events have been observed. Prophylactic regimens of rIX-FP administered once weekly to once every 14 days have been highly effective. When used for surgical prophylaxis, a single infusion of rIX-FP has been sufficient to maintain hemostasis, even during major orthopedic surgery. An ongoing study is now enrolling previously untreated patients and evaluating the possibility of extending the dosing interval to every 21 days. There is little doubt that rIX-FP will transform the treatment of hemophilia B. PMID:27288064

  17. Illustrated operative management of spontaneous bleeding and compartment syndrome of the lower extremity in a patient with acquired hemophilia A: a case report

    PubMed Central

    2014-01-01

    Introduction Spontaneous bleeding resulting in compartment syndrome at the lower adult leg due to acquired hemophilia A is rare. There are no reports on operative management of this entity. Case presentation We present a case of atraumatic compartment syndrome of the lower leg due to acquired factor VIII deficiency, in an 83-year-old Caucasian man of European descent. He was treated surgically with a long and complicated postoperative course after presenting to a community hospital with a 2-day history of increasing pain and swelling in his left lower leg without a previous history of trauma. Conclusions Awareness, prompt diagnosis and effective treatment of compartment syndrome caused by a rare bleeding disorder, which is usually acquired by the elderly, is essential and may spare a patient from surgery or even limb loss, if early administration of recombinant factor VIIa is effective. The course of disease in a patient with operative management of spontaneous bleeding, compartment syndrome and acquired hemophilia A may be prolonged. However, an interdisciplinary approach with meticulous surgical treatment and bleeding management with recombinant factor VIIa as well as inhibitor eradication by immunosuppressive treatment can be successful and expensive. PMID:24886030

  18. Successful immune tolerance induction with low-dose coagulation factor VIII in a patient with hemophilia A from a developing country.

    PubMed

    Ay, Yilmaz; Ersin, Toret; Yesim, Oymak; Hilkay, Karapinar Tuba; Dilek, Ince; Gulcihan, Ozek; Ahmet, Koc

    2016-09-01

    Inhibitor development is the most frequent and serious complication of the treatment in patients with hemophilia. Immune tolerance induction (ITI) is the only option of treatment for the eradication of factor VIII (FVIII) inhibitor. We would like to present our case with hemophilia whose FVIII inhibitor eradication was done by a low-dose ITI regimen. Our patient has been applied on-demand therapy until 8 years of age. Secondary prophylaxis was began because of having hemophilic arthropathy. A low titer of FVIII inhibitor (4.2 BU/ml) was detected in the fifth month of the prophylaxis. The peak inhibitor titer of patient was 4.6 BU/ml, and there was no decrease in inhibitor titer in the follow-up duration. The low-dose ITI (50 IU/kg, 3 days a week) was started. His inhibitor level was detected negative and the recovery test was ameliorated in the 15th of the ITI therapy. High-dose regimen ITI could not be given particularly in developing countries such as Turkey in view of the high cost of treatment. Patients who had good risk factors might be successfully treated by using low-dose ITI regimen as effective as high-dose ITI regimen. PMID:26484639

  19. 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…

  20. Cohort: critical science

    NASA Astrophysics Data System (ADS)

    Digney, Bruce L.

    2007-04-01

    Unmanned vehicle systems is an attractive technology for the military, but whose promises have remained largely undelivered. There currently exist fielded remote controlled UGVs and high altitude UAV whose benefits are based on standoff in low complexity environments with sufficiently low control reaction time requirements to allow for teleoperation. While effective within there limited operational niche such systems do not meet with the vision of future military UxV scenarios. Such scenarios envision unmanned vehicles operating effectively in complex environments and situations with high levels of independence and effective coordination with other machines and humans pursing high level, changing and sometimes conflicting goals. While these aims are clearly ambitious they do provide necessary targets and inspiration with hopes of fielding near term useful semi-autonomous unmanned systems. Autonomy involves many fields of research including machine vision, artificial intelligence, control theory, machine learning and distributed systems all of which are intertwined and have goals of creating more versatile broadly applicable algorithms. Cohort is a major Applied Research Program (ARP) led by Defence R&D Canada (DRDC) Suffield and its aim is to develop coordinated teams of unmanned vehicles (UxVs) for urban environments. This paper will discuss the critical science being addressed by DRDC developing semi-autonomous systems.

  1. 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

  2. Development of inhibitory antibodies to therapeutic factor VIII in severe hemophilia A is associated with microsatellite polymorphisms in the HMOX1 promoter

    PubMed Central

    Repessé, Yohann; Peyron, Ivan; Dimitrov, Jordan D; Dasgupta, Suryasarathi; Moshai, Elika Farrokhi; Costa, Catherine; Borel-Derlon, Annie; Guillet, Benoit; D’Oiron, Roseline; Aouba, Achille; Rothschild, Chantal; Oldenburg, Johannes; Pavlova, Anna; Kaveri, Srinivas V; Lacroix-Desmazes, Sébastien

    2013-01-01

    Induction of heme oxygenase-1, a stress-inducible enzyme with anti-inflammatory activity, reduces the immunogenicity of therapeutic factor VIII in experimental hemophilia A. In humans, heme oxygenase-1 expression is modulated by polymorphisms in the promoter of the heme oxygenase-1-encoding gene (HMOX1). We investigated the relationship between polymorphisms in the HMOX1 promoter and factor VIII inhibitor development in severe hemophilia A. We performed a case-control study on 99 inhibitor-positive patients and 263 patients who did not develop inhibitors within the first 150 cumulative days of exposure to therapeutic factor VIII. Direct sequencing and DNA fragment analysis were used to study (GT)n polymorphism and single nucleotide polymorphisms located at −1135 and −413 in the promoter of HMOX1. We assessed associations between the individual allele frequencies or genotypes, and inhibitor development. Our results demonstrate that inhibitor-positive patients had a higher frequency of alleles with large (GT)n repeats (L: n≥30), which are associated with lesser heme oxygenase-1 expression (odds ratio 2.31; 95% confidence interval 1.46–3.66; P<0.001]. Six genotypes (L/L, L/M, L/S, M/M, M/S and S/S) of (GT)n repeats were identified (S: n<21; M: 21≤n<30). The genotype group including L alleles (L/L, L/M and L/S) was statistically more frequent among inhibitor-positive than inhibitor-negative patients, as compared to the other genotypes (33.3% versus 17.1%) (odds ratio 2.21, 95% confidence interval 1.30–3.76; P<0.01). To our knowledge, this is the first association identified between HMOX1 promoter polymorphism and development of anti-drug antibodies. Our study paves the way towards modulation of the endogenous anti-inflammatory machinery of hemophilia patients to reduce the risk of inhibitor development PMID:23716558

  3. Improving Music Appreciation Class Using Cohort Analysis.

    ERIC Educational Resources Information Center

    Buel, Dona L.; Welch, Samuel C.

    2000-01-01

    Presents a college level music appreciation course that combines cohort analysis, action research methods, and distance learning. Students identify generational cohorts and use research methods to determine the preferred musical forms of the cohort. Describes a "cohort," a music appreciation Web site, the course structure, and benefits of the…

  4. A DNA fragment from Xq21 replaces a deleted region containing the entire FVIII gene in a severe hemophilia A patient

    SciTech Connect

    Murru, S.; Casula, L.; Moi, P.

    1994-09-15

    In this paper the authors report the molecular characterization of a large deletion that removes the entire Factor VIII gene in a severe hemophilia A patient. Accurate DNA analysis of the breakpoint region revealed that a large DNA fragment replaced the 300-kb one, which was removed by the deletion. Pulsed-field gel electrophoresis analysis revealed that the size of the inserted fragment is about 550 kb. In situ hybridization demonstrated that part of the inserted region normally maps to Xq21 and to the tip of the short arm of the Y chromosome (Yp). In this patient this locus is present both in Xq21 and in Xq28, in addition to the Yp, being thus duplicated in the X chromosome. Sequence analysis of the 3` breakpoint suggested that an illegitimate recombination is probably the cause of this complex rearrangement. 52 refs., 7 figs.

  5. Mutation, detection, prenatal testing, and delineation of the germline origin in a family with sporadic hemophilia B and no living hemophiliacs

    SciTech Connect

    Vielhaber, E.; Sommer, S.S.

    1994-01-15

    Hemophilia B is an X-linked recessive disorder affecting 1 in 30,000 males. Determination of carrier status for at risk females can be done by utilizing indirect methods such as DNA sequencing. However, in most cases, reliable carrier testing is not possible without first analyzing the DNA from an affected male in the family to determine his haplotype/causative sequence change. In the case presented here, the only affected male in the family has been deceased for 25 years; no DNA was available from him. The sister (III-2) of the affected individual was a suspected carrier based on her factor IX coagulant (36%); she was pregnant with a male fetus, and requested prenatal testing. 6 refs., 2 figs.

  6. Current difficulties and recent advances in bypass therapy for the management of hemophilia with inhibitors: a new and practical formulation of recombinant factor VIIa.

    PubMed

    Butros, Linda; Boayue, Koh; Mathew, Prasad

    2011-01-01

    Bypassing agents are the mainstay of treatment for patients with hemophilia with high-titer inhibitors. Whereas the availability of these agents has greatly advanced the management of bleeding episodes in this population, timely administration of bypassing agents continues to be hampered by a number of practical limitations, including the need for refrigerated storage of the agent and its reconstitution at room temperature prior to administration, among others. In this review, the importance of early treatment of bleeds and factors that influence this more timely therapeutic approach are highlighted, together with the advantages offered by the use of a new formulation of recombinant activated factor VII that permits improved storage and portability, potentially optimizing timely bypassing agent administration. PMID:21625417

  7. Compound heterozygous hemophilia A in a female patient and the identification of a novel missense mutation, p.Met1093Ile.

    PubMed

    Qiao, Shu-Kai; Ren, Han-Yun; Ren, Jin-Hai; Guo, Xiao-Nan

    2014-02-01

    Hemophilia A (HA) in females is rare. Female HA cases are often misdiagnosed as acquired HA (AHA) or as von Willebrand disease type 2N (vWD-2N). Here, we report the case of a 37-year-old female HA patient with a moderate factor VIII (FVIII) deficiency. The patient had no personal or family history of bleeding disorders, but presented with heavy uterine bleeding following surgery to remove an intrauterine device. IgG inhibitory antibodies against FVIII were undetected. A compound heterozygote mutation of the FVIII gene (F8) was found in this patient. The p.Val502Asp mutation, which has been reported previously, affects A2 domain function. A novel missense point mutation, p.Met1093Ile, was identified in the B domain. The compound heterozygote mutations in F8, p.Val502Asp and p.Met1093Ile, caused HA in this female patient, with a moderate phenotype. PMID:24317041

  8. Compound heterozygous hemophilia A in a female patient and the identification of a novel missense mutation, p.Met1093Ile

    PubMed Central

    QIAO, SHU-KAI; REN, HAN-YUN; REN, JIN-HAI; GUO, XIAO-NAN

    2014-01-01

    Hemophilia A (HA) in females is rare. Female HA cases are often misdiagnosed as acquired HA (AHA) or as von Willebrand disease type 2N (vWD-2N). Here, we report the case of a 37-year-old female HA patient with a moderate factor VIII (FVIII) deficiency. The patient had no personal or family history of bleeding disorders, but presented with heavy uterine bleeding following surgery to remove an intrauterine device. IgG inhibitory antibodies against FVIII were undetected. A compound heterozygote mutation of the FVIII gene (F8) was found in this patient. The p.Val502Asp mutation, which has been reported previously, affects A2 domain function. A novel missense point mutation, p.Met1093Ile, was identified in the B domain. The compound heterozygote mutations in F8, p.Val502Asp and p.Met1093Ile, caused HA in this female patient, with a moderate phenotype. PMID:24317041

  9. Cohort Profile Update: The 1982 Pelotas (Brazil) Birth Cohort Study

    PubMed Central

    Horta, Bernardo Lessa; Gigante, Denise P; Gonçalves, Helen; dos Santos Motta, JanainaVieira; Loret de Mola, Christian; Oliveira, Isabel O; Barros, Fernando C; Victora, Cesar G

    2015-01-01

    In this manuscript, we update the profile of the 1982 Pelotas Birth Cohort Study.In 1982, 5914 live births whose families lived in the urban are of Pelotas were enrolled in the cohort. In 2012–13, we tried to locate the whole original cohort; 3701 participants were interviewed who, added to the 325 known deaths, represented a follow-up rate of 68.1%. In contrast to the previous home interviews, in this wave all participants were invited to visit the research clinic to be interviewed and examined. The visit was carried out at a mean age of 30.2 years and mainly focused on four categories of outcomes: (i) mental health; (ii) body composition; (iii) precursors of complex chronic diseases; and (iv) human capital. Requests for collaboration by outside researchers are welcome. PMID:25733577

  10. Factor VIII A3 domain substitution N1922S results in hemophilia A due to domain-specific misfolding and hyposecretion of functional protein

    PubMed Central

    Summers, Ryan J.; Meeks, Shannon L.; Healey, John F.; Brown, Harrison C.; Parker, Ernest T.; Kempton, Christine L.; Doering, Christopher B.

    2011-01-01

    A point mutation leading to amino acid substitution N1922S in the A3 domain of factor VIII (fVIII) results in moderate to severe hemophilia A. A heterologous expression system comparing N1922S-fVIII and wild-type fVIII (wt-fVIII) demonstrated similar specific coagulant activities but poor secretion of N1922S-fVIII. Immunocytochemical analysis revealed that intracellular levels of N1922S-fVIII were similar to those of wt-fVIII. The specific activity of intracellular N1922S-fVIII was 10% of that of wt-fVIII, indicating the presence of large amounts of a nonfunctional N1922S-fVIII–folding intermediate. wt-fVIII colocalized with both endoplasmic reticulum (ER)– and Golgi-resident proteins. In contrast, N1922S-fVIII colocalized only with ER-resident proteins, indicating a block in transit from the ER to the Golgi. A panel of conformation-dependent monoclonal antibodies was used to determine native or nonnative folding of N1922S-fVIII. Intracellular N1922S-fVIII but not secreted N1922S-fVIII displayed abnormal folding in the A3 and C1 domains, indicating that the A1, A2, and C2 domains fold independently into antigenically intact tertiary structures, but that folding is stalled in the mutant A3 and its contiguous C1 domain. In summary, the N1922S substitution results in poor secretion of a functional protein, and the domain-specific defect in folding and intracellular trafficking of N1922S-fVIII is a novel mechanism for secretion defects leading to hemophilia A. PMID:21217077

  11. 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

  12. Studies on hemophilia A in Sardinia bearing on the problems of multiple allelism, carrier detection, and differential mutation rate in the two sexes.

    PubMed Central

    Filippi, G; Mannucci, P M; Coppola, R; Farris, A; Rinaldi, A; Siniscalco, M

    1984-01-01

    A large survey of hemophilia A carried out with almost complete ascertainment on the island of Sardinia suggests that the variation of plasma levels of Factor VIII coagulant activity in normal individuals is largely controlled by a series of normal isoalleles or by closely linked modifiers. This variation is expected to affect the laboratory detection of the hemophilia A (HA) heterozygotes in addition to the X-inactivation-dependent mosaicism and the type of deficient mutant present in a given pedigree. The Sardinian pedigrees yielded 13 new cases of nonrecombinants between the loci for HA and glucose-6-phosphate dehydrogenase (G6PD), as well as four nonrecombinants between HA and Deutan color blindness. These findings bring to a total of 58 the number of scorable sibs and nonrecombinants thus far known for the linkage HA-G6PD. From such a figure it has been possible to infer that the 90% upper limit of meiotic recombination between the two loci is below 4%, thus justifying the application of the "linkage diagnostic test" for the detection of HA heterozygotes and the prenatal diagnosis of the hemophilic fetuses in families that segregate at both loci. In three out of the five HA pedigrees of our series that segregate also for G6PD or Deutan color blindness, the observed segregation of the combined phenotypes can be best explained by assuming the occurrence of a fresh mutation in the maternal grandfathers. Such a finding points out the opportunity to reevaluate Haldane's hypothesis of a possible higher incidence of X-linked mutations in the human male. It is anticipated that each of the issues addressed by the present study will be amenable to experimental verification as soon as suitable molecular probes become available to screen for common multiallelic DNA polymorphisms in the subtelomeric region of the X-chromosome long arm. PMID:6421151

  13. Long-acting recombinant coagulation factor IX albumin fusion protein (rIX-FP) in hemophilia B: results of a phase 3 trial

    PubMed Central

    Martinowitz, Uri; Lissitchkov, Toshko; Pan-Petesch, Brigitte; Hanabusa, Hideji; Oldenburg, Johannes; Boggio, Lisa; Negrier, Claude; Pabinger, Ingrid; von Depka Prondzinski, Mario; Altisent, Carmen; Castaman, Giancarlo; Yamamoto, Koji; Álvarez-Roman, Maria-Teresa; Voigt, Christine; Blackman, Nicole; Jacobs, Iris

    2016-01-01

    A global phase 3 study evaluated the pharmacokinetics, efficacy, and safety of recombinant fusion protein linking coagulation factor IX with albumin (rIX-FP) in 63 previously treated male patients (12-61 years) with severe hemophilia B (factor IX [FIX] activity ≤2%). The study included 2 groups: group 1 patients received routine prophylaxis once every 7 days for 26 weeks, followed by either 7-, 10-, or 14-day prophylaxis regimen for a mean of 50, 38, or 51 weeks, respectively; group 2 patients received on-demand treatment of bleeding episodes for 26 weeks and then switched to a 7-day prophylaxis regimen for a mean of 45 weeks. The mean terminal half-life of rIX-FP was 102 hours, 4.3-fold longer than previous FIX treatment. Patients maintained a mean trough of 20 and 12 IU/dL FIX activity on prophylaxis with rIX-FP 40 IU/kg weekly and 75 IU/kg every 2 weeks, respectively. There was 100% reduction in median annualized spontaneous bleeding rate (AsBR) and 100% resolution of target joints when subjects switched from on-demand to prophylaxis treatment with rIX-FP (P < .0001). The median AsBR was 0.00 for all prophylaxis regimens. Overall, 98.6% of bleeding episodes were treated successfully, including 93.6% that were treated with a single injection. No patient developed an inhibitor, and no safety concerns were identified. These results indicate rIX-FP is safe and effective for preventing and treating bleeding episodes in patients with hemophilia B at dosing regimens of 40 IU/kg weekly and 75 IU/kg every 2 weeks. This trial was registered at www.clinicaltrials.gov as #NCT0101496274. PMID:26755710

  14. Long-acting recombinant coagulation factor IX albumin fusion protein (rIX-FP) in hemophilia B: results of a phase 3 trial.

    PubMed

    Santagostino, Elena; Martinowitz, Uri; Lissitchkov, Toshko; Pan-Petesch, Brigitte; Hanabusa, Hideji; Oldenburg, Johannes; Boggio, Lisa; Negrier, Claude; Pabinger, Ingrid; von Depka Prondzinski, Mario; Altisent, Carmen; Castaman, Giancarlo; Yamamoto, Koji; Álvarez-Roman, Maria-Teresa; Voigt, Christine; Blackman, Nicole; Jacobs, Iris

    2016-04-01

    A global phase 3 study evaluated the pharmacokinetics, efficacy, and safety of recombinant fusion protein linking coagulation factor IX with albumin (rIX-FP) in 63 previously treated male patients (12-61 years) with severe hemophilia B (factor IX [FIX] activity ≤2%). The study included 2 groups: group 1 patients received routine prophylaxis once every 7 days for 26 weeks, followed by either 7-, 10-, or 14-day prophylaxis regimen for a mean of 50, 38, or 51 weeks, respectively; group 2 patients received on-demand treatment of bleeding episodes for 26 weeks and then switched to a 7-day prophylaxis regimen for a mean of 45 weeks. The mean terminal half-life of rIX-FP was 102 hours, 4.3-fold longer than previous FIX treatment. Patients maintained a mean trough of 20 and 12 IU/dL FIX activity on prophylaxis with rIX-FP 40 IU/kg weekly and 75 IU/kg every 2 weeks, respectively. There was 100% reduction in median annualized spontaneous bleeding rate (AsBR) and 100% resolution of target joints when subjects switched from on-demand to prophylaxis treatment with rIX-FP (P< .0001). The median AsBR was 0.00 for all prophylaxis regimens. Overall, 98.6% of bleeding episodes were treated successfully, including 93.6% that were treated with a single injection. No patient developed an inhibitor, and no safety concerns were identified. These results indicate rIX-FP is safe and effective for preventing and treating bleeding episodes in patients with hemophilia B at dosing regimens of 40 IU/kg weekly and 75 IU/kg every 2 weeks. This trial was registered atwww.clinicaltrials.govas #NCT0101496274. PMID:26755710

  15. Heat treatment of samples improve the performance of the Nijmegen-Bethesda assay in hemophilia A patients undergoing immune tolerance induction.

    PubMed

    de Lima Montalvão, Silmara Aparecida; Tucunduva, Alini Camargo; de Almeida Sambo, Andrea Luísa; De Paula, Erich Vinicius; de Souza Medina, Samuel; Ozelo, Margareth Castro

    2015-12-01

    Nijmegen-Bethesda assay is the gold standard to assess inhibitory antibodies against factor (F) VIII. This method has some limitations, including high coefficient of variation and possible interference of residual endogenous or exogenous factor VIII. Heat-treatment of samples at 56 °C for 30 min could be a strategy to improve the sensitivity of this test. The aim of this study was to compare inhibitor quantification in hemophilia patients with and without inhibitor performed in previously heated and non-heated samples. A total of 109 analyses from 46 patients with severe hemophilia A were performed. Patients were divided into three groups: 20 patients with no history of inhibitor, recently and not recently exposed to FVIII (group I), 21 patients with history of inhibitor not exposed to FVIII (group II), and 5 patients (68 samples) undergoing an immune tolerance induction (ITI) protocol (group III). For patients with no history of inhibitor, heat-treatment did not modify the results (p=0.24). However, differences in inhibitor levels between heated and non-heated samples were observed in patients with history of inhibitor (group II, p<0.05) and in patients in ITI (group III, p<0.001). In 11 samples, inhibitor quantification shifted from negative to positive. Additionally, a longitudinal evaluation of each ITI patient showed similar trend line for the results of heated and non-heated samples. In this study, we demonstrated that heating samples increase sensitivity of Nijmegen-Bethesda assay, with no shift from negative to positive results in patients with no history of inhibitor. Furthermore, this procedure has an important role to patients undergoing an ITI protocol. PMID:26344704

  16. Living with Hemophilia

    MedlinePlus

    ... are swimming, biking (wearing a helmet), walking, and golf. To prevent bleeding, you also may be able ... periods apply As children grow, it's important to learn about available options for insurance. Look into what ...

  17. Learning about Hemophilia

    MedlinePlus

    ... for Patient Care Education All About the Human Genome Project Fact Sheets Genetic Education Resources for Teachers ... Education Kit Online Genetics Education Resources Smithsonian NHGRI Genome Exhibition Talking Glossary: English Talking Glossary: Español Issues ...

  18. 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

  19. Cohort Default Rates in Context

    ERIC Educational Resources Information Center

    Looney, Shannon M.

    2011-01-01

    Burgeoning student loan debt indicates problems not only for the country's borrowers but also for the postsecondary system. The rise in student loan defaults signifies a rise in institutional cohort default rates (CDRs)--a measure of accountability that informs the government and the general public how well an institution prepares its students for…

  20. 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…

  1. Comparison of Clot-based, Chromogenic, and Fluorescence Assays for Measurement of Factor VIII Inhibitors in the U.S. Hemophilia Inhibitor Research Study

    PubMed Central

    Miller, Connie H.; Rice, Anne S.; Boylan, Brian; Shapiro, Amy D.; Lentz, Steven R.; Wicklund, Brian M.; Kelly, Fiona M.; Soucie, J. Michael

    2015-01-01

    Summary Background Detection and validation of inhibitors (antibodies) to hemophilia treatment products are important for clinical care, evaluation of product safety, and assessment of population trends. Methods Centralized monitoring for factor VIII (FVIII) inhibitors was conducted for patients in the Hemophilia Inhibitor Research Study using a previously reported modified Nijmegen-Bethesda clotting assay (NBA), a chromogenic Bethesda assay (CBA), and a novel fluorescence immunoassay (FLI). Results NBA and CBA were performed on 1005 specimens and FLI on 272 specimens. CBA was negative on 880/883 specimens (99.7%) with Nijmegen-Bethesda units (NBU)<0.5 and positive on 42/42 specimens (100%) with NBU≥2.0 and 43/80 specimens (53.8%) with NBU 0.5–1.9. Among specimens with positive NBA and negative CBA, 58.1% were FLI-negative, 12.9% had evidence of lupus anticoagulant, and 35.5% had non-time-dependent inhibition. CBA and FLI were positive on 72.4% and 100% of 1.0–1.9 NBU specimens and 43.1% and 50.0% of 0.5–0.9 NBU specimens. FLI detected antibodies in 98.0% of CBA-positive and 81.6% of NBA-positive specimens (P=0.004). Among 21 new inhibitors detected by NBA, 5 (23.8%) with 0.7–1.3 NBU did not react in CBA or FLI. Among previously positive patients with 0.5–1.9 NBU, 7/25 (28%) were not CBA or FLI positive. FLI was positive on 36/169 NBU-negative specimens (21.3%). Conclusions FVIII specificity could not be demonstrated by CBA or FLI for 26% of inhibitors of 0.5–1.9 NBU; such results must be interpreted with caution. Low titer inhibitors detected in clot-based assays should always be repeated, with consideration given to evaluating their reactivity with FVIII using more specific assays. PMID:23601690

  2. Characterization of the factor VIII defect in 147 patients with sporadic hemophilia A: family studies indicate a mutation type-dependent sex ratio of mutation frequencies.

    PubMed Central

    Becker, J.; Schwaab, R.; Möller-Taube, A.; Schwaab, U.; Schmidt, W.; Brackmann, H. H.; Grimm, T.; Olek, K.; Oldenburg, J.

    1996-01-01

    The clinical manifestation of hemophilia A is caused by a wide range of different mutations. In this study the factor VIII genes of 147 severe hemophilia A patients--all exclusively from sporadic families--were screened for mutations by use of the complete panel of modern DNA techniques. The pathogenous defect could be characterized in 126 patients (85.7 percent). Fifty-five patients (37.4 percent) showed a F8A-gene inversion, 47 (32.0 percent) a point mutation, 14 (9.5 percent) a small deletion, 8 (5.4 percent) a large deletion, and 2 (1.4 percent) a small insertion. Further, four (2.7 percent) mutations were localized but could not be sequenced yet. No mutation could be identified in 17 patients (11.6 percent). Sixteen (10.9 percent) of the identified mutations occurred in the B domain. Four of these were located in an adenosine nucleotide stretch at codon 1192, indicating a mutation hotspot. Somatic mosaicisms were detected in 3 (3.9 percent) of 76 patients, mothers, comprising 3 of 16 de novo mutations in the patients mothers. Investigation of family relatives allowed detection of a de novo mutation in 16 of 76 two-generation and 28 of 34 three-generation families. On the basis of these data, the male:female ratio of mutation frequencies (k) was estimated as k = 3.6. By use of the quotients of mutation origin in maternal grandfather to patients mother or to maternal grandmother, k was directly estimated as k = 15 and k = 7.5, respectively. Considering each mutation type separately, we revealed a mutation type-specific sex ratio of mutation frequencies. Point mutations showed a 5-to-10-fold-higher and inversions a >10-fold-higher mutation rate in male germ cells, whereas deletions showed a >5-fold-higher mutation rate in female germ cells. Consequently, and in accordance with the data of other diseases like Duchenne muscular dystrophy, our results indicate that at least for X-chromosomal disorders the male:female mutation rate of a disease is determined by its

  3. Characterization of the factor VIII defect in 147 patients with sporadic hemophilia A: Family studies indicate a mutation type-dependent sex ratio of mutation frequencies

    SciTech Connect

    Becker, J.; Schmidt, W.; Olek, K.

    1996-04-01

    The clinical manifestation of hemophilia A is caused by a wide range of different mutations. In this study the factor VIII genes of 147 severe hemophilia A patients-all exclusively from sporadic families-were screened for mutations by use of the complete panel of modern DNA techniques. The pathogenous defect could be characterized in 126 patients (85.7%). Fifty-five patients (37.4%) showed a F8A-gene inversion, 47 (32.0%) a point mutation, 14 (9.5%) a small deletion, 8 (5.4%) a large deletion, and 2 (1.4%) a small insertion. Further, four (2.7%) mutations were localized but could not be sequenced yet. No mutation could be identified in 17 patients (11.6%). Sixteen (10.9%) of the P identified mutations occurred in the B domain. Four of these were located in an adenosine nucleotide stretch at codon 1192, indicating a mutation hotspot. Somatic mosaicisms were detected in 3 (3.9%) of 76 patients` mothers, comprising 3 of 16 de novo mutations in the patients` mothers. Investigation of family relatives allowed detection of a de novo mutation in 16 of 76 two-generation and 28 of 34 three-generation families. On the basis of these data, the male:female ratio of mutation frequencies (k) was estimated as k = 3.6. By use of the quotients of mutation origin in maternal grandfather to patient`s mother or to maternal grandmother, k was directly estimated as k = 15 and k = 7.5, respectively. Considering each mutation type separately, we revealed a mutation type-specific sex ratio of mutation frequencies. Point mutations showed a 5-to-10-fold-higher and inversions a >10-fold- higher mutation rate in male germ cells, whereas deletions showed a >5-fold-higher mutation rate in female germ cells. Consequently, and in accordance with the data of other diseases like Duchenne muscular dystrophy, our results indicate that at least for X-chromosomal disorders the male:female mutation rate of a disease is determined by its proportion of the different mutation types. 68 refs., 1 fig., 5 tabs.

  4. Riyadh Mother and Baby Multicenter Cohort Study: The Cohort Profile

    PubMed Central

    Esmaeil, Samia; Alzeidan, Rasmieh; Elawad, Mamoun; Tabassum, Rabeena; Hansoti, Shehnaz; Magzoup, Mohie Edein; Al-Kadri, Hanan; Elsherif, Elham; Al-Mandil, Hazim; Al-Shaikh, Ghadeer; Zakaria, Nasria

    2016-01-01

    Objectives To assess the effects of non-communicable diseases, such as diabetes, hypertension and obesity, on the mother and the infant. Methods A multicentre cohort study was conducted in three hospitals in the city of Riyadh in Saudi Arabia. All Saudi women and their babies who delivered in participating hospitals were eligible for recruitment. Data on socio-demographic characteristics in addition to the maternal and neonatal outcomes of pregnancy were collected. The cohort demographic profile was recorded and the prevalence of maternal conditions including gestational diabetes, pre-gestational diabetes, hypertensive disorders in pregnancy and obesity were estimated. Findings The total number of women who delivered in participating hospitals during the study period was 16,012 of which 14,568 women participated in the study. The mean age of the participants was 29 ± 5.9 years and over 40% were university graduates. Most of the participants were housewives, 70% were high or middle income and 22% were exposed to secondhand smoke. Of the total cohort, 24% were married to a first cousin. More than 68% of the participants were either overweight or obese. The preterm delivery rate was 9%, while 1.5% of the deliveries were postdate. The stillbirth rate was 13/1000 live birth. The prevalence of gestational diabetes was 24% and that of pre-gestational diabetes was 4.3%. The preeclampsia prevalence was 1.1%. The labour induction rate was 15.5% and the cesarean section rate was 25%. Conclusion Pregnant women in Saudi Arabia have a unique demographic profile. The prevalence of obesity and diabetes in pregnancy are among the highest in the world. PMID:26937965

  5. The dataset from administration of single or combined immunomodulation agents to modulate anti-FVIII antibody responses in FVIII plasmid or protein primed hemophilia A mice.

    PubMed

    Liu, Chao Lien; Lyle, Meghan J; Shin, Simon C; Miao, Carol H

    2016-06-01

    Hemophilia A mice with pre-existing inhibitory antibodies against factor VIII (FVIII) were treated with single agents, AMD3100 and GCS-F, respectively. Inhibitor titers in treated mice and control HemA inhibitors mice were followed over time. Total B cells and plasma cells (PCs) were characterized by flow cytometry. HemA inhibitor mice were then treated with a combination regimen of IL-2/IL-2mAb complexes plus rapamycin and AMD3100. Finally, HemA inhibitor mice were treated with a new combination therapy using include IL-2/IL-2mAb complexes + Anti-CD20+AMD3100+G-CSF. The timeline of combination therapy was illustrated. Inhibitor titers following treatment in FVIII plasmid or protein induced inhibitor mice were evaluated overtime. A representative figure and gating strategies to characterize the subsets of Treg cells and B cells are presented. Please see http://dx.doi.org/10.1016/j.cellimm.2016.01.005 [1] for interpretation and discussion of these data and results. PMID:27081675

  6. Evolutionary pattern of mutation in the factor IX genes of great apes: How does it compare to the pattern of recent germline mutation in patients with hemophilia B?

    SciTech Connect

    Grouse, L.H.; Ketterling, R.P.; Sommer, S.S.

    1994-09-01

    Most mutations causing hemophilia B have arisen within the past 150 years. By correcting for multiple biases, the underlying rates of spontaneous germline mutation have been estimated in the factor IX gene. From these rates, an underlying pattern of mutation has emerged. To determine if this pattern compares to a underlying pattern found in the great apes, sequence changes were determined in intronic regions of the factor IX gene. The following species were studied: Gorilla gorilla, Pan troglodytes (chimpanzee), Pongo pygmacus (orangutan) and Homo sapiens. Intronic sequences at least 200 bp from a splice junction were randomly chosen, amplified by cross-species PCR, and sequenced. These regions are expected to be subject to little if any selective pressure. Early diverged species of Old World monkeys were also studied to help determine the direction of mutational changes. A total of 62 sequence changes were observed. Initial data suggest that the average pattern since evolution of the great apes has a paucity of transitions at CpG dinucleotides and an excess of microinsertions to microdeletions when compared to the pattern observed in humans during the past 150 years (p<.05). A larger study is in progress to confirm these results.

  7. Identification of 31 novel mutations in the F8 gene in Spanish hemophilia A patients: structural analysis of 20 missense mutations suggests new intermolecular binding sites.

    PubMed

    Venceslá, Adoración; Corral-Rodríguez, María Angeles; Baena, Manel; Cornet, Mónica; Domènech, Montserrat; Baiget, Montserrat; Fuentes-Prior, Pablo; Tizzano, Eduardo F

    2008-04-01

    Hemophilia A (HA) is an X-linked bleeding disorder caused by a wide variety of mutations in the factor 8 (F8) gene, leading to absent or deficient factor VIII (FVIII). We analyzed the F8 gene of 267 unrelated Spanish patients with HA. After excluding patients with the common intron-1 and intron-22 inversions and large deletions, we detected 137 individuals with small mutations, 31 of which had not been reported previously. Eleven of these were nonsense, frameshift, and splicing mutations, whereas 20 were missense changes. We assessed the impact of the 20 substitutions based on currently available information about FV and FVIII structure and function relationship, including previously reported results of replacements at these and topologically equivalent positions. Although most changes are likely to cause gross structural perturbations and concomitant cofactor instability, p.Ala375Ser is predicted to affect cofactor activation. Finally, 3 further mutations (p.Pro64Arg, p.Gly494Val, and p.Asp2267Gly) appear to affect cofactor interactions with its carrier protein, von Willebrand factor, with the scavenger receptor low-density lipoprotein receptor-related protein (LRP), and/or with the substrate of the FVIIIapi*FIXa (Xase) complex, factor X. Characterization of these novel mutations is important for adequate genetic counseling in HA families, but also contributes to a better understanding of FVIII structure-function relationship. PMID:18184865

  8. Identification of 31 novel mutations in the F8 gene in Spanish hemophilia A patients: structural analysis of 20 missense mutations suggests new intermolecular binding sites

    PubMed Central

    Venceslá, Adoración; Corral-Rodríguez, María Ángeles; Baena, Manel; Cornet, Mónica; Domènech, Montserrat; Baiget, Montserrat; Fuentes-Prior, Pablo

    2008-01-01

    Hemophilia A (HA) is an X-linked bleeding disorder caused by a wide variety of mutations in the factor 8 (F8) gene, leading to absent or deficient factor VIII (FVIII). We analyzed the F8 gene of 267 unrelated Spanish patients with HA. After excluding patients with the common intron-1 and intron-22 inversions and large deletions, we detected 137 individuals with small mutations, 31 of which had not been reported previously. Eleven of these were nonsense, frameshift, and splicing mutations, whereas 20 were missense changes. We assessed the impact of the 20 substitutions based on currently available information about FV and FVIII structure and function relationship, including previously reported results of replacements at these and topologically equivalent positions. Although most changes are likely to cause gross structural perturbations and concomitant cofactor instability, p.Ala375Ser is predicted to affect cofactor activation. Finally, 3 further mutations (p.Pro64Arg, p.Gly494Val, and p.Asp2267Gly) appear to affect cofactor interactions with its carrier protein, von Willebrand factor, with the scavenger receptor low-density lipoprotein receptor–related protein (LRP), and/or with the substrate of the FVIIIapi•FIXa (Xase) complex, factor X. Characterization of these novel mutations is important for adequate genetic counseling in HA families, but also contributes to a better understanding of FVIII structure-function relationship. PMID:18184865

  9. Hemophilia as a defect of the tissue factor pathway of blood coagulation: Effect of factors VIII and IX on factor X activation in a continuous-flow reactor

    SciTech Connect

    Repke, D.; Gemmell, C.H.; Guha, A.; Turitto, V.T.; Nemerson, Y. ); Broze, G.J. Jr. )

    1990-10-01

    The effect of factors VIII and IX on the ability of the tissue factor-factor VIIa complex to activate factor X was studied in a continuous-flow tubular enzyme reactor. Tissue factor immobilized in a phospholipid bilayer on the inner surface of the tube was exposed to a perfusate containing factors VIIa, VIII, IX, and X flowing at a wall shear rate of 57, 300, or 1130 sec{sup {minus}1}. The addition of factors VIII and IX at their respective plasma concentrations resulted in a further 2{endash}-to 3{endash}fold increase. The direct activation of factor X by tissue factor-factor VIIa could be virtually eliminated by the lipoprotein-associated coagulation inhibitor. These results suggest that the tissue factor pathway, mediated through factors VIII and IX, produces significant levels of factor Xa even in the presence of an inhibitor of the tissue factor-factor VIIa complex; moreover, the activation is dependent on local shear conditions. These findings are consistent both with a model of blood coagulation in which initiation of the system results from tissue factor and with the bleeding observed in hemophilia.

  10. Soy Phosphatidylinositol-Containing Lipid Nanoparticle Prolongs the Plasma Survival and Hemostatic Efficacy of B-domain-Deleted Recombinant Canine Factor VIII in Hemophilia A Dogs.

    PubMed

    Shetty, Krithika A; Merricks, Elizabeth P; Raymer, Robin; Rigsbee, Natalie; Nichols, Timothy C; Balu-Iyer, Sathy V

    2016-08-01

    Soy phosphatidylinositol (PI)-containing lipid nanoparticles prolong plasma survival, improve hemostatic efficacy, and decrease immunogenicity of human B-domain-deleted factor VIII (BDD FVIII) in hemophilia A (HA) mice. We hypothesize that PI-associated BDD FVIII is more potent than the free protein and, using mathematical modeling, have projected that PI-associated BDD FVIII could be used for once-weekly prophylactic dosing in patients. To facilitate translation to the clinic, comparative plasma survival and ex vivo efficacy of PI-associated recombinant canine FVIII (PI-rcFVIII) were evaluated in HA dogs. Two HA dogs were administered a 50-U/kg intravenous dose of free or PI-rcFVIII. rcFVIII activity measurements and ex vivo efficacy analyses such as whole blood clotting time and thromboelastography were conducted on recovered plasma and whole blood samples. PI association decreased clearance (∼25%) and increased plasma exposure (∼1.4-fold) of rcFVIII. PI-rcFVIII-treated animals had prolonged improvements in whole blood clotting time and thromboelastography parameters compared to free rcFVIII-treated animals. Because rcFVIII is a BDD form of FVIII, these studies provide proof of principle that observations with human BDD FVIII in mice translate to higher animal species. In addition, PI-rcFVIII has potential applications in canine HA management and as a bypass therapy in inhibitor-positive HA patients. PMID:27372547

  11. Targeting of the human F8 at the multicopy rDNA locus in Hemophilia A patient-derived iPSCs using TALENickases.

    PubMed

    Pang, Jialun; Wu, Yong; Li, Zhuo; Hu, Zhiqing; Wang, Xiaolin; Hu, Xuyun; Wang, Xiaoyan; Liu, Xionghao; Zhou, Miaojin; Liu, Bo; Wang, Yanchi; Feng, Mai; Liang, Desheng

    2016-03-25

    Hemophilia A (HA) is a monogenic disease due to lack of the clotting factor VIII (FVIII). This deficiency may lead to spontaneous joint hemorrhages or life-threatening bleeding but there is no cure for HA until very recently. In this study, we derived induced pluripotent stem cells (iPSCs) from patients with severe HA and used transcription activator-like effector nickases (TALENickases) to target the factor VIII gene (F8) at the multicopy ribosomal DNA (rDNA) locus in HA-iPSCs, aiming to rescue the shortage of FVIII protein. The results revealed that more than one copy of the exogenous F8 could be integrated into the rDNA locus. Importantly, we detected exogenous F8 mRNA and FVIII protein in targeted HA-iPSCs. After they were differentiated into endothelial cells (ECs), the exogenous FVIII protein was still detectable. Thus, it is showed that the multicopy rDNA locus could be utilized as an effective target site in patient-derived iPSCs for gene therapy. This strategy provides a novel iPSCs-based therapeutic option for HA and other monogenic diseases. PMID:26921444

  12. The dataset from administration of single or combined immunomodulation agents to modulate anti-FVIII antibody responses in FVIII plasmid or protein primed hemophilia A mice

    PubMed Central

    Liu, Chao Lien; Lyle, Meghan J.; Shin, Simon C.; Miao, Carol H.

    2016-01-01

    Hemophilia A mice with pre-existing inhibitory antibodies against factor VIII (FVIII) were treated with single agents, AMD3100 and GCS-F, respectively. Inhibitor titers in treated mice and control HemA inhibitors mice were followed over time. Total B cells and plasma cells (PCs) were characterized by flow cytometry. HemA inhibitor mice were then treated with a combination regimen of IL-2/IL-2mAb complexes plus rapamycin and AMD3100. Finally, HemA inhibitor mice were treated with a new combination therapy using include IL-2/IL-2mAb complexes + Anti-CD20+AMD3100+G-CSF. The timeline of combination therapy was illustrated. Inhibitor titers following treatment in FVIII plasmid or protein induced inhibitor mice were evaluated overtime. A representative figure and gating strategies to characterize the subsets of Treg cells and B cells are presented. Please see http://dx.doi.org/10.1016/j.cellimm.2016.01.005 [1] for interpretation and discussion of these data and results. PMID:27081675

  13. 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

    2015-03-01

    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. PMID:25568350

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

    PubMed Central

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

    2015-01-01

    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 × 1012 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. PMID:25568350

  15. A Cohort Model of Fertility Postponement

    PubMed Central

    Goldstein, Joshua R.; Cassidy, Thomas

    2015-01-01

    We introduce a new formal model in which demographic behavior such as fertility is postponed by differing amounts depending only on cohort membership. The cohort-based model shows the effects of cohort shifts on period fertility measures and provides an accompanying tempo adjustment to determine the period fertility that would have occurred without postponement. Cohort-based postponement spans multiple periods and produces “fertility momentum,” with implications for future fertility rates. We illustrate several methods for model estimation and apply the model to fertility in several countries. We also compare the fit of period-based and cohort-based shift models to the recent Dutch fertility surface, showing how cohort- and period-based postponement can occur simultaneously. PMID:25233957

  16. A cohort model of fertility postponement.

    PubMed

    Goldstein, Joshua R; Cassidy, Thomas

    2014-10-01

    We introduce a new formal model in which demographic behavior such as fertility is postponed by differing amounts depending only on cohort membership. The cohort-based model shows the effects of cohort shifts on period fertility measures and provides an accompanying tempo adjustment to determine the period fertility that would have occurred without postponement. Cohort-based postponement spans multiple periods and produces "fertility momentum," with implications for future fertility rates. We illustrate several methods for model estimation and apply the model to fertility in several countries. We also compare the fit of period-based and cohort-based shift models to the recent Dutch fertility surface, showing how cohort- and period-based postponement can occur simultaneously. PMID:25233957

  17. Age, Birth Cohorts, and Drinking: An Illustration of the Hazards of Inferring Effects from Cohort Data.

    ERIC Educational Resources Information Center

    Glenn, Norval D.

    1981-01-01

    Analyzes problems in the use of cohort data as illustrated by cohort data on drinking alcoholic beverages taken from American national surveys conducted during the late 1950s, late 1960s, and late 1970s. Researchers are cautioned that all available "side information" should be considered before statistical cohort models are tested. (Author/RC)

  18. Cohort Crowding and Nonresident College Enrollment

    ERIC Educational Resources Information Center

    Winters, John V.

    2012-01-01

    This study uses a fixed effects panel data framework to examine the effects of cohort crowding and other variables on nonresident enrollment at four-year public colleges and universities. The results suggest that larger cohorts of resident students crowd out nonresident students at flagship universities, but there is inconsistent evidence of crowd…

  19. 2011 Cohort Graduation and Dropout Rate Report

    ERIC Educational Resources Information Center

    Utah State Office of Education, 2011

    2011-01-01

    To align with new federal No Child Left Behind (NCLB) regulations for graduation rate calculations, the Utah State Office of Education (USOE) is reporting a new graduation rate beginning with the 2011 graduating class (also known as the 2011 cohort). The four-year cohort rate (includes all students who started 9th grade in 2007-2008 plus…

  20. REGRESSION MODELS FOR COHORT MORTALITY STUDIES

    EPA Science Inventory

    Cohort studies evaluate suspect health hazards from occupational or environmental exposures by recording tile facts and causes of deaths in the exposed group as they occur over an extended time period. his article reviews several methods for analyzing cohort: mortality data and s...

  1. Graduate Cohort Approach in Teacher Education

    ERIC Educational Resources Information Center

    Mattson-Gearhart, Jeanine

    2012-01-01

    The use of the cohorts in teacher education has steadily increased over the last decade. Research indicates both beneficial and negative aspects to this approach, with the field undecided. This study focuses on a Midwestern university's accelerated graduate program for special educators. The program uses a mixed cohort approach to model…

  2. Anti-factor VIII IgA as a potential marker of poor prognosis in acquired hemophilia A: results from the GTH-AH 01/2010 study.

    PubMed

    Tiede, Andreas; Hofbauer, Christoph J; Werwitzke, Sonja; Knöbl, Paul; Gottstein, Saskia; Scharf, Rüdiger E; Heinz, Jürgen; Groß, Jürgen; Holstein, Katharina; Dobbelstein, Christiane; Scheiflinger, Fritz; Koch, Armin; Reipert, Birgit M

    2016-05-12

    Neutralizing autoantibodies against factor VIII (FVIII), also called FVIII inhibitors, are the cause of acquired hemophilia A (AHA). They are quantified in the Bethesda assay or Nijmegen-modified Bethesda assay by their ability to neutralize FVIII in normal human plasma. However, FVIII inhibitors do not represent the whole spectrum of anti-FVIII autoantibodies. Here, we studied isotypes, immunoglobulin G subclasses, and apparent affinities of anti-FVIII autoantibodies to assess their prognostic value for the outcome in AHA. We analyzed baseline samples from patients enrolled in the prospective GTH-AH 01/2010 study. Our data suggest that anti-FVIII immunoglobulin A (IgA) autoantibodies are predictors of poor outcome in AHA. Anti-FVIII IgA-positive patients achieved partial remission similar to anti-FVIII IgA-negative patients but had a higher risk of subsequent recurrence. Consequently, IgA-positive patients achieved complete remission less frequently (adjusted hazard ratio [aHR], 0.35; 95% confidence interval [CI], 0.18-0.68; P < .01) and had a higher risk of death (aHR, 2.62; 95% CI, 1.11-6.22; P < .05). Anti-FVIII IgA was the strongest negative predictor of recurrence-free survival after achieving partial remission and remained significant after adjustment for baseline demographic and clinical characteristics. In conclusion, anti-FVIII IgA represents a potential novel biomarker that could be useful to predict prognosis and tailor immunosuppressive treatment of AHA. PMID:26912467

  3. 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

    2016-08-01

    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

  4. Recombinant factor VIIa analog in the management of hemophilia with inhibitors: results from a multicenter, randomized, controlled trial of vatreptacog alfa

    PubMed Central

    Lentz, S R; Ehrenforth, S; Abdul Karim, F; Matsushita, T; Weldingh, K N; Windyga, J; Mahlangu, J N; For the Adept™2 Investigators

    2014-01-01

    Background 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. Objectives To confirm the safety and assess the efficacy of vatreptacog alfa in treating bleeding episodes in hemophilic patients with inhibitors. Patients and methods 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. Results 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. Conclusions 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. PMID:24931322

  5. 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

  6. 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

  7. European Birth Cohorts for Environmental Health Research

    PubMed Central

    Casas, Maribel; Bergström, Anna; Carmichael, Amanda; Cordier, Sylvaine; Eggesbø, Merete; Eller, Esben; Fantini, Maria P.; Fernández, Mariana F.; Fernández-Somoano, Ana; Gehring, Ulrike; Grazuleviciene, Regina; Hohmann, Cynthia; Karvonen, Anne M.; Keil, Thomas; Kogevinas, Manolis; Koppen, Gudrun; Krämer, Ursula; Kuehni, Claudia E.; Magnus, Per; Majewska, Renata; Andersen, Anne-Marie Nybo; Patelarou, Evridiki; Petersen, Maria Skaalum; Pierik, Frank H.; Polanska, Kinga; Porta, Daniela; Richiardi, Lorenzo; Santos, Ana Cristina; Slama, Rémy; Sram, Radim J.; Thijs, Carel; Tischer, Christina; Toft, Gunnar; Trnovec, Tomáš; Vandentorren, Stephanie; Vrijkotte, Tanja G.M.; Wilhelm, Michael; Wright, John; Nieuwenhuijsen, Mark

    2011-01-01

    Background: Many pregnancy and birth cohort studies investigate the health effects of early-life environmental contaminant exposure. An overview of existing studies and their data is needed to improve collaboration, harmonization, and future project planning. Objectives: Our goal was to create a comprehensive overview of European birth cohorts with environmental exposure data. Methods: Birth cohort studies were included if they a) collected data on at least one environmental exposure, b) started enrollment during pregnancy or at birth, c) included at least one follow-up point after birth, d) included at least 200 mother–child pairs, and e) were based in a European country. A questionnaire collected information on basic protocol details and exposure and health outcome assessments, including specific contaminants, methods and samples, timing, and number of subjects. A full inventory can be searched on www.birthcohortsenrieco.net. Results: Questionnaires were completed by 37 cohort studies of > 350,000 mother–child pairs in 19 European countries. Only three cohorts did not participate. All cohorts collected biological specimens of children or parents. Many cohorts collected information on passive smoking (n = 36), maternal occupation (n = 33), outdoor air pollution (n = 27), and allergens/biological organisms (n = 27). Fewer cohorts (n = 12–19) collected information on water contamination, ionizing or nonionizing radiation exposures, noise, metals, persistent organic pollutants, or other pollutants. All cohorts have information on birth outcomes; nearly all on asthma, allergies, childhood growth and obesity; and 26 collected information on child neurodevelopment. Conclusion: Combining forces in this field will yield more efficient and conclusive studies and ultimately improve causal inference. This impressive resource of existing birth cohort data could form the basis for longer-term and worldwide coordination of research on environment and child health. PMID

  8. Cohort Learning for Graduate Students at the Dissertation Stage

    ERIC Educational Resources Information Center

    Holmes, Barbara D.; Birds, Kimberly; Seay, Angela D.; Smith, Debra B.; Wilson, Kimberly N.

    2010-01-01

    Doctoral students discuss the power of collaborative cohort learning in transforming the dissertation phase of doctoral study. Innovative components of doctoral cohort learning and dissertation preparation are detailed.

  9. The cohort effect in childhood disease dynamics.

    PubMed

    He, Daihai; Earn, David J D

    2016-07-01

    The structure of school terms is well known to influence seasonality of transmission rates of childhood infectious diseases in industrialized countries. A less well-studied aspect of school calendars that influences disease dynamics is that all children enter school on the same day each year. Rather than a continuous inflow, there is a sudden increase in the number of susceptible individuals in schools at the start of the school year. Based on the standard susceptible-exposed-infectious-recovered (SEIR) model, we show that school cohort entry alone is sufficient to generate a biennial epidemic pattern, similar to many observed time series of measles incidence. In addition, cohort entry causes an annual decline in the effective transmission that is evident in observed time series, but not in models without the cohort effect. Including both cohort entry and school terms yields a model fit that is significantly closer to observed measles data than is obtained with either cohort entry or school terms alone (and just as good as that obtained with Schenzle's realistic age-structured model). Nevertheless, we find that the bifurcation structure of the periodically forced SEIR model is nearly identical, regardless of whether forcing arises from cohort entry, school terms and any combination of the two. Thus, while detailed time-series fits are substantially improved by including both cohort entry and school terms, the overall qualitative dynamic structure of the SEIR model appears to be insensitive to the origin of periodic forcing. PMID:27440254

  10. Cohort Profile: Recruitment cohorts in the neuropsychological substudy of the Multicenter AIDS Cohort Study.

    PubMed

    Becker, James T; Kingsley, Lawrence A; Molsberry, Samantha; Reynolds, Sandra; Aronow, Aaron; Levine, Andrew J; Martin, Eileen; Miller, Eric N; Munro, Cynthia A; Ragin, Ann; Sacktor, Ned; Selnes, Ola A

    2015-10-01

    The Multicenter AIDS Cohort Study (MACS) is one of the largest and longest running studies of the natural and treated history of HIV disease. The Neuropsychological (NP) substudy was begun in 1988 following reports of significant adverse neurological consequences of HIV disease, including dementia. The goal was to characterize the neuropsychological deficits among individuals with HIV disease, and track the natural history of the neurological complications over time. There were three distinct MACS recruitment stages that focused on different groups of HIV-infected men, or men at risk for infection. Initially, a subcohort was evaluated semi-annually with NP tests but, beginning in 2005, the entire group of MACS participants have had NP examinations biannually, unless closer follow-up was warranted. The participants complete a battery of NP tests, and are classified as either normal, mildly or severely impaired using the Antinori criteria for HIV-Associated Neurocognitive Disorder (HAND). Additional behavioural data, including mood state and psychoactive substance use, are recorded as part of the main MACS data collection. The MACS public data set (PDS) has been available since 1994 and includes baseline and 6-monthly follow-up data. Beginning in October 1995, the PDS has been released annually with new releases superseding previous versions. PMID:24771276

  11. Matching-adjusted indirect comparisons of efficacy of BAY 81-8973 vs two recombinant factor VIII for the prophylactic treatment of severe hemophilia A

    PubMed Central

    Pocoski, Jennifer; Li, Nanxin; Ayyagari, Rajeev; Church, Nikki; Maas Enriquez, Monika; Xiang, Quer; Kelkar, Sneha; Du, Ella X; Wu, Eric Q; Xie, Jipan

    2016-01-01

    Background No head-to-head trials comparing recombinant factor VIII (rFVIII) products currently exist. This was a matching-adjusted indirect comparison (MAIC) study of efficacy of BAY 81-8973 with antihemophilic factor (recombinant) plasma/albumin-free method (rAHF-PFM) and turoctocog alfa for the prophylaxis of severe hemophilia A. Methods A systematic literature review was conducted to identify trials of rAHF-PFM and turoctocog alfa. Comparisons were conducted using BAY 81-8973 individual patient data (IPD) from LEOPOLD trials and published data from rAHF-PFM and turoctocog alfa trials. Differences in outcome reporting were reconciled using transformation of BAY 81-8973 IPD. Patients in pooled LEOPOLD trials were weighted to match baseline characteristics for rAHF-PFM or turoctocog alfa trials using MAICs. After matching, annualized bleed rates (ABRs) were compared using weighted t-tests. Results Two rAHF-PFM trials and one turoctocog alfa trial were identified. In these trials, rFVIIIs were dosed thrice weekly or every other day; in LEOPOLD trials, BAY 81-8973 was dosed twice- or thrice weekly. Three MAICs were conducted because the two rAHF-PFM trials calculated ABRs differently, matching for age, race, and weight (turoctocog alfa only). BAY 81-8973 had similar ABR of all bleeds vs rAHF-PFM (two trials: 4.8 vs 6.3, 1.9 vs 1.8 [square root transform]) and lower ABR of spontaneous bleeds and trauma bleeds (2.6 vs 4.1, 2.1 vs 4.7; both P<0.05). BAY 81-8973 showed lower ABR of all bleeds and spontaneous bleeds vs turoctocog alfa (4.3 vs 6.5, 2.8 vs 4.3; both P<0.05) and similar ABR of trauma bleeds (1.5 vs 1.6). In subgroup analysis, twice-weekly BAY 81-8973 had similar ABRs of all bleeds, spontaneous bleeds, and trauma bleeds compared to rAHF-PFM and turoctocog alfa. Conclusion This indirect comparison found that prophylaxis with BAY 81-8973, even including the lower frequency of two times a week and lower factor VIII consumption, has efficacy comparable to r

  12. Survival of 125iodine-labeled Factor VIII in normals and patients with classic hemophilia. Observations on the heterogeneity of human Factor VIII.

    PubMed Central

    Over, J; Sixma, J J; Bruïne, M H; Trieschnigg, M C; Vlooswijk, R A; Beeser-Visser, N H; Bouma, B N

    1978-01-01

    Radiolabeled human Factor VIII was used to study its survival in normals and patients with classic hemophilia, and to study the heterogeneity of Factor VIII; Purified Factor VIII was radiolabeled with 125iodine (125I-VIII) without loss of its structural integrity. The survival of 125I-VIII was studied in six normals and six hemophiliacs of whom four of the hemophiliacs had received transfusions with normal cryoprecipitate before the 125I-VIII infusion. No significant difference was observed between the disappearance of Factor VIII coagulant activity and radioactivity in these hemophiliacs. 125I-VIII in plasma showed a biphasic disappearance with an average t1/2 of 2.9 +/- 0.4 h (SEM) for the first phase and 18.6 +/- 0.7 h (SEM) for the second phase, respectively. The survival of 125I-VIII was similar comparing normals and hemophiliacs. The highest molecular weight forms of Factor VIII disappear more rapidly than the lower molecular weight ones. This was established by analysis of the fractions obtained by gel chromatography of plasma collected at several times after infusion and by analysis of the in vivo disappearance of three subfractions of Factor VIII. The fraction of 125I-VIII binding to platelets in the presence of ristocetin (containing the highest molecular weight forms of Factor VIII including the ristocetin cofactor) represented about 50% of the radioactivity present in plasma after infusion and showed a t 1/2 of 11.7 +/- 0.9 h (SEM) for the second phase. The fraction, which was recovered in cryoprecipitate of the recipient's plasma, represented about 90% of the initial radioactivity and showed a t 1/2 of 16.3 +/- 0.8 h (SEM) for the second phase. The fraction of 125I-VIII remaining in the cryosupernatant plasma (containing low molecular weight forms of Factor (VIII) showed a t 1/2 of 27.2 +/- 1.1 h (SEM). The first phase of the disappearance of 125I-VIII is caused in part by the disappearance of the highest molecular weight forms, which are possibly

  13. Cohort versus Non-Cohort High School Students' Math Performance: Achievement Test Scores and Coursework

    ERIC Educational Resources Information Center

    Parke, Carol S.; Keener, Dana

    2011-01-01

    The purpose of this study is to compare multiple measures of mathematics achievement for 1,378 cohort students who attended the same high school in a district from 9th to 12th grade with non-cohort students in each grade level. Results show that mobility had an impact on math achievement. After accounting for gender, ethnicity, and SES, adjusted…

  14. Regulation of Viable and Optimal Cohorts

    SciTech Connect

    Aubin, Jean-Pierre

    2015-10-15

    This study deals with the evolution of (scalar) attributes (resources or income in evolutionary demography or economics, position in traffic management, etc.) of a population of “mobiles” (economic agents, vehicles, etc.). The set of mobiles sharing the same attributes is regarded as an instantaneous cohort described by the number of its elements. The union of instantaneous cohorts during a mobile window between two attributes is a cohort. Given a measure defining the number of instantaneous cohorts, the accumulation of the mobile attributes on a evolving mobile window is the measure of the cohort on this temporal mobile window. Imposing accumulation constraints and departure conditions, this study is devoted to the regulation of the evolutions of the attributes which are1.viable in the sense that the accumulations constraints are satisfied at each instant;2.and, among them, optimal, in the sense that both the duration of the temporal mobile window is maximum and that the accumulation on this temporal mobile window is the largest viable one. This value is the “accumulation valuation” function. Viable and optimal evolutions under accumulation constraints are regulated by an “implicit Volterra integro-differential inclusion” built from the accumulation valuation function, solution to an Hamilton–Jacobi–Bellman partial differential equation under constraints which is constructed for this purpose.

  15. Cohort studies in health sciences librarianship

    PubMed Central

    Eldredge, Jonathan

    2002-01-01

    Question: What are the key characteristics of the cohort study design and its varied applications, and how can this research design be utilized in health sciences librarianship? Data Sources: The health, social, behavioral, biological, library, earth, and management sciences literatures were used as sources. Study Selection: All fields except for health sciences librarianship were scanned topically for either well-known or diverse applications of the cohort design. The health sciences library literature available to the author principally for the years 1990 to 2000, supplemented by papers or posters presented at annual meetings of the Medical Library Association. Data Extraction: A narrative review for the health, social, behavioral, biological, earth, and management sciences literatures and a systematic review for health sciences librarianship literature for the years 1990 to 2000, with three exceptions, were conducted. The author conducted principally a manual search of the health sciences librarianship literature for the years 1990 to 2000 as part of this systematic review. Main Results: The cohort design has been applied to answer a wide array of theoretical or practical research questions in the health, social, behavioral, biological, and management sciences. Health sciences librarianship also offers several major applications of the cohort design. Conclusion: The cohort design has great potential for answering research questions in the field of health sciences librarianship, particularly evidence-based librarianship (EBL), although that potential has not been fully explored. PMID:12398244

  16. Review of Cohort Studies for Mood Disorders.

    PubMed

    Jeon, Hong Jin; Baek, Ji Hyun; Ahn, Yong-Min; Kim, Se Joo; Ha, Tae Hyun; Cha, Boseok; Moon, Eunsoo; Kang, Hee-Ju; Ryu, Vin; Cho, Chul-Hyun; Heo, Jung-Yoon; Kim, Kiwon; Lee, Heon-Jeong

    2016-05-01

    This paper aimed to review currently available cohort studies of subjects with mood disorders such as major depressive disorder (MDD) and bipolar disorder (BD). Using the PubMed and KoreaMed databases, we reviewed eight major cohort studies. Most studies recruited participants with MDD and BD separately, so direct comparison of factors associated with diagnostic changes was difficult. Regular and frequent follow-up evaluations utilizing objective mood ratings and standardized evaluation methods in a naturalistic fashion are necessary to determine detailed clinical courses of mood disorders. Further, biological samples should also be collected to incorporate clinical findings in the development of new diagnostic and therapeutic approaches. An innovative cohort study that can serve as a platform for translational research for treatment and prevention of mood disorders is critical in determining clinical, psychosocial, neurobiological and genetic factors associated with long-term courses and consequences of mood disorders in Korean patients. PMID:27247592

  17. Review of Cohort Studies for Mood Disorders

    PubMed Central

    Jeon, Hong Jin; Baek, Ji Hyun; Ahn, Yong-Min; Kim, Se Joo; Ha, Tae Hyun; Cha, Boseok; Moon, Eunsoo; Kang, Hee-Ju; Ryu, Vin; Cho, Chul-Hyun; Heo, Jung-Yoon; Kim, Kiwon

    2016-01-01

    This paper aimed to review currently available cohort studies of subjects with mood disorders such as major depressive disorder (MDD) and bipolar disorder (BD). Using the PubMed and KoreaMed databases, we reviewed eight major cohort studies. Most studies recruited participants with MDD and BD separately, so direct comparison of factors associated with diagnostic changes was difficult. Regular and frequent follow-up evaluations utilizing objective mood ratings and standardized evaluation methods in a naturalistic fashion are necessary to determine detailed clinical courses of mood disorders. Further, biological samples should also be collected to incorporate clinical findings in the development of new diagnostic and therapeutic approaches. An innovative cohort study that can serve as a platform for translational research for treatment and prevention of mood disorders is critical in determining clinical, psychosocial, neurobiological and genetic factors associated with long-term courses and consequences of mood disorders in Korean patients. PMID:27247592

  18. Dose effect and efficacy of rFVIIa in the treatment of haemophilia patients with inhibitors: analysis from the Hemophilia and Thrombosis Research Society Registry.

    PubMed

    Parameswaran, R; Shapiro, A D; Gill, J C; Kessler, C M

    2005-03-01

    Recombinant activated factor VII (rFVIIa), licensed in 1999 for treatment of haemophilia patients with inhibitors (HI), represents an important advance in the therapeutic armamentarium. Standard bolus dosing ranges from 90 to 120 mcg kg(-1) every 2-3 h until arrest of bleeding. As licensure, clinical use of rFVIIa has increased and broadened. Clinicians now use a wide dose range, 90-300 mcg kg(-1). High-dose regimens may optimize thrombin generation or burst, and may allow for prolonged dose interval. The Hemophilia and Thrombosis Research Society (HTRS) maintains a registry database to study haemophilia treatment and related disorders, particularly treatment of acute bleeding in HI, acquired haemophilia, FVII deficiency and von Willebrand's disease (VWD). To assess the effect of rFVIIa dose on efficacy and safety in the treatment of acute bleeding in HI, data from the HTRS database from January 2000 through June 2002 were analysed. Bleeding episodes were grouped by bolus rFVIIa dose range: <100, 100-150, 150-200 and >200 mcg kg(-1). Investigator-reported efficacy for the first 72 h of treatment was evaluated. Thirty-eight congenital HI patients were treated for 555 bleeding episodes. Patient age range was 1-55 years (median: 14). Bleeding episodes were spontaneous (45%), caused by trauma (38%), or because of surgery, dental, diagnostic, or medical procedures (17%); bleeding occurred in joint, muscle, and intra/extracranial sites. Treatment location included: 80% at home, 12% at other facilities (treatment centres, ER, inpatient and OR), and 8% at both home/other facilities. Median total dose given over 72 h was 360 mcg kg(-1) (range: 40-4281, mean: 537). Bleeding stopped in 87% of the episodes. Bleeding cessation rate was 84% for the three lower dose groups, and 97% for the highest dose group (P < 0.001). Five patients experienced nine adverse events (AEs). AE rates were <1% for <100, 5% for 100-150, 0% for 150-200, <1% for >200 mcg kg(-1) dose group. Decreased

  19. Cohort profile: the lidA Cohort Study-a German Cohort Study on Work, Age, Health and Work Participation.

    PubMed

    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

    2014-12-01

    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

  20. 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

  1. Steep increase in best-practice cohort life expectancy.

    PubMed

    Shkolnikov, Vladimir M; Jdanov, Dmitri A; Andreev, Evgeny M; Vaupel, James W

    2011-01-01

    We analyze trends in best-practice life expectancy among female cohorts born from 1870 to 1950. Cohorts experience declining rather than constant death rates, and cohort life expectancy usually exceeds period life expectancy. Unobserved mortality rates in non-extinct cohorts are estimated using the Lee-Carter model for mortality in 1960–2008. Best-practice cohort and period life expectancies increased nearly linearly. Across cohorts born from 1870 to 1920 the annual increase in cohort length of life was 0.43 years. Across calendar years from 1870 to 2008, the annual increase was 0.28 years. Cohort life expectancy increased from 53.7 years in the 1870 cohort to 83.8 years in the 1950 cohort. The corresponding cohort/period longevity gap increased from 1.2 to 10.3 years. Among younger cohorts, survival to advanced ages is substantially higher than could have been anticipated by period mortality regimes when these cohorts were young or middle-aged. A large proportion of the additional expected years of life are being lived at ages 65 and older. This substantially changes the balance between the stages of the life cycle. PMID:22167810

  2. Orthodontic therapists--the first Bristol cohort.

    PubMed

    Bain, S; Lee, W; Day, C J; Ireland, A J; Sandy, J R

    2009-09-12

    This paper outlines the development of the training of orthodontic therapists in the UK, the experiences of the first cohort to pass through the Bristol course, the roles and responsibilities of the therapist and possible issues with future orthodontic manpower planning. PMID:19749720

  3. Brain-Science Based Cohort Studies

    ERIC Educational Resources Information Center

    Koizumi, Hideaki

    2011-01-01

    This article describes a number of human cohort studies based on the concept of brain-science and education. These studies assess the potential effects of new technologies on babies, children and adolescents, and test hypotheses drawn from animal and genetic case studies to see if they apply to people. A flood of information, virtual media,…

  4. Cohort Analysis of Variations in Political Knowledge.

    ERIC Educational Resources Information Center

    Caudill, Ed

    A cohort analysis of data gathered in three national election surveys (1956, 1968, 1980) was used to study the effect of media use on political knowledge, which was divided into knowledge of issues, personalities, and political parties. Knowledge levels were calculated by creating indices from open-ended questions about why a person liked or…

  5. Knowledge Building in an Online Cohort

    ERIC Educational Resources Information Center

    Engstrom, Mary E.; Santo, Susan A.; Yost, Rosanne M.

    2008-01-01

    This study sought to understand how an online cohort in a master's program, comprised of teachers from the same school district, constructed knowledge about instructional theories and practices. Participants in this descriptive study included 10 teachers from the same rural school district. Data collection consisted of a focus group and written…

  6. Cohort Survival and Withdrawal Study District Report.

    ERIC Educational Resources Information Center

    Shainline, Michael

    At the completion of the 1986-87 school year, the Albuquerque (New Mexico) Public Schools (APS) conducted a cohort survival and withdrawal study to follow-up 5,976 students who had begun the ninth grade within the district in 1983-84. Current records were matched with those from the 1983-84 school year to determine whether members of the…

  7. Cohort Size and the Academic Labor Market.

    ERIC Educational Resources Information Center

    Stapleton, David C.

    1989-01-01

    Argues that policymakers should be skeptical of forecasts that predict faculty shortages and surpluses according to population trends and analyzes an economic model of the academic labor market. Concludes that forecasts from such models do not support policies designed to offset the impact of cohort size on the academic labor market. (Author/CH)

  8. Teacher Education in an Interdisciplinary Cohort Model

    ERIC Educational Resources Information Center

    Smith, Douglas

    2007-01-01

    In this article, the author describes the Interdisciplinary Cohort Model of Teacher Preparation at the University of Kentucky. It has been successful in preparing business and marketing teachers in a one-year period, has made educational foundations an integral part of classroom practice, and fostered collaboration between business and marketing…

  9. 4-Year Cohort Graduation Rate: Overview

    ERIC Educational Resources Information Center

    Pennsylvania Department of Education, 2010

    2010-01-01

    Federal law requires Pennsylvania, and all other states, to transition to a new calculation method for determining high school graduation rates. Beginning in 2012, using graduation data from the Classes of 2010 and 2011, the "4-Year Cohort Graduation Rate" calculation will replace the "4-Year Leaver Graduation Rate" calculation. The new…

  10. Reexamining the Dominance of Birth Cohort Effects on Mortality.

    PubMed

    Murphy, Michael

    2010-01-01

    The association between birth cohort and subsequent mortality has been of interest especially following publication of studies around 1930 of cohorts born up to the latter part of the nineteenth century, particularly for England and Wales. Updated results are presented for this population, together with those for two other cohorts, twentieth-century Japanese and British populations born about 1930, which have been identified as having particularly clear-cut birth cohort patterns, and which are used to underpin incorporation of cohort effects in both British official and actuarial mortality forecasts. Graphical methods used to identify cohort patterns are discussed. A number of limitations and difficulties are identified that mean that the conclusions about the predominance of cohort effects are less robust than often assumed. It is argued that alternative explanations should be considered and that the concentration on birth cohorts with particularly advantaged patterns may distort research priorities. PMID:20734557

  11. The Doctoral Cohort Model: Increasing Opportunities for Success

    ERIC Educational Resources Information Center

    Nimer, Mary

    2009-01-01

    Participation in a doctoral program cohort significantly increases the chances for the successful completion of the course of studies for all members of the cohort. After examining the concept of the cohort and the current research literature, the author shares her experiences in the Ed. D., Instructional Leadership program at Western Connecticut…

  12. Cohort Variation in Happiness: Some Hypotheses and Exploratory Analyses.

    ERIC Educational Resources Information Center

    Felton, Barbara J.

    1987-01-01

    Drew portraits of two cohorts of older adults from historical and sociological sources and tested hypotheses about cohort-specific values with data collected in 1957 and 1976. Results support view that adults born before 1900 were distinctive from other cohorts in that their happiness levels were closely linked with survival needs and firmly…

  13. 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

    ... challenge before official cohort default rates are issued. 668.185 Section 668.185 Education Regulations of... cohort default rates and your ability to challenge before official cohort default rates are issued. (a... may not be otherwise voluntarily released to the public by a data manager. (4) Any challenge...

  14. 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

    ... challenge before official cohort default rates are issued. 668.185 Section 668.185 Education Regulations of... cohort default rates and your ability to challenge before official cohort default rates are issued. (a... may not be otherwise voluntarily released to the public by a data manager. (4) Any challenge...

  15. 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

    ... challenge before official cohort default rates are issued. 668.185 Section 668.185 Education Regulations of... cohort default rates and your ability to challenge before official cohort default rates are issued. (a... may not be otherwise voluntarily released to the public by a data manager. (4) Any challenge...

  16. 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

    ... challenge before official cohort default rates are issued. 668.185 Section 668.185 Education Regulations of... cohort default rates and your ability to challenge before official cohort default rates are issued. (a... may not be otherwise voluntarily released to the public by a data manager. (4) Any challenge...

  17. 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

    ... challenge before official cohort default rates are issued. 668.185 Section 668.185 Education Regulations of... cohort default rates and your ability to challenge before official cohort default rates are issued. (a... may not be otherwise voluntarily released to the public by a data manager. (4) Any challenge...

  18. Parvenus and conflict in elite cohorts.

    PubMed

    Michael Lindsay, D; Schachter, Ariela; Porter, Jeremy R; Sorge, David C

    2014-09-01

    Previous studies find that greater workplace diversity leads to higher degrees of conflict in low and medium-status workgroups. This paper examines whether similar dynamics operate in elite cohorts. We use data from a survey of White House Fellows (N=475) to look at how the presence of parvenus-individuals from underrepresented groups in elite environments-change the rate at which fellows reported conflict with each other and with the director of the program. We find that there is no unified "parvenu experience." Analysis of the interaction between race and cohort diversity reveals inflection points consistent with Kanter's (1977) theory of tokenism, but the effects of increasing diversity diverge: for Hispanics, conflict with the director increases with diversity, while for Asians, conflict falls with diversity. While other groups' level of conflict with their peers stays roughly constant, Asians' reported level of conflict with their peers increases with diversity. PMID:24913951

  19. A cohort mortality study of petrochemical workers

    SciTech Connect

    Austin, S.G.; Schnatter, A.R.

    1983-04-01

    A historical prospective cohort mortality study was conducted for a cohort of 6,588 white male employees of a Texas petrochemical plant because of a suspected increased incidence of malignant brain tumors. Mortality experience from 1941 to 1977 was determined and compared with that of the general U.S. white male population adjusting for age and time period. Overall and cause-specific standardized mortality ratios were calculated for various subgroups of the population defined by length of employment, latency and payroll status. Significant deficits in total cohort mortality were found for all causes of death, all circulatory diseases, all respiratory diseases and all digestive diseases. Although not statistically significant, fewer deaths were observed (O) than expected (E) for all malignant neoplasms. No statistically significant excess of malignant brain tumors was found in the overall plant population (O/E = 12/7.42 = 1.62). A borderline significant excess of brain cancer deaths was found among hourly employees with more than six months' employment based on 10 observed and five expected deaths. This excess was observed to occur among elderly employees (over 55 years) and in later follow-up years (post-1970). Risk did not appear to be related to length of employment. Because of the nature of the problem that prompted this study, the small number of cases involved and the lack of a suspect agent in the plant that could have produced this excess, insufficient evidence was found to conclude that these tumors were occupationally related.

  20. 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 Central

    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.

    2015-01-01

    Abstract 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

  1. 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

  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. Challenges of the management of severe hemophilia A with inhibitors: two case reports emphasizing the potential interest of a high-purity human Factor VIII/von Willebrand factor concentrate and individually tailored prophylaxis guided by thrombin-generation test.

    PubMed

    Mathieu, Sophie; Crampe, Carine; Dargaud, Yesim; Lavigne-Lissalde, Géraldine; Escuriola-Ettingshausen, Carmen; Tardy, Brigitte; Meley, Roland; Thouvenin, Sandrine; Stephan, Jean L; Berger, Claire

    2015-12-01

    Severe hemophilia A is an X-linked bleeding disorder. Immune tolerance induction (ITI) is the best strategy of treatment when patients develop inhibitors. The objective is to illustrate the benefit of a high-purity human factor VIII/von Willebrand factor (VWF) concentrate (Octanate) in the management of ITI. We also wanted to raise the potential interest of laboratory assays such as thrombin-generation test (TGT) and epitope mapping. Two patients were treated during ITI, first with a recombinant FVIII and then with plasma-derived factor VIII without success, and, finally, with Octanate. Bypassing agents were used based on the results of TGT. Epitope mapping was performed during ITI therapy. These observations suggest the potential contribution of Octanate in the management of ITI in difficult cases. The use of bypassing agents can be necessary in prophylaxis or to treat bleedings, and may be guided by TGT results. Epitope mapping is used to describe the inhibitor. This article shows a decrease of the inhibitor directed against the C2 domain after initiation of Octanate. A high-purity human factor VIII/von Willebrand factor concentrate (Octanate) may be a valuable therapeutical option for ITI therapy. TGT and epitope mapping could be of help in the management of ITI. PMID:26517064

  4. Period Effects, Cohort Effects, and the Narrowing Gender Wage Gap

    PubMed Central

    Campbell, Colin; Pearlman, Jessica

    2015-01-01

    Despite the abundance of sociological research on the gender wage gap, questions remain. In particular, the role of cohorts is under investigated. Using data from the Current Population Survey, we use Age-Period-Cohort analysis to uniquely estimate age, period, and cohort effects on the gender wage gap. The narrowing of the gender wage gap that occurred between 1975 and 2009 is largely due to cohort effects. Since the mid-1990s, the gender wage gap has continued to close absent of period effects. While gains in female wages contributed to declines in the gender wage gap for cohorts born before 1950, for later cohorts the narrowing of the gender wage gap is primarily a result of declines in male wages. PMID:24090861

  5. Period effects, cohort effects, and the narrowing gender wage gap.

    PubMed

    Campbell, Colin; Pearlman, Jessica

    2013-11-01

    Despite the abundance of sociological research on the gender wage gap, questions remain. In particular, the role of cohorts is under investigated. Using data from the Current Population Survey, we use age-period-cohort analysis to uniquely estimate age, period, and cohort effects on the gender wage gap. The narrowing of the gender wage gap that occurred between 1975 and 2009 is largely due to cohort effects. Since the mid-1990s, the gender wage gap has continued to close absent of period effects. While gains in female wages contributed to declines in the gender wage gap for cohorts born before 1950, for later cohorts the narrowing of the gender wage gap is primarily a result of declines in male wages. PMID:24090861

  6. 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. PMID:25126104

  7. Estimation of Error Components in Cohort Studies: A Cross-Cohort Analysis of Dutch Mathematics Achievement

    ERIC Educational Resources Information Center

    Keuning, Jos; Hemker, Bas

    2014-01-01

    The data collection of a cohort study requires making many decisions. Each decision may introduce error in the statistical analyses conducted later on. In the present study, a procedure was developed for estimation of the error made due to the composition of the sample, the item selection procedure, and the test equating process. The math results…

  8. Cerebral palsy in two national cohort studies.

    PubMed

    Emond, A; Golding, J; Peckham, C

    1989-06-01

    The prevalence of cerebral palsy in the 1958 British Perinatal Mortality Survey and the 1970 British Births Survey remained constant at 2.5/1000 births (40 and 41 cases, respectively). The prevalence at 10 years was higher in the 1970 cohort in which all children with cerebral palsy survived, whereas 22% of the cases in the 1958 cohort died during the first 10 years of life. A case-control study matched three controls for social class, maternal age, parity and marital state, and a further three controls for the infant's sex, gestation, and birth weight. Comparison of cases and controls showed no consistent differences in social and environmental factors, history of pregnancy, labour, or delivery. Important differences were found in the incidence of respiratory and neurological symptoms in the neonatal period. These prospective data derived form two whole populations of births support the hypothesis that most cases of cerebral palsy are not associated with adverse obstetric factors, and confirm that neonatal neurological symptoms are associated with subsequent cerebral palsy. PMID:2774617

  9. AGRICOH: A Consortium of Agricultural Cohorts

    PubMed Central

    Leon, Maria E.; Beane Freeman, Laura E.; Douwes, Jeroen; Hoppin, Jane A.; Kromhout, Hans; Lebailly, Pierre; Nordby, Karl-Christian; Schenker, Marc; Schüz, Joachim; Waring, Stephen C.; Alavanja, Michael C.R.; Annesi-Maesano, Isabella; Baldi, Isabelle; Dalvie, Mohamed Aqiel; Ferro, Giles; Fervers, Béatrice; Langseth, Hilde; London, Leslie; Lynch, Charles F.; McLaughlin, John; Merchant, James A.; Pahwa, Punam; Sigsgaard, Torben; Stayner, Leslie; Wesseling, Catharina; Yoo, Keun-Young; Zahm, Shelia H.; Straif, Kurt; Blair, Aaron

    2011-01-01

    AGRICOH is a recently formed consortium of agricultural cohort studies involving 22 cohorts from nine countries in five continents: South Africa (1), Canada (3), Costa Rica (2), USA (6), Republic of Korea (1), New Zealand (2), Denmark (1), France (3) and Norway (3). The aim of AGRICOH, initiated by the US National Cancer Institute (NCI) and coordinated by the International Agency for Research on Cancer (IARC), is to promote and sustain collaboration and pooling of data to investigate the association between a wide range of agricultural exposures and a wide range of health outcomes, with a particular focus on associations that cannot easily be addressed in individual studies because of rare exposures (e.g., use of infrequently applied chemicals) or relatively rare outcomes (e.g., certain types of cancer, neurologic and auto-immune diseases). To facilitate future projects the need for data harmonization of selected variables is required and is underway. Altogether, AGRICOH provides excellent opportunities for studying cancer, respiratory, neurologic, and auto-immune diseases as well as reproductive and allergic disorders, injuries and overall mortality in association with a wide array of exposures, prominent among these the application of pesticides. PMID:21655123

  10. Cohort study of atypical pressure ulcers development.

    PubMed

    Jaul, Efraim

    2014-12-01

    Atypical pressure ulcers (APU) are distinguished from common pressure ulcers (PU) with both unusual location and different aetiology. The occurrence and attempts to characterise APU remain unrecognised. The purpose of this cohort study was to analyse the occurrence of atypical location and the circumstances of the causation, and draw attention to the prevention and treatment by a multidisciplinary team. The cohort study spanned three and a half years totalling 174 patients. The unit incorporates two weekly combined staff meetings. One concentrates on wound assessment with treatment decisions made by the physician and nurse, and the other, a multidisciplinary team reviewing all patients and coordinating treatment. The main finding of this study identified APU occurrence rate of 21% within acquired PU over a three and a half year period. Severe spasticity constituted the largest group in this study and the most difficult to cure wounds, located in medial aspects of knees, elbows and palms. Medical devices caused the second largest occurrence of atypical wounds, located in the nape of the neck, penis and nostrils. Bony deformities were the third recognisable atypical wound group located in shoulder blades and upper spine. These three categories are definable and time observable. APU are important to be recognisable, and can be healed as well as being prevented. The prominent role of the multidisciplinary team is primary in identification, prevention and treatment. PMID:23374746

  11. Global teaching and training initiatives for emerging cohort studies.

    PubMed

    Paulus, Jessica K; Santoyo-Vistrain, Rocío; Havelick, David; Cohen, Amy; Kalyesubula, Robert; Ajayi, Ikeoluwapo O; Mattsson, Jens G; Adami, Hans-Olov; Dalal, Shona

    2012-09-01

    A striking disparity exists across the globe, with essentially no large-scale longitudinal studies ongoing in regions that will be significantly affected by the oncoming non-communicable disease epidemic. The successful implementation of cohort studies in most low-resource research environments presents unique challenges that may be aided by coordinated training programs. Leaders of emerging cohort studies attending the First World Cohort Integration Workshop were surveyed about training priorities, unmet needs and potential cross-cohort solutions to these barriers through an electronic pre-workshop questionnaire and focus groups. Cohort studies representing India, Mexico, Nigeria, South Africa, Sweden, Tanzania and Uganda described similar training needs, including on-the-job training, data analysis software instruction, and database and bio-bank management. A lack of funding and protected time for training activities were commonly identified constraints. Proposed solutions include a collaborative cross-cohort teaching platform with web-based content and interactive teaching methods for a range of research personnel. An international network for research mentorship and idea exchange, and modifying the graduate thesis structure were also identified as key initiatives. Cross-cohort integrated educational initiatives will efficiently meet shared needs, catalyze the development of emerging cohorts, speed closure of the global disparity in cohort research, and may fortify scientific capacity development in low-resource settings. PMID:23856451

  12. Neuroimaging of the Philadelphia Neurodevelopmental Cohort

    PubMed Central

    Satterthwaite, Theodore D.; Elliott, Mark A.; Ruparel, Kosha; Loughead, James; Prabhakaran, Karthik; Calkins, Monica E.; Hopson, Ryan; Jackson, Chad; Keefe, Jack; Riley, Marisa; Mensh, Frank D.; Sleiman, Patrick; Verma, Ragini; Davatzikos, Christos; Hakonarson, Hakon; Gur, Ruben C.; Gur, Raquel E.

    2013-01-01

    The Philadelphia Neurodevelopmental Cohort (PNC) is a large-scale, NIMH funded initiative to understand how brain maturation mediates cognitive development and vulnerability to psychiatric illness, and understand how genetics impacts this process. As part of this study, 1,445 adolescents ages 8–21 at enrollment underwent multimodal neuroimaging. Here, we highlight the conceptual basis for the effort, the study design, and measures available in the dataset. We focus on neuroimaging measures obtained, including T1-weighted structural neuroimaging, diffusion tensor imaging, perfusion neuroimaging using arterial spin labeling, functional imaging tasks of working memory and emotion identification, and resting state imaging of functional connectivity. Furthermore, we provide characteristics regarding the final sample acquired. Finally, we describe mechanisms in place for data sharing that will allow the PNC to become a freely available public resource to advance our understanding of normal and pathological brain development. PMID:23921101

  13. Cohort Change in Images of Older Adults, 1974-1981.

    ERIC Educational Resources Information Center

    Ferraro, Kenneth F.

    1992-01-01

    Examined images of older people held by adults of all ages in 1974 (n=4,254) and 1981 (n=3,427). Cohort changes in such perceptions over time were examined. Multivariate analysis indicated that social class and health status evaluations of older adults declined between the two surveys, principally because of the assessment by more recent cohorts.…

  14. MILLARD COUNTY, UTAH DRINKING WATER ARSENIC COHORT STUDY

    EPA Science Inventory

    Cohort members: Assembly of the cohort is based on historic membership records of members of the Church of Jesus Christ of Latter-Day Saints (LDS) in an area of Millard County, Utah which is located in the central western part of the state. Personal information including name, bi...

  15. The Cohort Model: Lessons Learned When Principals Collaborate

    ERIC Educational Resources Information Center

    Umekubo, Lisa A.; Chrispeels, Janet H.; Daly, Alan J.

    2015-01-01

    This study explored a formal structure, the cohort model that a decentralized district put in place over a decade ago. Schools were clustered into cohorts to facilitate professional development for leadership teams for all 44 schools within the district. Drawing upon Senge's components of organizational learning, we used a single case study design…

  16. Cohort Size Effects on Earnings: Differences by College Major.

    ERIC Educational Resources Information Center

    Berger, Mark C.

    1988-01-01

    Examines effects of cohort size on starting salaries of college graduates from different areas of study. Increases in the size of graduating classes relative to the population depress their starting salaries relative to other workers. Smallest negative cohort size effects are found for engineering and business graduates, while the largest are…

  17. Matriculation Evaluation Using the New Student Cohort, Fall 1992.

    ERIC Educational Resources Information Center

    Birdsall, Les

    An analysis of student matriculation was conducted at Diablo Valley College, in California, using the cohort of 4,251 students identified as new in fall 1992. Data indicate that 22.3% of this cohort did not enroll in any courses after applying, being tested, and completing orientation and advising; 8.4% continued on in the semester, but dropped…

  18. Building the Future with Cohorts: Communities of Inquiry

    ERIC Educational Resources Information Center

    Rausch, David W.; Crawford, Elizabeth

    2012-01-01

    With recent interest in communities of practice, learning communities, and critical inquiry theory, the University of Tennessee at Chattanooga (UTC) developed, implemented, and studied the relationship of community and the cohort model. This paper shares information about successes and opportunities for improvement. Cohort-based learners across a…

  19. Age, Period and Cohort Effects on Social Capital

    ERIC Educational Resources Information Center

    Schwadel, Philip; Stout, Michael

    2012-01-01

    Researchers hypothesize that social capital in the United States is not just declining, but that it is declining across "generations" or birth cohorts. Testing this proposition, we examine changes in social capital using age-period-cohort intrinsic estimator models. Results from analyses of 1972-2010 General Social Survey data show (1) that…

  20. THE MEDICAL FOLLOW-UP AGENCY COHORT CATALOG

    EPA Science Inventory

    The Cohort Catalog describes a remarkable collection of study populations of former military personnel assembled as part of proposed or completed research dating back to the 1940's. The catalog provides summary information for each listed cohort. Summaries contain background info...

  1. A Collaborative Cohort Approach to Teacher Education: Modeling Inclusive Practices.

    ERIC Educational Resources Information Center

    Smith, Sean J.; Frey, Bruce B.; Tollefson, Nona

    2003-01-01

    Assessed student teachers' views of a collaborative cohort experience where four faculty members provided seamless instruction to illustrate effective collaboration. Data surveys and focus groups indicated that, in contrast to campus-based instruction, the collaborative cohort model improved preservice teachers' attitudes toward integrating…

  2. What Drives Teacher Engagement: A Study of Different Age Cohorts

    ERIC Educational Resources Information Center

    Guglielmi, Dina; Bruni, Ilaria; Simbula, Silvia; Fraccaroli, Franco; Depolo, Marco

    2016-01-01

    Despite the growing body of research on work engagement, little is known about what drives work engagement among different age cohorts. This study aims to investigate whether engagement varies across age cohorts and examines the job resources that foster teacher engagement. A questionnaire was distributed to 537 teachers who were employed in…

  3. Statins and congenital malformations: cohort study

    PubMed Central

    Hernandez-Diaz, Sonia; Fischer, Michael A; Seely, Ellen W; Ecker, Jeffrey L; Franklin, Jessica M; Desai, Rishi J; Allen-Coleman, Cora; Mogun, Helen; Avorn, Jerry; Huybrechts, Krista F

    2015-01-01

    Objective To examine the teratogenic potential of statins. Design Cohort study. Setting United States. Participants A cohort of 886 996 completed pregnancies linked to liveborn infants of women enrolled in Medicaid from 2000 to 2007. Methods We examined the risk of major congenital malformations and organ specific malformations in offspring associated with maternal use of a statin in the first trimester. Propensity score based methods were used to control for potential confounders, including maternal demographic characteristics, obstetric and medical conditions, and use of other drugs. Results 1152 (0.13%) women used a statin during the first trimester. In unadjusted analyses, the prevalence of malformations in the offspring of these women was 6.34% compared with 3.55% in those of women who did not use a statin in the first trimester (relative risk 1.79, 95% confidence interval 1.43 to 2.23). Controlling for confounders, particularly pre-existing diabetes, accounted for this increase in risk (1.07, 0.85 to 1.37). There were also no statistically significant increases in any of the organ specific malformations assessed after accounting for confounders. Results were similar across a range of sensitivity analyses. Conclusions Our analysis did not find a significant teratogenic effect from maternal use of statins in the first trimester. However, these findings need to be replicated in other large studies, and the long term effects of in utero exposure to statins needs to be assessed, before use of statins in pregnancy can be considered safe. PMID:25784688

  4. Achieving Synergy: Linking an Internet-Based Inflammatory Bowel Disease Cohort to a Community-Based Inception Cohort and Multicentered Cohort in Inflammatory Bowel Disease

    PubMed Central

    Aldridge, Molly; Cook, Suzanne Follan; Bright, Renee; Mallette, Meaghan; Moniz, Heather; Shah, Samir A; LeLeiko, Neal S; Shapiro, Jason; Sands, Bruce E; Chen, Wenli; Jaeger, Elizabeth; Galanko, Joseph; Long, Millie D; Martin, Christopher F; Sandler, Robert S; Kappelman, Michael D

    2016-01-01

    Background Traditional cohort studies are important contributors to our understanding of inflammatory bowel diseases, but they are labor intensive and often do not focus on patient-reported outcomes. Internet-based studies provide new opportunities to study patient-reported outcomes and can be efficiently implemented and scaled. If a traditional cohort study was linked to an Internet-based study, both studies could benefit from added synergy. Existing cohort studies provide an opportunity to develop and test processes for cohort linkage. The Crohn’s and Colitis Foundation of America’s (CCFA) Partners study is an Internet-based cohort of more than 14,000 participants. The Ocean State Crohn’s and Colitis Area Registry (OSCCAR) is an inception cohort. The Sinai-Helmsley Alliance for Research Excellence (SHARE) is a multicentered cohort of inflammatory bowel disease patients. Both the later cohorts include medical record abstraction, patient surveys, and biospecimen collection. Objective Given the complementary nature of these existing cohorts, we sought to corecruit and link data. Methods Eligible OSCCAR and SHARE participants were invited to join the CCFA Partners study and provide consent for data sharing between the 2 cohorts. After informed consent, participants were directed to the CCFA Partners website to complete enrollment and a baseline Web-based survey. Participants were linked across the 2 cohorts by the matching of an email address. We compared demographic and clinical characteristics between OSCCAR and SHARE participants who did and did not enroll in CCFA Partners and the data linkage. Results Of 408 participants in the OSCCAR cohort, 320 were eligible for participation in the CCFA Partners cohort. Of these participants, 243 consented to participation; however, only 44 enrolled in CCFA Partners and completed the linkage. OSCCAR participants who enrolled in CCFA Partners were better educated (17% with doctoral degrees) than those who did not (3% with

  5. Cohort Profile update: The 1993 Pelotas (Brazil) Birth Cohort follow-up visits in adolescence

    PubMed Central

    Gonçalves, Helen; Assunção, Maria CF; Wehrmeister, Fernando C; Oliveira, Isabel O; Barros, Fernando C; Victora, Cesar G; Hallal, Pedro C; Menezes, Ana MB

    2014-01-01

    In this paper we update the profile of the 1993 Pelotas (Brazil) Birth Cohort Study, with emphasis on a shift of priority from maternal and child health research topics to four main categories of outcome variables, collected throughout adolescence: (i) mental health; (ii) body composition; (iii) risk factors for non-communicable diseases (NCDs); (iv) human capital. We were able to trace 81.3% (n = 4106) of the original cohort at 18 years of age. For the first time, the 18-years visit took place entirely on the university premises, in a clinic equipped with state-of-the-art equipment for the assessment of body composition. We welcome requests for data analyses from outside scientists. For more information, refer to our website (http://www.epidemio-ufpel.org.projetos_de_pesquisas/estudos/coorte_1993) or e-mail the corresponding author. PMID:24729426

  6. Investing in Prospective Cohorts for Etiologic Study of Occupational Exposures

    PubMed Central

    Blair, A.; Hines, C.J.; Thomas, K.W.; Alavanja, M.C.R.; Beane Freeman, L.E.; Hoppin, J.A.; Kamel, F.; Lynch, C.F.; Lubin, J.H.; Silverman, D.T.; Whelan, E.; Zahm, S. H.; Sandler, D. P.

    2015-01-01

    Prospective cohorts have played a major role in understanding the contribution of diet, physical activity, medical conditions, and genes to the development of many diseases, but have not been widely used for occupational exposures. Studies in agriculture are an exception. We draw upon our experience using this design to study agricultural workers to identify conditions that might foster use of prospective cohorts to study other occupational settings. Prospective cohort studies are perceived by many as the strongest epidemiologic design. It allows updating of information on exposure and other factors, collection of biologic samples before disease diagnosis for biomarker studies, assessment of effect modification by genes, lifestyle, and other occupational exposures, and evaluation of a wide range of health outcomes. Increased use of prospective cohorts would be beneficial in identifying hazardous exposures in the workplace. Occupational epidemiologists should seek opportunities to initiate prospective cohorts to investigate high priority, occupational exposures. PMID:25603935

  7. Cohort profile: golestan hepatitis B cohort study- a prospective long term study in northern iran ​.

    PubMed

    Poustchi, Hossein; Katoonizadeh, Aezam; Ostovaneh, Mohammad Reza; Moossavi, Shirin; Sharafkhah, Maryam; Esmaili, Saeed; Pourshams, Akram; Mohamadkhani, Ashraf; Besharat, Sima; Merat, Shahin; Mohamadnejad, Mehdi; George, Jacob; Malekzadeh, Reza

    2014-10-01

    Hepatitis B virus (HBV) infection is the most common cause of end stage liver disease in Iran and in Golestan province. Large-scale population-based prospective cohort studies with long term follow-up are the method of choice to accurately understand the natural course of HBV infection. To date, several studies of HBV epidemiology, natural history, progression to cirrhosis and association with HCC have been reported from other countries. However, few of these are prospective and fewer still are population-based. Moreover, the underlying molecular mechanisms and immunogenetic determinants of the outcome of HBV infection especially in low and middle income countries remains largely unknown. Therefore, the hepatitis B cohort study (HBCS), nested as part of the Golestan Cohort Study (GCS), Golestan, Iran was established in 2008 with the objective to prospectively investigate the natural course of chronic hepatitis B with reference to its epidemiology, viral/host genetic interactions, clinical features and outcome in the Middle East where genotype D HBV accounts for >90% of infections. In 2008, a baseline measurement of HBV surface antigen (HBsAg) was performed on stored serum samples of all GCS participants. A sub-cohort of 3,505 individuals were found to be HBsAg positive and were enrolled in the Golestan HBCS. In 2011, all first degree relatives of HBsAg positive subjects including their children and spouses were invited for HBV serology screening and those who were positive for HBsAg were also included in the Golestan HBCS. PMID:25349681

  8. Southern community cohort study: establishing a cohort to investigate health disparities.

    PubMed Central

    Signorello, Lisa B.; Hargreaves, Margaret K.; Steinwandel, Mark D.; Zheng, Wei; Cai, Qiuyin; Schlundt, David G.; Buchowski, Maciej S.; Arnold, Carolyne W.; McLaughlin, Joseph K.; Blot, William J.

    2005-01-01

    OBJECTIVES: To demonstrate the methods of recruitment of a low-income, predominantly African-American study population for the Southern Community Cohort Study (SCCS), a prospective epidemiologic investigation of racial disparities in cancer risk. METHODS: Partnerships with community health centers (CHCs) were formed to reach underserved populations throughout the south. Recruitment of participants (aged 40-79) in CHCs began in March 2002. Participants complete a comprehensive baseline interview and provide a blood or buccal cell sample. Recruitment will expand to the general population of the south to achieve a broad cross-section of socioeconomic status, The final cohort size is expected to be approximately 100,000. RESULTS: A high level of cooperation and recruitment was achieved in the CHCs. From March 2002 to October 2004, 32,632 participants (80% black, 41% male, 62% with total household income < $15,000, 34% with < 12 years schooling) enrolled. Participants reported a high prevalence of medical conditions (21% diabetic, 44% obese) and adverse health behaviors (45% current smokers). CONCLUSIONS: Working in CHCs is successful for recruiting a population that has been difficult to reach in previous studies. The SCCS is a unique cohort that will provide a rich resource for evaluating disparities in cancer and other chronic disease risk as it is followed over time. PMID:16080667

  9. 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. PMID:25344943

  10. Testing Persistence of Cohort Effects in the Epidemiology of Suicide: an Age-Period-Cohort Hysteresis Model

    PubMed Central

    Chauvel, Louis; Leist, Anja K.; Ponomarenko, Valentina

    2016-01-01

    Birth cohort effects in suicide rates are well established, but to date there is no methodological approach or framework to test the temporal stability of these effects. We use the APC-Detrended (APCD) model to robustly estimate intensity of cohort effects identifying non-linear trends (or ‘detrended’ fluctuations) in suicide rates. The new APC-Hysteresis (APCH) model tests temporal stability of cohort effects. Analysing suicide rates in 25 WHO countries (periods 1970–74 to 2005–09; ages 20–24 to 70–79) with the APCD method, we find that country-specific birth cohort membership plays an important role in suicide rates. Among 25 countries, we detect 12 nations that show deep contrasts among cohort-specific suicide rates including Italy, Australia and the United States. The APCH method shows that cohort fluctuations are not stable across the life course but decline in Spain, France and Australia, whereas they remain stable in Italy, the United Kingdom and the Netherlands. We discuss the Spanish case with elevated suicide mortality of cohorts born 1965–1975 which declines with age, and the opposite case of the United States, where the identified cohort effects of those born around 1960 increase smoothly, but statistically significant across the life course. PMID:27442027

  11. 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,...

  12. Cohort Profile: The International Collaboration of Incident HIV and Hepatitis C in Injecting Cohorts (InC3) Study

    PubMed Central

    Grebely, Jason; Morris, Meghan D; Rice, Thomas M; Bruneau, Julie; Cox, Andrea L; Kim, Arthur Y; McGovern, Barbara H; Shoukry, Naglaa H; Lauer, Georg; Maher, Lisa; Lloyd, Andrew R; Hellard, Margaret; Prins, Maria; Dore, Gregory J; Page, Kimberly

    2013-01-01

    The International Collaboration of Incident HIV and Hepatitis C in Injecting Cohorts (InC3) Study is an international multi-cohort project of pooled biological and behavioural data from nine prospective cohorts of people who inject drugs (PWID). InC3 brings together researchers from Australia, Canada, USA and the Netherlands with expertise in epidemiology, biostatistics, clinical and behavioural sciences, virology and immunology to investigate research questions relevant to hepatitis C virus (HCV) and HIV outcomes. InC3 was established to: (i) create a merged multi-cohort study of pooled data from well-characterized cohorts of PWID with prospective data on HIV and HCV infections, with a particular focus on HCV; (ii) facilitate new studies not possible within individual cohorts; and (iii) bring together researchers across disciplines to answer a broad range of research questions. Study cohorts identify acute HCV cases through follow-up of high-risk HCV antibody–negative PWID or through clinical referral networks. To date, data from 1986 to 2010 have been received from all contributing cohorts, with 821 HCV-infected and 1216 HCV-uninfected participants (overall, n = 2037). Data collected include demographics, host genetics, HCV ribonucleic acid testing, alanine aminotransferase testing, HIV/hepatitis B virus testing, HCV therapy, loss to follow-up and mortality. Potential collaborators should contact the InC3 PI Dr Kimberley Page (kPage@psg.ucsf.edu) for further information. PMID:23203695

  13. Testing Persistence of Cohort Effects in the Epidemiology of Suicide: an Age-Period-Cohort Hysteresis Model.

    PubMed

    Chauvel, Louis; Leist, Anja K; Ponomarenko, Valentina

    2016-01-01

    Birth cohort effects in suicide rates are well established, but to date there is no methodological approach or framework to test the temporal stability of these effects. We use the APC-Detrended (APCD) model to robustly estimate intensity of cohort effects identifying non-linear trends (or 'detrended' fluctuations) in suicide rates. The new APC-Hysteresis (APCH) model tests temporal stability of cohort effects. Analysing suicide rates in 25 WHO countries (periods 1970-74 to 2005-09; ages 20-24 to 70-79) with the APCD method, we find that country-specific birth cohort membership plays an important role in suicide rates. Among 25 countries, we detect 12 nations that show deep contrasts among cohort-specific suicide rates including Italy, Australia and the United States. The APCH method shows that cohort fluctuations are not stable across the life course but decline in Spain, France and Australia, whereas they remain stable in Italy, the United Kingdom and the Netherlands. We discuss the Spanish case with elevated suicide mortality of cohorts born 1965-1975 which declines with age, and the opposite case of the United States, where the identified cohort effects of those born around 1960 increase smoothly, but statistically significant across the life course. PMID:27442027

  14. PanScan, the Pancreatic Cancer Cohort Consortium, and the Pancreatic Cancer Case-Control Consortium

    Cancer.gov

    The Pancreatic Cancer Cohort Consortium consists of more than a dozen prospective epidemiologic cohort studies within the NCI Cohort Consortium, whose leaders work together to investigate the etiology and natural history of pancreatic cancer.

  15. Case-cohort analysis of clusters of recurrent events.

    PubMed

    Chen, Feng; Chen, Kani

    2014-01-01

    The case-cohort sampling, first proposed in Prentice (Biometrika 73:1-11, 1986), is one of the most effective cohort designs for analysis of event occurrence, with the regression model being the typical Cox proportional hazards model. This paper extends to consider the case-cohort design for recurrent events with certain specific clustering feature, which is captured by a properly modified Cox-type self-exciting intensity model. We discuss the advantage of using this model and validate the pseudo-likelihood method. Simulation studies are presented in support of the theory. Application is illustrated with analysis of a bladder cancer data. PMID:23832308

  16. Oral presentation bias: a retrospective cohort study.

    PubMed

    Decullier, Evelyne; Chapuis, François

    2007-03-01

    The aim of this paper was to assess oral presentation bias at a national level. This was a retrospective cohort study with initial characteristics of the approved protocols extracted from the committee's archives, and follow-up characteristics obtained from a questionnaire mailed to the principal investigators. A representative sample of French research ethics committees (25/48), the only committees legally endorsed for ethical authorisation in biomedical research, were studied. All completed research protocols, which had been approved in 1994 by these committees, were included. Initial characteristics (design, study size, investigator) of completed studies and follow-up information (direction of results, rates of publication and rates of oral presentation) were collected. Complete information on results and their dissemination was available for 248 completed non-confidential protocols. Half of these (49%) were declared as orally presented. The observed ranking for strategies to disseminate results was the following: orally presented and published, published only, neither orally presented nor published and orally presented only. Confirmatory results were more often orally presented, with an adjusted OR of 6.4 (95% CI 2.69 to 15.22). Other associated variables are the following: national/international scope of the study, protocol writer's university status, adverse events and interim analysis. There is a trend to submit or accept confirmatory results for oral presentations: meetings are a biased representation of research, and oral presentation bias could even be higher than publication bias. PMID:17325393

  17. Antiepileptics and blood dyscrasias: a cohort study.

    PubMed

    Blackburn, S C; Oliart, A D; García Rodríguez, L A; Pérez Gutthann, S

    1998-01-01

    We conducted a cohort study to investigate the frequency of serious blood dyscrasias in patients age 10-74 years, taking antiepileptic drugs between January 1, 1990, and October 31, 1994. Main outcome measures were validated diagnoses of neutropenia, agranulocytosis, hemolytic anemia, thrombocytopenia, bicytopenia, pancytopenia, or aplastic anemia. A total of 29,357 recipients of antiepileptic therapy received 684,706 prescriptions. Among them there were 21 cases of serious blood dyscrasia of which only 18 could be considered to have a temporal relationship to drug use. Seventeen cases occurred in current users of carbamazepine, phenobarbital, phenytoin or valproate, and 7 in patients taking two or more drugs. Twenty of the 21 patients recovered. The overall rate of blood dyscrasias was 3-4/100,000 prescriptions. The rate in those age less than 60 years was 2.0 (range 0.9-3.6)/100,000 prescriptions compared with 4.0 (range 1.6-8.2) for those age 60 or older. The overall rate of neutropenia was 1.2 (0.5-2.3)/100,000 prescriptions, compared with 0.9 (0.3-1.9) for thrombocytopenia and 0.4 (0.1-1.3) for hemolytic anemia. Rates did not differ among the four drugs. Serious blood dyscrasias are rare in patients taking antiepileptic agents. PMID:9855327

  18. Cohort profile: the Young Lives study.

    PubMed

    Barnett, Inka; Ariana, Proochista; Petrou, Stavros; Penny, Mary E; Duc, Le Thuc; Galab, S; Woldehanna, Tassew; Escobal, Javier A; Plugge, Emma; Boyden, Jo

    2013-06-01

    Young Lives is an international longitudinal study investigating the changing nature of childhood poverty in four low-income countries [Ethiopia, India (Andhra Pradesh), Peru and Vietnam] over a 15-year period. In each country, the cohort is comprised of ≈ 2000 children aged between 6 and 18 months and up to 1000 children aged between 7 and 8 years, recruited in 2002 and sampled from 20 sentinel sites. The first survey data collection from primary caregivers and older children took place in 2002, the second in 2006-07 and the third in 2009-10. Data on the community contexts were collected to complement the household surveys. To elaborate and extend the quantitative data, longitudinal qualitative research with a subgroup of the children was carried out in 2007, 2008 and 2010-11. Topic areas covered included nutrition, health and well-being, cognitive and physical development, health behaviours and education, as well as the social, demographic and economic status of the household. Survey data from the study are archived in the International Section of the UK Public Data Archive. PMID:22617687

  19. Observations of a large Dent disease cohort.

    PubMed

    Blanchard, Anne; Curis, Emmanuel; Guyon-Roger, Tiphaine; Kahila, Diana; Treard, Cyrielle; Baudouin, Véronique; Bérard, Etienne; Champion, Gérard; Cochat, Pierre; Dubourg, Julie; de la Faille, Renaud; Devuyst, Olivier; Deschenes, Georges; Fischbach, Michel; Harambat, Jérôme; Houillier, Pascal; Karras, Alexandre; Knebelmann, Bertrand; Lavocat, Marie-Pierre; Loirat, Chantal; Merieau, Elodie; Niaudet, Patrick; Nobili, François; Novo, Robert; Salomon, Rémi; Ulinski, Tim; Jeunemaître, Xavier; Vargas-Poussou, Rosa

    2016-08-01

    Dent disease classically combines low-molecular-weight proteinuria, hypercalciuria with nephrocalcinosis, and renal failure. Nephrotic range proteinuria, normal calciuria, and hypokalemia have been rarely reported. It is unknown whether the changes in phenotype observed over time are explained by a decrease in glomerular filtration rate (GFR) or whether there is any phenotype-genotype relationship. To answer this we retrospectively analyzed data from 109 male patients with CLCN5 mutations (Dent-1) and 9 patients with mutation of the OCRL gene (Dent-2). In Dent-1 disease, the estimated GFR decreased with age, by 1.0 to 1.6 ml/min per 1.73 m(2)/yr in the absence and presence of nephrocalcinosis, respectively, with no significant difference. Median values of low-molecular-weight proteinuria were in the nephrotic range and remained at the same level even in late renal disease. End-stage renal disease occurred in 12 patients, at a median age of 40 years. Hypercalciuria decreased with glomerular filtration and was absent in 40% of the patients under 30 and 85% of those over the age of 30. Hypophosphatemia did not resolve with age and calcitriol concentrations were in the upper normal range. Kalemia decreased with age, with half of the patients over the age of 18 presenting with hypokalemia. Thus, no phenotype/genotype correlation was observed in this cohort of patients with Dent disease. PMID:27342959

  20. The mummy's curse: historical cohort study

    PubMed Central

    Nelson, Mark R

    2002-01-01

    Objective To examine survival of individuals exposed to the “mummy's curse” reputedly associated with the opening of the tomb of Tutankhamen in Luxor, Egypt, between February 1923 and November 1926. Design Retrospective cohort study. Participants 44 Westerners identified by Howard Carter as present in Egypt at the specified dates, 25 of whom were potentially exposed to the curse. Main outcome measures Length of survival after date of potential exposure. Results In the 25 people exposed to the curse the mean age at death was 70 years (SD 12) compared with 75 (13) in those not exposed (P=0.87 for difference). Survival after the date of exposure was 20.8 (15.2) v 28.9 (13.6) years respectively (P=0.95 for difference). Female sex was a predictor for survival (P=0.02). Conclusions There was no significant association between exposure to the mummy's curse and survival and thus no evidence to support the existence of a mummy's curse. What is already known on this topicThe methods of evidence based medicine have not been used to investigate the reality of the “mummy's curse”The arguments against the curse have been as anecdotal as the contemporary newspapers that reported itWhat this study addsThere was no association between potential exposure to the mummy's curse during the excavation of Tutankamen's tomb and death within 10 yearsNo evidence was found for the existence of a mummy's curse PMID:12493675

  1. Supporting Iterative Cohort Construction with Visual Temporal Queries.

    PubMed

    Krause, Josua; Perer, Adam; Stavropoulos, Harry

    2016-01-01

    Many researchers across diverse disciplines aim to analyze the behavior of cohorts whose behaviors are recorded in large event databases. However, extracting cohorts from databases is a difficult yet important step, often overlooked in many analytical solutions. This is especially true when researchers wish to restrict their cohorts to exhibit a particular temporal pattern of interest. In order to fill this gap, we designed COQUITO, a visual interface that assists users defining cohorts with temporal constraints. COQUITO was designed to be comprehensible to domain experts with no preknowledge of database queries and also to encourage exploration. We then demonstrate the utility of COQUITO via two case studies, involving medical and social media researchers. PMID:26529690

  2. Public perceptions of cohort studies and biobanks in Germany.

    PubMed

    Starkbaum, Johannes; Gottweis, Herbert; Gottweis, Ursula; Kleiser, Christina; Linseisen, Jakob; Meisinger, Christa; Kamtsiuris, Panagiotis; Moebus, Susanne; Jöckel, Karl-Heinz; Börm, Sonja; Wichmann, H-Erich

    2014-04-01

    Cohort studies and biobank projects have led to public discussions in several European countries in the past. In Germany, many medium-sized studies are currently running successfully in terms of respondent rates. However, EU-wide research on general public perceptions of biobanks and cohort studies have shown that Germany is among those countries where people express the highest reluctance for providing body material and other data for research purposes. Because of early efforts of the just-initiated German National Cohort Study, we are able to begin to investigate in greater detail how various groups of people across Germany reflect and discuss the ongoing implementation of cohort studies and biobanking in Germany. Our research is based on 15 focus group discussions in four German regions, as well as on Eurobarometer poll data on biobanking. PMID:24749879

  3. 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.

  4. Cohort size and migration in a West Indian population.

    PubMed

    Brittain, A W

    1990-01-01

    The author examines the relationship between cohort size and migration patterns among the population of the French West Indies island of St. Barthelemy. Data show that "for people born from 1878 to 1967, neither cohort size nor fluctuations in external demands for labor had a lasting effect on the probability of eventual migration. Emigration rates only slowed after the development of the local tourist industry brought prosperity to the island." PMID:12283449

  5. Atypical antipsychotic drugs and pregnancy outcome: a prospective, cohort study.

    PubMed

    Habermann, Frank; Fritzsche, Juliane; Fuhlbrück, Frederike; Wacker, Evelin; Allignol, Arthur; Weber-Schoendorfer, Corinna; Meister, Reinhard; Schaefer, Christof

    2013-08-01

    Women of childbearing age are often affected with psychotic disorders, requiring the use of antipsychotic medication during pregnancy. In the present study, we prospectively followed the pregnancies of 561 women exposed to second-generation antipsychotic agents (SGAs; study cohort) and compared these to 284 pregnant women exposed to first-generation antipsychotic agents (FGAs; comparison cohort I) and to 1122 pregnant women using drugs known as not harmful to the unborn (comparison cohort II). Subjects were enrolled through the Institute's consultation service. Major malformation rates of SGA exposed were higher compared to comparison cohort II (adjusted odds ratio, 2.17; 95% confidence interval, 1.20-3.91), possibly reflecting a detection bias concerning atrial and ventricular septal defects. Postnatal disorders occurred significantly more often in infants prenatally exposed to SGAs (15.6%) and FGAs (21.6%) compared to 4.2% of comparison cohort II. Cumulative incidences of elective terminations of pregnancy were significantly higher in both the study cohort (17%) and comparison cohort I (21%) compared to comparison cohort II (3%), whereas the rates of spontaneous abortions did not differ. The numbers of stillbirths and neonatal deaths were within the reference range. Preterm birth and low birth weight were more common in infants exposed to FGAs. To conclude, our findings did not reveal a major teratogenic risk for SGAs, making the better studied drugs of this group a treatment option during pregnancy. Because neonates exposed to SGAs or FGAs in the last gestational week are at higher risk of postnatal disorders, delivery should be planned in clinics with neonatal intensive care units. PMID:23764684

  6. Cohort Profile: Wisconsin longitudinal study (WLS)

    PubMed Central

    Herd, Pamela; Carr, Deborah; Roan, Carol

    2014-01-01

    The Wisconsin Longitudinal Study (WLS) is a longitudinal study of men and women who graduated from Wisconsin high schools in 1957 and one of their randomly selected siblings. Wisconsin is located in the upper midwest of the United States and had a population of approximately 14 000 000 in 1957, making it the 14th most populous state at that time. Data spanning almost 60 years allow researchers to link family background, adolescent characteristics, educational experiences, employment experiences, income, wealth, family formation and social and religious engagement to midlife and late-life physical health, mental health, psychological well-being, cognition, end of life planning and mortality. The WLS is one of the few longitudinal data sets that include an administrative measure of cognition from childhood. Further, recently collected saliva samples allow researchers to explore the inter-relationships among genes, behaviours and environment, including genetic determinants of behaviours (e.g. educational attainment); the interactions between genes and environment; and how these interactions predict behaviours. Most panel members were born in 1939, and the sample is broadly representative of White, non-Hispanic American men and women who have completed at least a high school education. Siblings cover several adjoining cohorts: they were born primarily between 1930 and 1948. At each interview, about two-thirds of the sample lived in Wisconsin, and about one-third lived elsewhere in the United States or abroad. The data, along with documentation, are publicly accessible and can be accessed at http://www.ssc.wisc.edu/wlsresearch/. Requests for protected data or assistance should be sent to wls@ssc.wisc.edu. PMID:24585852

  7. Cohort Profile: The French Childhood Cancer Survivor Study For Leukaemia (LEA Cohort)

    PubMed Central

    Berbis, Julie; Michel, Gérard; Baruchel, André; Bertrand, Yves; Chastagner, Pascal; Demeocq, François; Kanold, Justyna; Leverger, Guy; Plantaz, Dominique; Poirée, Marilyne; Stephan, Jean-Louis; Auquier, Pascal; Contet, Audrey; Dalle, Jean-Hugues; Ducassou, Stéphane; Gandemer, Virginie; Lutz, Patrick; Sirvent, Nicolas; Tabone, Marie-Dominique; Thouvenin-Doulet, Sandrine

    2015-01-01

    The main aim of the Leucémies de l’Enfant et l’Adolescent (LEA) project (Childhood and Adolescent Leukaemia) is to study the determinants (medical, socioeconomic, behavioural and environmental) of medium- and long-term outcomes of patients treated for childhood acute leukaemia (AL). The LEA study began in 2004 and is based on a French multicentric prospective cohort. Included are children treated for AL since January 1980 (incident and prevalent cases), surviving at month 24 for myeloblastic AL and lymphoblastic AL grafted in first complete remission or at month 48 for lymphoblastic AL not grafted in first complete remission. Information is collected during specific medical visits and notably includes the following data: socioeconomic data, AL history, physical late effects (such as fertility, cardiac function and metabolic syndrome) and quality of life. Data are collected every 2 years until the patient is 20 years old and has had a 10-year follow-up duration from diagnosis or last relapse. Thereafter, assessments are planned every 4 years. In active centres in 2013, eligible patients number more than 3000. The cohort has already included 2385 survivors, with rate of exhaustiveness of almost 80%. Data access can be requested from principal coordinators and must be approved by the steering committee. PMID:24639445

  8. 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…

  9. Draft Cohort Default Rate Guide for FFEL Program and Direct Loan Program Loans, FY 1999.

    ERIC Educational Resources Information Center

    Department of Education, Washington, DC. Default Management Div.

    This publication is intended to help postsecondary schools understand FY 1999 draft cohort default rate data. It explains how the Department of Education calculates cohort default rates, the effect of cohort default rates, and how to read the cohort default rate loan record detail reports. Also, it reviews electronic reports available from the…

  10. Draft Cohort Default Rate Guide for FFEL Program and Direct Loan Program Loans, FY 1998.

    ERIC Educational Resources Information Center

    Department of Education, Washington, DC. Default Management Div.

    This publication is intended to help postsecondary schools understand draft cohort default rate data. It explains how the Department of Education calculates cohort default rates, the effect of cohort default rates, and how to read cohort default rate loan record detail reports. Also, it reviews electronic reports available from the Department of…

  11. Cohort shifts in the timing of births in Ghana.

    PubMed

    Oheneba-sakyi, Y

    1989-01-01

    A comparison of cohorts of ever-married Chanaian women suggests evidence of a fertility transition beginning among younger women and select subgroups. Ghana's crude birth rate declined from a high of 50/1000 population in 1970 to 38.8/1000 in 1985. To ascertain whether marital fertility is now being controlled through conscious attempts to lengthen birth intervals, World Fertility Survey data from 1979-80 on the timing of births among different birth cohorts were analyzed. It was hypothesized that, as a result of the influence of Western values that stress independence from parents and the introduction of compulsory education, cohorts of the mid-1950s and 1960s would be more likely to postpone childbearing, more active in the modern sector of the economy, and more accepting of modern contraceptive usage for birth spacing than women in the 1930-39, 1940-49, and 1950-59 cohorts. For the 1940-49 cohort, it took 10.8 months for 25% to have a birth following 1st marriage, 18.7 months for 50% to have a 1st birth, and 27.4 months for 75% to complete this step. By comparison, these figures for the 1955-64 birth cohort were 9.9, 16.7, and 20.5 months, respectively. The significantly shorter (p 0.01) interval between marriage and 1st birth found among younger women in part reflects rising age at marriage; mean age at 1st marriage was 17.9 years for the 1940 cohort and 21.6 years for the most recent cohort. After the birth of the 1st child, recent cohorts were more likely to wait longer for the 2nd birth. For women born in 1950-64, it took 21.8, 36.7, and 44.6 months for 25%, 50%, and 75%, respectively, to reach parity 2. This pattern of lengthened birth interval beyond the 1st birth was apparent at all parities in the youngest cohort and indicates increasing acceptance of contraception among those who have come of age during a period of rapid social change. PMID:12342944

  12. A cohort study of bacteremic pneumonia

    PubMed Central

    Guillamet, Cristina Vazquez; Vazquez, Rodrigo; Noe, Jonas; Micek, Scott T.; Kollef, Marin H.

    2016-01-01

    Abstract Bacteremic pneumonia is usually associated with greater mortality. However, risk factors associated with hospital mortality in bacteremic pneumonia are inadequately described. The study was a retrospective cohort study, conducted in Barnes-Jewish Hospital (2008–2015). For purposes of this investigation, antibiotic susceptibility was determined according to ceftriaxone susceptibility, as ceftriaxone represents the antimicrobial agent most frequently recommended for hospitalized patients with community-acquired pneumonia as opposed to nosocomial pneumonia. Two multivariable analyses were planned: the first model included resistance to ceftriaxone as a variable, whereas the second model included the various antibiotic-resistant species (methicillin-resistant Staphylococcus aureus, Pseudomonas aeruginosa, and Enterobacteriaceae). In all, 1031 consecutive patients with bacteremic pneumonia (mortality 37.1%) were included. The most common pathogens associated with infection were S aureus (34.1%; methicillin resistance 54.0%), Enterobacteriaceae (28.0%), P aeruginosa (10.6%), anaerobic bacteria (7.3%), and Streptococcus pneumoniae (5.6%). Compared with ceftriaxone-susceptible pathogens (46.8%), ceftriaxone-resistant pathogens (53.2%) were significantly more likely to receive inappropriate initial antibiotic treatment (IIAT) (27.9% vs 7.1%; P < 0.001) and to die during hospitalization (41.5% vs 32.0%; P = 0.001). The first logistic regression analysis identified IIAT with the greatest odds ratio (OR) for mortality (OR 2.2, 95% confidence interval [CI] 1.5–3.2, P < 0.001). Other independent predictors of mortality included age, mechanical ventilation, immune suppression, prior hospitalization, prior antibiotic administration, septic shock, comorbid conditions, and severity of illness. In the second multivariable analysis that included the antibiotic-resistant species, IIAT was still associated with excess mortality, and P aeruginosa infection was

  13. Cohort Estimates of Nonmarital Fertility for U.S. Women

    PubMed Central

    WU, LAWRENCE L.

    2008-01-01

    Historical trends in U.S. nonmarital fertility have been compiled almost exclusively from vital statistics on births. This paper complements this historical record by providing cohort estimates of nonmarital fertility for cohorts of U.S. women spanning approximately 50 years of cohort experience. Life table estimates using retrospective marital and fertility histories in the June 1980, 1985, 1990, and 1995 Current Population Surveys reveal nonnegligible levels of nonmarital fertility historically. For women born between 1925 and 1929, nearly 1 in 10 had at least one nonmarital birth by age 30. For women born between 1965 and 1969, more than 1 of 4 had one or more nonmarital births by age 30, with roughly 1 of 5 white, 3 of 5 black, and 1 in 3 Hispanic women having at least one nonmarital birth by age 30. Life table estimates reveal a twofold increase between ages 20 and 30 in the percentage of women with at least one child outside of formal marriage for all cohorts of white and Hispanic women, and an increase of roughly two-thirds for all cohorts of black women. I also document qualitative differences in nonmarital fertility by race/ethnicity, with the percentage of nonmarital births following a divorce or marital separation for white women approximately twice that for black or Hispanic women. Finally, I introduce a new measure, the cohort nonmarital fertility ratio (CNMFR), which provides a cohort complement to the standard period nonmarital fertility ratio. Conservative estimates reveal a roughly threefold increase in the CNMFR for women born from 1925–1929 to 1950–1954 for both whites and blacks, despite substantially higher levels of nonmarital fertility among black women. Overall, these findings reveal surprisingly high levels of nonmarital fertility for women born since the 1920s and confirm that nonmarital fertility has become an increasingly substantial component of overall U.S. fertility. PMID:18390299

  14. Monte Carlo estimation of stage structured development from cohort data.

    PubMed

    Knape, Jonas; De Valpine, Perry

    2016-04-01

    Cohort data are frequently collected to study stage-structured development and mortalities of many organisms, particularly arthropods. Such data can provide information on mean stage durations, among-individual variation in stage durations, and on mortality rates. Current statistical methods for cohort data lack flexibility in the specification of stage duration distributions and mortality rates. In this paper, we present a new method for fitting models of stage-duration distributions and mortality to cohort data. The method is based on a Monte Carlo within MCMC algorithm and provides Bayesian estimates of parameters of stage-structured cohort models. The algorithm is computationally demanding but allows for flexible specifications of stage-duration distributions and mortality rates. We illustrate the algorithm with an application to data from a previously published experiment on the development of brine shrimp from Mono Lake, California, through nine successive stages. In the experiment, three different food supply and temperature combination treatments were studied. We compare the mean duration of the stages among the treatments while simultaneously estimating mortality rates and among-individual variance of stage durations. The method promises to enable more detailed studies of development of both natural and experimental cohorts. An R package implementing the method and which allows flexible specification of stage duration distributions is provided. PMID:27220215

  15. Studies on the extended Techa river cohort: cancer risk estimation

    SciTech Connect

    Kossenko, M M.; Preston, D L.; Krestinina, L Y.; Degteva, M O.; Startsev, N V.; Thomas, T; Vyushkova, O V.; Anspaugh, L R.; Napier, Bruce A. ); Kozheurov, V P.; Ron, E; Akleyev, A V.

    2001-12-01

    Initial population-based studies of riverside residents were begun in the late 1950s and in 1967 a systematic effort was undertaken to develop a well-defined fixed cohort of Techa river residents, to carry out ongoing mortality and (limited) clinical follow-up of this cohort, and to provide individualized dose estimates for cohort members. Over the past decade, extensive efforts have been made to refine the cohort definition and improve both the follow-up and dosimetry data. Analyses of the Techa river cohort can provide useful quantitative estimates of the effects of low dose rate, chronic external and internal exposures on cancer mortality and incidence and non-cancer mortality rates. These risk estimates complement quantitative risk estimates for acute exposures based on the atomic bomb survivors and chronic exposure risk estimates from worker studies, including Mayak workers and other groups with occupational radiation exposures. As the dosimetry and follow-up are refined it may also be possible to gain useful insights into risks associated with 90Sr exposures.

  16. Cohort Profile Update: The TRacking Adolescents’ Individual Lives Survey (TRAILS)

    PubMed Central

    Oldehinkel, Albertine J; Rosmalen, Judith GM; Buitelaar, Jan K; Hoek, Hans W; Ormel, Johan; Raven, Dennis; Reijneveld, Sijmen A; Veenstra, René; Verhulst, Frank C; Vollebergh, Wilma AM; Hartman, Catharina A

    2015-01-01

    TRAILS consists of a population cohort (N = 2230) and a clinical cohort (N = 543), both of which were followed from about age 11 years onwards. To date, the population cohort has been assessed five times over a period of 11 years, with retention rates ranging between 80% and 96%. The clinical cohort has been assessed four times over a period of 8 years, with retention rates ranging between 77% and 85%. Since the IJE published a cohort profile on the TRAILS in 2008, the participants have matured from adolescents into young adults. The focus shifted from parents and school to entry into the labour market and family formation, including offspring. Furthermore, psychiatric diagnostic interviews were administered, the database was linked to a Psychiatric Case Registry, and the availability of genome-wide SNP variations opened the door to genome-wide association studies regarding a wide range of (endo)phenotypes. With some delay, TRAILS data are available to researchers outside the TRAILS consortium without costs; access can be obtained by submitting a publication proposal (see www.trails.nl). PMID:25431468

  17. Asbestos and cancer: a cohort followed up to death.

    PubMed Central

    Enterline, P E; Hartley, J; Henderson, V

    1987-01-01

    The mortality experience of 1074 white men who retired from a United States asbestos company during the period 1941-67 and who were exposed to asbestos working as production and maintenance employees for the company is reported to the end of 1980 when 88% of this cohort was known to be dead. As noted in earlier reports the mortality for respiratory and gastrointestinal cancer was raised. A more detailed examination of causes of death shows that the excess in gastrointestinal cancer was largely due to a statistically significant excess in stomach cancer. A statistically significant excess was also noted for kidney cancer, cancer of the eye, and non-malignant respiratory disease. Eight deaths from malignant mesothelioma were observed, two of which were peritoneal. Asbestos exposures for these mesothelioma cases were low relative to other members of the cohort. Continuing follow up of this cohort shows a dose response relation for respiratory cancer that has become increasingly linear. Standardised mortality ratios peaked 10 to 15 years after retirement and were relatively constant at around 250 in each five year interval starting in 1950. This excess might have been detected as early as 1960 but certainly by 1965. The mortality experience of this cohort reflects the ultimate effects of asbestos since nearly all of the cohort has now died. PMID:3606968

  18. Endogenous hormones and breast cancer: a prospective cohort study.

    PubMed

    Toniolo, P G; Pasternack, B S; Shore, R E; Sonnenschein, E; Koenig, K L; Rosenberg, C; Strax, P; Strax, S

    1991-05-01

    A cohort study is under way in New York City to evaluate how levels of endogenous reproductive hormones influence the risk of breast cancer. The study, in which approximately 15,000 women are being recruited, utilizes a prospective design in which volunteers are asked to provide repeated specimens of serum during the period 1985-1992. A case-control study nested within the cohort is planned by which specimens from all cases arising in the population and from a randomly selected sample of time-matched controls will be analyzed and compared. As of December 31, 1989, 13,609 volunteers had donated blood specimens, about 50% of whom had already donated more than once. Of the 187 incident breast cancer cases who are expected to arise in the cohort before the end of 1992, 77 have been detected thus far. PMID:1873553

  19. The Effects of Multiple Reformed Courses on Freshman Cohorts

    NASA Astrophysics Data System (ADS)

    Lynch, Robert B.; West, Emily A.; Potter, Wendell H.

    2010-02-01

    Beginning fall 2007 successive 48-student cohorts of entering freshmen bio-science majors have been enrolled in reformed course sections to test the proposition that students who were exposed simultaneously to both math and science courses, which explicitly stress sense-making rather than memorization, would more quickly develop habits of mind and approaches to learning that are more productive and useful than the memorization mindset that is so typical of entering freshmen. Preliminary results show positive performance gains of the cohort students in subsequent courses. Variations in the sequence of course offerings has allowed the separate analysis of the impact of taking a radically reformed physics course even on immediately following science courses in the freshman year. Longitudinal performance data through fall-quarter 2009 for cohorts entering in 2007 and 2008 will be presented as well as qualitative interview and survey data. )

  20. Systematically missing confounders in individual participant data meta-analysis of observational cohort studies.

    PubMed

    Jackson, Dan; White, Ian; Kostis, J B; Wilson, A C; Folsom, A R; Wu, K; Chambless, L; Benderly, M; Goldbourt, U; Willeit, J; Kiechl, S; Yarnell, J W G; Sweetnam, P M; Elwood, P C; Cushman, M; Psaty, B M; Tracy, R P; Tybjaerg-Hansen, A; Haverkate, F; de Maat, M P M; Thompson, S G; Fowkes, F G R; Lee, A J; Smith, F B; Salomaa, V; Harald, K; Rasi, V; Vahtera, E; Jousilahti, P; D'Agostino, R; Kannel, W B; Wilson, P W F; Tofler, G; Levy, D; Marchioli, R; Valagussa, F; Rosengren, A; Wilhelmsen, L; Lappas, G; Eriksson, H; Cremer, P; Nagel, D; Curb, J D; Rodriguez, B; Yano, K; Salonen, J T; Nyyssönen, K; Tuomainen, T-P; Hedblad, B; Engström, G; Berglund, G; Loewel, H; Koenig, W; Hense, H W; Meade, T W; Cooper, J A; De Stavola, B; Knottenbelt, C; Miller, G J; Cooper, J A; Bauer, K A; Rosenberg, R D; Sato, S; Kitamura, A; Naito, Y; Iso, H; Salomaa, V; Harald, K; Rasi, V; Vahtera, E; Jousilahti, P; Palosuo, T; Ducimetiere, P; Amouyel, P; Arveiler, D; Evans, A E; Ferrieres, J; Juhan-Vague, I; Bingham, A; Schulte, H; Assmann, G; Cantin, B; Lamarche, B; Despres, J-P; Dagenais, G R; Tunstall-Pedoe, H; Lowe, G D O; Woodward, M; Ben-Shlomo, Y; Davey Smith, G; Palmieri, V; Yeh, J L; Meade, T W; Rudnicka, A; Brennan, P; Knottenbelt, C; Cooper, J A; Ridker, P; Rodeghiero, F; Tosetto, A; Shepherd, J; Lowe, G D O; Ford, I; Robertson, M; Brunner, E; Shipley, M; Feskens, E J M; Di Angelantonio, E; Kaptoge, S; Lewington, S; Lowe, G D O; Sarwar, N; Thompson, S G; Walker, M; Watson, S; White, I R; Wood, A M; Danesh, J

    2009-04-15

    One difficulty in performing meta-analyses of observational cohort studies is that the availability of confounders may vary between cohorts, so that some cohorts provide fully adjusted analyses while others only provide partially adjusted analyses. Commonly, analyses of the association between an exposure and disease either are restricted to cohorts with full confounder information, or use all cohorts but do not fully adjust for confounding. We propose using a bivariate random-effects meta-analysis model to use information from all available cohorts while still adjusting for all the potential confounders. Our method uses both the fully adjusted and the partially adjusted estimated effects in the cohorts with full confounder information, together with an estimate of their within-cohort correlation. The method is applied to estimate the association between fibrinogen level and coronary heart disease incidence using data from 154,012 participants in 31 cohorts PMID:19222087

  1. Smoking and psychopathology increasingly associated in recent birth cohorts*

    PubMed Central

    Talati, Ardesheer; Wickramaratne, Priya J; Keyes, Katherine M; Hasin, Deborah S; Levin, Frances R; Weissman, Myrna M.

    2013-01-01

    Background: In recent decades, smoking has become an increasingly non-normative behavior. Because deviant behaviors are associated with greater clinical and genetic risks, current-generation smokers may have greater concentrations of psychiatric comorbidity than previous generations. We examined this question empirically by testing whether associations between measures of smoking, psychiatric diagnoses, and riskassociated personality traits, increased across seven birth-cohorts of the 20th century. Method: 4,326 subjects from a cross-sectional NIMH control sample were categorized into one of seven groups based on birth (born before 1930, and 1930s-‘80s) and one of three smoking levels (lifetime dependent smoker, never dependent smoker, never smoker smoking and ND were assessed using the Fagerstrom Test for Nicotine Dependence; psychiatric diagnoses (drug and alcohol dependence, major depression, and generalized anxiety disorder) using the Composite International Diagnostic Interview-Short Form, and personality traits (neuroticism and extraversion) with the Eysenck Personality Questionnaire. Result: Lifetime prevalence of smoking decreased across the seven cohorts. Associations between smoking and drug dependence, generalized anxiety, and neuroticism, as well as total psychiatric comorbidity, were greater in more recent cohorts [smoking-by-cohort interaction: p<0.01], with greatest increases contributed by nicotine-dependent smokers. Smoking was also independently associated with alcohol dependence and depression, but these associations did not significantly vary across cohorts. Conclusions: More recent generations included fewer persons who smoked, but their smoking was associated with greater psychiatric morbidity. Failure to account for systematic variation in comorbidity across smoking cohorts may lead to unwanted heterogeneity in clinical, and possibly genetic, studies of nicotine dependence. PMID:24071570

  2. Longitudinal patterns of enrollment and expenditures for a Medicaid cohort

    PubMed Central

    Howell, Embry M.; Andrews, Roxanne M.; Gornick, Marian

    1988-01-01

    This article is based on 4 years of data for a cohort of Medicaid enrollees in California and Georgia to determine patterns of enrollment and expenditures. The analyses were developed from the statistical system known as Tape-to-Tape, which is based on Medicaid enrollment and claims files from these and other States. The composition of the cohort changed over time as a result of the differential rates of turnover for subgroups of the Medicaid population. Longitudinal expenditure patterns also varied by health service and eligibility group. These Medicaid expenditure patterns differed from those observed previously in Medicare studies, undoubtedly reflecting differences in service coverage under Medicare and Medicaid. PMID:10312822

  3. Data linkage in an established longitudinal cohort: the Western Australian Pregnancy Cohort (Raine) Study.

    PubMed

    Mountain, Jenny A; Nyaradi, Anett; Oddy, Wendy H; Glauert, Rebecca A; de Klerk, Nick H; Straker, Leon M; Stanley, Fiona J

    2016-01-01

    The Western Australian Data Linkage System is one of a few comprehensive, population-based data linkage systems worldwide, creating links between information from different sources relating to the same individual, family, place or event, while maintaining privacy. The Raine Study is an established cohort study with more than 2000 currently active participants. Individual consent was obtained from participants for information in publicly held databases to be linked to their study data. A waiver of consent was granted where it was impracticable to obtain consent. Approvals to link the datasets were obtained from relevant ethics committees and data custodians. The Raine Study dataset was subsequently linked to academic testing data collected by the Western Australian Department of Education. Examination of diet and academic performance showed that children who were predominantly breastfed for at least 6 months scored higher academically at age 10 than children who were breastfed for less than 6 months. A further study found that better diet quality at ages 1, 2 and 3 years was associated with higher academic scores at ages 10 and 12 years. Examination of nutritional intake at 14 years of age found that a better dietary pattern was associated with higher academic performance. The detailed longitudinal data collected in the Raine Study allowed for adjustment for multiple covariates and confounders. Data linkage reduces the burden on cohort participants by providing additional information without the need to contact participants. It can give information on participants who have been lost to follow-up; provide or complement missing data; give the opportunity for validation studies comparing recall of participants with administrative records; increase the population sample of studies by adding control participants from the general population; and allow for the adjustment of multiple covariates and confounders. The Raine Study dataset is extensive and detailed, and can be

  4. MILLARD COUNTY, UTAH, DRINKING WATER ARSENIC COHORT STUDY

    EPA Science Inventory

    Assembly of the cohort is based on historic membership records of members of the Church of Jesus Christ of Latter-Day Saints (LDS) in an area of Millard County, Utah, which is located in the central western part of the state. Personal information including name, birth date, town ...

  5. Exposure Assessment in Cohort Studies of Childhood Asthma

    PubMed Central

    Arrandale, Victoria H.; Brauer, Michael; Brook, Jeffrey R.; Brunekreef, Bert; Gold, Diane R.; London, Stephanie J.; Miller, J. David; Özkaynak, Halûk; Ries, Nola M.; Sears, Malcolm R.; Silverman, Frances S.; Takaro, Tim K.

    2011-01-01

    Background The environment is suspected to play an important role in the development of childhood asthma. Cohort studies are a powerful observational design for studying exposure–response relationships, but their power depends in part upon the accuracy of the exposure assessment. Objective The purpose of this paper is to summarize and discuss issues that make accurate exposure assessment a challenge and to suggest strategies for improving exposure assessment in longitudinal cohort studies of childhood asthma and allergies. Data synthesis Exposures of interest need to be prioritized, because a single study cannot measure all potentially relevant exposures. Hypotheses need to be based on proposed mechanisms, critical time windows for effects, prior knowledge of physical, physiologic, and immunologic development, as well as genetic pathways potentially influenced by the exposures. Modifiable exposures are most important from the public health perspective. Given the interest in evaluating gene–environment interactions, large cohort sizes are required, and planning for data pooling across independent studies is critical. Collection of additional samples, possibly through subject participation, will permit secondary analyses. Models combining air quality, environmental, and dose data provide exposure estimates across large cohorts but can still be improved. Conclusions Exposure is best characterized through a combination of information sources. Improving exposure assessment is critical for reducing measurement error and increasing power, which increase confidence in characterization of children at risk, leading to improved health outcomes. PMID:21081299

  6. Student Cohorts in Teacher Education: Support Groups or Intellectual Communities?

    ERIC Educational Resources Information Center

    Seifert, Kelvin; Mandzuk, David

    2006-01-01

    Recent initiatives in preservice teacher education have experimented with cohorts as a way to create supportive ties among peers, mutual intellectual support, and a sense of professionalism. The initiatives reflect a belief in collaboration, one expressed in educational literature supporting related forms of collaboration in education, such as…

  7. DRINKING WATER ARSENIC IN UTAH: A COHORT MORTALITY STUDY

    EPA Science Inventory

    The association of drinking water arsenic and mortality outcome was investigated in a cohort of residents from Millard County, Utah. Median drinking water arsenic concentrations for selected study towns ranged from 14 to 166 ppb and were from public and private samples collected ...

  8. [Mortality in a cohort of asbestos cement workers in Bari].

    PubMed

    Coviello, Vincenzo; Carbonara, Monica; Bisceglia, Lucia; Di Pierri, Carmela; Ferri, Giovanni M; Lo Izzo, Antonio; Porro, Antonio; Sivo, Donato; Assennato, Giorgio

    2002-01-01

    The study describes the mortality of 417 workers employed in a asbestos-cement plant, located in Bari, Puglia, Southern Italy. Follow up started on February 1st 1972. The vital status and cause of death were ascertained at 1995. The mortality experience of the Apulian population was used as comparison. Using 90% confidence limits (CLs), a significant increase in mortality was observed in our cohort from: all causes of death (SMR 118, CL 100-139), pneumoconiosis (SMR 14810, CL 10298-20683), all types of cancer (SMR 139, CL 105-181), lung (SMR 191, CL 126-277), pleural (SMR 1560 CL 431-4081) and peritoneum (SMR 1705, CL 303-5367) malignant neoplasms. In our cohort, the discrepancy between observed and expected mortality for lung and pleural cancer occurred 30 years after the first exposure, after 40 years for all neoplasms and peritoneum cancer. Under the Cox regression model, lung cancer SMR showed a curvilinear trend along time since first exposure, the peak being detected at 35 years. Finally, SMRs from our cohort were compared to a previously described cohort including workers from the same plant compensated for asbestosis by INAIL. PMID:12125387

  9. Working Adults in Accelerated Cohorts: More than a Learning Community

    ERIC Educational Resources Information Center

    Spaid, Robin; Duff, Evan D.

    2009-01-01

    There are 54 million working adults in the United States without bachelor's degrees (Pusser et al., 2007). Many would like to obtain a college degree but need an educational program that fits their needs. A viable alternative to a traditional college program is an accelerated program in a cohort format. This article highlights best practices for…

  10. MMed cohort supervision: A path out of the swamp?

    PubMed

    Rout, C; Sommerville, T; Aldous, C

    2015-04-01

    The authors present the case for collaborative cohort supervision (CCM), including both master's students and novice supervisors, as a possible way to rapidly increase the number of supervisors needed to address the recent implementation of a compulsory research component to specialist registration with the Health Professions Council of South Africa. Different models of CCM are discussed and possible pitfalls highlighted. PMID:26294866

  11. Investing in Prospective Cohorts for Etiologic Study of Occupational Exposures

    EPA Science Inventory

    Prospective cohorts have played a major role in understanding the role of diet, physical activity, medical conditions, and genes in the development of many diseases, but have not been widely used in the study of occupational exposures. Studies in agriculture are an exception. W...

  12. Pressing On: Persistence through a Doctoral Cohort Program in Education

    ERIC Educational Resources Information Center

    Santicola, Leslie

    2013-01-01

    The focus of this research was to investigate the characteristics that led to persistence in a doctoral cohort program of study. The significance of this study is to provide insights into the specific aspects of the individuals that made them successful in an intensive program. A phenomenological case study approach, utilizing a comprehensive…

  13. Using a Hybrid Approach for a Leadership Cohort Program

    ERIC Educational Resources Information Center

    Norman, Maxine A.

    2013-01-01

    Because information technology continues to change rapidly, Extension is challenged with learning and using technology appropriately. We assert Extension cannot shy away from the challenges but must embrace technology because audiences and external forces demand it. A hybrid, or blended, format of a leadership cohort program was offered to public…

  14. Realising e-Learning Matters in a Bioscience Cohort

    ERIC Educational Resources Information Center

    Parry, Damian; Larsen, Carl; Marwood, Simon; Walsh, Cathy

    2007-01-01

    The use of blended learning, face-to-face contact alongside e-based activities, provides academic staff with an opportunity to match their teaching strategies with the changing student cohort. This study report students' perceptions of e-learning activities early in bioscience modules; students from all three levels of undergraduate study were…

  15. Socioeconomic Status and Injury in a Cohort of Saskatchewan Farmers

    ERIC Educational Resources Information Center

    Pickett, William; Day, Andrew G.; Hagel, Louise; Sun, Xiaoqun; Day, Lesley; Marlenga, Barbara; Brison, Robert J.; Pahwa, Punam; Crowe, Trever; Voaklander, Donald C.; Dosman, James

    2011-01-01

    Purpose: To estimate the strength of relationships between socioeconomic status and injury in a large Canadian farm population. Methods: We conducted a prospective cohort study of 4,769 people from 2,043 farms in Saskatchewan, Canada. Participants reported socioeconomic exposures in 2007 and were followed for the occurrence of injury through 2009…

  16. Cohort follow-up: the 21st century procedures.

    PubMed

    Bahr, Debra E; Hughes, Therese; Aldrich, Timothy E; Silver, Kenneth Z; Brion, Gall M

    2009-01-01

    The basic logic of designing an occupational cohort study has changed little since William R. Gaffey outlined the issues of follow-up, measurement of exposure, and analysis of data. However, many new avenues of tracking workers for epidemiological studies have been developed since Gaffey wrote his paper in 1973. Many disease registries also perform follow-up of subjects for vital status determination, so the procedures used with this process are common to the two applications. This article speaks to cohort construction for this occupational research as well as describes the 2007 methods for vital status follow-up. Rises in concern about work-related disease risks and the scientific resources for performing these studies coincided with the computer revolution. Government and private sources of data on vital status have changed in several ways over the 35 years since Gaffey's seminal paper. Some systems make the process of follow-up more rapid and productive, and some barriers have been imposed as societal concerns for privacy have risen. We describe the process of linking 5 sources of data to compile a roster of 6,820 workers employed at the Paducah Gaseous Diffusion Plant from 1953 to 2003. The record linkage processes achieved a final death cohort of 1672 deaths--the ascertainment of these deaths (by time period) was 1379 (1979-2003) and 293 (1953-1978); follow-up then was 100% for this cohort. PMID:19670694

  17. 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…

  18. Cohort Size and Migration in a West Indian Population.

    ERIC Educational Resources Information Center

    Brittain, Ann W.

    1990-01-01

    Data from St. Barthelemy (French West Indies) show that, for people born from 1878 to 1967, neither cohort size nor fluctuations in external demands for labor had a lasting effect on the probability of eventual migration. Emigration slowed only after development of local tourism brought prosperity to the island. (AF)

  19. RISK FACTORS FOR ENDEMIC GASTROINTESTINAL ILLNESS AMONG A WASHINGTON COHORT

    EPA Science Inventory

    RISK FACTORS FOR ENDEMIC GASTROINTESTINAL ILLNESS AMONG A WASHINGTON COHORT

    *Christina A. Peterson 1,2,3 and Rebecca L. Calderon 2

    1 Department of Epidemiology
    School of Public Health (SPH)
    University of North Carolina at Chapel Hill (UNC-CH), 27516
    2 Nat...

  20. The Southern Community Cohort Study: Investigating Health Disparities

    PubMed Central

    Signorello, Lisa B.; Hargreaves, Margaret K.; Blot, William J.

    2010-01-01

    Summary Over 73,700 adults age 40–79, nearly 70% African American, were recruited at community health centers across 12 southeastern states; individual characteristics were recorded and biologic specimens collected at baseline for later follow-up. The Southern Community Cohort Study is a unique national resource for assessing determinants of racial/ethnic differentials in diseases. PMID:20173283

  1. 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

  2. Environmental Variation and Cohort Effects in an Antarctic Predator

    NASA Technical Reports Server (NTRS)

    Garrott, Robert A.; Rotella, Jay J.; Siniff, Donald B.; Parkinson, Claire L.; Stauffer, Glenn E.

    2011-01-01

    Understanding the potential influence of environmental variation experienced by animals during early stages of development on their subsequent demographic performance can contribute to our understanding of population processes and aid in predicting impacts of global climate change on ecosystem functioning. Using data from 4,178 tagged female Weddell seal pups born into 20 different cohorts, and 30 years of observations of the tagged seals, we evaluated the hypothesis that environmental conditions experienced by young seals, either indirectly through maternal effects and/or directly during the initial period of juvenile nutritional independence, have long-term effects on individual demographic performance. We documented an approximately 3-fold difference in the proportion of each cohort that returned to the pupping colonies and produced a pup within the first 10 years after birth. We found only weak evidence for a correlation between annual environmental conditions during the juvenile-independence period and cohort recruitment probability. Instead, the data strongly supported an association between cohort recruitment probability and the regional extent of sea ice experienced by the mother during the winter the pup was in utero. We suggest that inter-annual variation in winter sea-ice extent influences the foraging success of pregnant seals by moderating the regional abundance of competing predators that cannot occupy areas of consolidated sea ice, and by directly influencing the abundance of mid-trophic prey species that are sea-ice obligates. We hypothesize that this environmentally-induced variation in maternal nutrition dictates the extent of maternal energetic investment in offspring, resulting in cohort variation in mean size of pups at weaning which, in turn, contributes to an individual?s phenotype and its ultimate fitness. These linkages between sea ice and trophic dynamics, combined with demonstrated and predicted changes in the duration and extent of sea

  3. The Lisbon Cohort of men who have sex with men

    PubMed Central

    Meireles, Paula; Lucas, Raquel; Martins, Ana; Carvalho, Ana Cláudia; Fuertes, Ricardo; Brito, João; Campos, Maria José; Mendão, Luís; Barros, Henrique

    2015-01-01

    Purpose Newly diagnosed HIV infections among men who have sex with men (MSM) are rising in many European countries. Surveillance tools must be tailored to the current state of the epidemic, and include decentralised prospective monitoring of HIV incidence and behavioural changes in key populations. In this scenario, an open prospective cohort study was assembled—The Lisbon Cohort of MSM—aiming to dynamically monitor the frequency of disease and its predictors. Participants The Lisbon Cohort of MSM is an ongoing observational prospective study conducted at a community-based voluntary HIV counselling and testing centre in Lisbon, Portugal (CheckpointLX). Men testing negative for HIV, aged 18 or over and reporting having had sex with men are invited to follow-up visits every 6 months. At each evaluation, a face-to-face interview using a structured questionnaire is conducted, and HIV and syphilis rapid tests are performed by trained peer counsellors. From April 2011 to February 2014, 3106 MSM were eligible to the cohort of whom 923 (29.7%) did not participate. The remaining 2183 (70.3%) MSM were enrolled and 804 had at least one follow-up evaluation, for a total of 893 person-years of observation. Future plans The study findings will be disseminated in peer-reviewed journals and presented at national and international conferences. The follow-up of this cohort of HIV-negative MSM will be a valuable tool for monitoring HIV incidence in a setting where limited prospective information existed. Moreover, it will allow for a deeper analytical approach to the study of population time trends and individual changes in risk factors that currently shape the HIV epidemic among MSM. PMID:25967995

  4. Epilepsy in adults with mitochondrial disease: A cohort study

    PubMed Central

    Devine, Helen E.; Gorman, Grainne S.; Schaefer, Andrew M.; Horvath, Rita; Ng, Yi; Nesbitt, Victoria; Lax, Nichola Z.; McFarland, Robert; Cunningham, Mark O.; Taylor, Robert W.; Turnbull, Douglass M.

    2015-01-01

    Objective The aim of this work was to determine the prevalence and progression of epilepsy in adult patients with mitochondrial disease. Methods We prospectively recruited a cohort of 182 consecutive adult patients attending a specialized mitochondrial disease clinic in Newcastle upon Tyne between January 1, 2005 and January 1, 2008. We then followed this cohort over a 7‐year period, recording primary outcome measures of occurrence of first seizure, status epilepticus, stroke‐like episode, and death. Results Overall prevalence of epilepsy in the cohort was 23.1%. Mean age of epilepsy onset was 29.4 years. Prevalence varied widely between genotypes, with several genotypes having no cases of epilepsy, a prevalence of 34.9% in the most common genotype (m.3243A>G mutation), and 92.3% in the m.8344A>G mutation. Among the cohort as a whole, focal seizures, with or without progression to bilateral convulsive seizures, was the most common seizure type. Conversely, all of the patients with the m.8344A>G mutation and epilepsy experienced myoclonic seizures. Patients with the m.3243A>G mutation remain at high risk of developing stroke‐like episodes (1.16% per year). However, although the standardized mortality ratio for the entire cohort was high (2.86), this ratio did not differ significantly between patients with epilepsy (2.96) and those without (2.83). Interpretation Epilepsy is a common manifestation of mitochondrial disease. It develops early in the disease and, in the case of the m.3243A>G mutation, often presents in the context of a stroke‐like episode or status epilepticus. However, epilepsy does not itself appear to contribute to the increased mortality in mitochondrial disease. Ann Neurol 2015;78:949–957 PMID:26381753

  5. Leptospirosis and Peripheral Artery Occlusive Disease: A Nationwide Cohort Analysis.

    PubMed

    Chiu, Chun-Hsiang; Lin, Cheng-Li; Lee, Feng-You; Wang, Ying-Chuan; Kao, Chia-Hung

    2016-03-01

    Data on the association between peripheral artery occlusive disease (PAOD) and leptospirosis are limited. We conducted a retrospective cohort study for determining whether leptospirosis is one of the possible risk factors for PAOD. Patients diagnosed with leptospirosis by using 2000 to 2010 data from the Taiwan National Health Insurance Research Database. Patients with leptospirosis without a history of PAOD were selected. For each leptospirosis patient, 4 controls without a history of leptospirosis and PAOD were randomly selected and frequency-matched for sex, age, the year of the index date, and comorbidity diseases. The follow-up period was from the time of the initial diagnosis of leptospirosis to the diagnosis date of PAOD, or December 31, 2011. The Cox proportional hazard regression models were used for analyzing the risk of PAOD. During the follow-up period, the cumulative incidence of PAOD was higher among the patients from the leptospirosis cohort than among the nonleptospirosis cohort (log-rank test, P < 0.001). In total, 29 patients with PAOD from the leptospirosis cohort and 81 from the nonleptospirosis cohort were observed with the incidence rates of 2.1 and 1.3 per 1000 person-years, respectively, yielding a crude hazards ratio (HR) of 1.62 (95% confidence interval [CI] = 1.44-1.81) and adjusted HR (aHR) of 1.75 (95% CI = 1.58-1.95).The risk of PAOD was 1.75-fold higher in the patients with leptospirosis than in the general population. PMID:26986166

  6. Mysid Population Responses to Resource Limitation Differ from those Predicted by Cohort Studies

    EPA Science Inventory

    Effects of anthropogenic stressors on animal populations are often evaluated by assembling vital rate responses from isolated cohort studies into a single demographic model. However, models constructed from cohort studies are difficult to translate into ecological predictions be...

  7. Review Finds Mixed Success with Hemophilia Treatment

    MedlinePlus

    ... treatment of men with severe forms of the blood-clotting disorder To use the sharing features on this ... of standard of care multidisciplinary services and preventive blood clotting factor treatments to further normalize the lives of ...

  8. Hemophilia Treatments Have Come a Long Way

    MedlinePlus

    ... blood. Today, an increasing number are made using recombinant DNA technology (a form of artificial DNA), with ... Medical Devices Nutrition Radiation-Emitting Products Tobacco Products Vaccines, Blood & Biologics Articulos en Espanol Alimentos y Bebidas ...

  9. [The benefit of large-scale cohort studies for health research: the example of the German National Cohort].

    PubMed

    Ahrens, Wolfgang; Jöckel, K-H

    2015-08-01

    The prospective nature of large-scale epidemiological multi-purpose cohort studies with long observation periods facilitates the search for complex causes of diseases, the analysis of the natural history of diseases and the identification of novel pre-clinical markers of disease. The German National Cohort (GNC) is a population-based, highly standardised and in-depth phenotyped cohort. It shall create the basis for new strategies for risk assessment and identification, early diagnosis and prevention of multifactorial diseases. The GNC is the largest population-based cohort study in Germany to date. In the year 2014 the examination of 200,000 women and men aged 20-69 years started in 18 study centers. The study facilitates the investigation of the etiology of chronic diseases in relation to lifestyle, genetic, socioeconomic, psychosocial and environmental factors. By this the GNC creates the basis for the development of methods for early diagnosis and prevention of these diseases. Cardiovascular and respiratory diseases, cancer, diabetes, neurodegenerative/-psychiatric diseases, musculoskeletal and infectious diseases are in focus of this study. Due to its mere size, the study could be characterized as a Big Data project. We deduce that this is not the case. PMID:26077870

  10. Suicide in Texas: A Cohort Analysis of Trends in Suicide Rates, 1945-1980.

    ERIC Educational Resources Information Center

    Lloyd, Linda; And Others

    1987-01-01

    Used cohort method of analysis to examine teenage suicide in Texas. Beginning with suicide rates for white males aged 15-19 in 1945, suicide rates were calculated and plotted for five-year age cohorts entering late teenage years. Analysis confirmed rising risk factor associated with age group. Cohort patterns for suicide revealed recent…

  11. Comment: Distinguishing Cohort Effects from Age*Period Effects on Non-Marital Fertility

    ERIC Educational Resources Information Center

    Martin, Steve

    2009-01-01

    In the article "Cohort Effects on Non-marital Fertility," in this issue of "Social Forces," Jean Stockard employs a novel strategy for disentangling cohort, period, and age effects on the non-marital fertility ratio. In a model with fixed-effect controls for age and for time period, the author documents evidence for three cohort-specific factors…

  12. 78 FR 18350 - Designation of a Class of Employees for Addition to the Special Exposure Cohort

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-03-26

    ... HUMAN SERVICES Designation of a Class of Employees for Addition to the Special Exposure Cohort AGENCY... an addition to the Special Exposure Cohort (SEC) under the Energy Employees Occupational Illness... of employees included in the Special Exposure Cohort. This designation will become effective on...

  13. Learning Communities or Support Groups: The Use of Student Cohorts in Doctoral Educational Leadership Programs

    ERIC Educational Resources Information Center

    Brown, Christy J.

    2011-01-01

    This mixed-method study explored how students in a doctoral educational leadership cohort at one university used the cohort structure as a learning community or as a method of social support. Survey data were collected from 45 past and present cohort students and qualitative data were collected from three focus groups of 15 participants total. The…

  14. 77 FR 76489 - Designation of a Class of Employees for Addition to the Special Exposure Cohort

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-12-28

    ... HUMAN SERVICES Designation of a Class of Employees for Addition to the Special Exposure Cohort AGENCY... an addition to the Special Exposure Cohort (SEC) under the Energy Employees Occupational Illness... Exposure Cohort. This designation will become effective on January 6, 2013, unless Congress...

  15. 77 FR 58381 - Designation of a Class of Employees for Addition to the Special Exposure Cohort

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-09-20

    ... HUMAN SERVICES Designation of a Class of Employees for Addition to the Special Exposure Cohort AGENCY..., as an addition to the Special Exposure Cohort (SEC) under the Energy Employees Occupational Illness... included in the Special Exposure Cohort. This designation will become effective on September 22,...

  16. 77 FR 9250 - Designation of a Class of Employees for Addition to the Special Exposure Cohort

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-02-16

    ... HUMAN SERVICES Designation of a Class of Employees for Addition to the Special Exposure Cohort AGENCY... Special Exposure Cohort (SEC) under the Energy Employees Occupational Illness Compensation Program Act of... other classes of employees included in the Special Exposure Cohort. This designation will...

  17. 77 FR 58382 - Designation of a Class of Employees for Addition to the Special Exposure Cohort

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-09-20

    ... HUMAN SERVICES Designation of a Class of Employees for Addition to the Special Exposure Cohort AGENCY... Special Exposure Cohort (SEC) under the Energy Employees Occupational Illness Compensation Program Act of... established for one or more other classes of employees included in the Special Exposure Cohort....

  18. 77 FR 76489 - Designation of a Class of Employees for Addition to the Special Exposure Cohort

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-12-28

    ... HUMAN SERVICES Designation of a Class of Employees for Addition to the Special Exposure Cohort AGENCY..., Massachusetts, as an addition to the Special Exposure Cohort (SEC) under the Energy Employees Occupational... Cohort. This designation will become effective on January 6, 2013, unless Congress provides...

  19. 75 FR 22410 - Designation of a Class of Employees for Addition to the Special Exposure Cohort

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-04-28

    ... HUMAN SERVICES Designation of a Class of Employees for Addition to the Special Exposure Cohort AGENCY... Electric Corp., Bloomfield, New Jersey, as an addition to the Special Exposure Cohort (SEC) under the... or more other classes of employees included in the Special Exposure Cohort. This designation...

  20. 34 CFR 674.5 - Federal Perkins Loan program cohort default rate and penalties.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 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 institution's cohort default rate meets the following levels, a default penalty is imposed on the...

  1. 75 FR 22410 - Designation of a Class of Employees for Addition to the Special Exposure Cohort

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-04-28

    ... HUMAN SERVICES Designation of a Class of Employees for Addition to the Special Exposure Cohort AGENCY... Livermore National Laboratory in Livermore, California, as an addition to the Special Exposure Cohort (SEC... of employees in the Special Exposure Cohort. This designation will become effective on May 5,...

  2. 77 FR 58382 - Designation of a Class of Employees for Addition to the Special Exposure Cohort

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-09-20

    ... HUMAN SERVICES Designation of a Class of Employees for Addition to the Special Exposure Cohort AGENCY... Special Exposure Cohort (SEC) under the Energy Employees Occupational Illness Compensation Program Act of... established for one or more other classes of employees in the Special Exposure Cohort. This designation...

  3. Pre-Service Teacher Cohorts: Characteristics and Issues--A Review of the Literature

    ERIC Educational Resources Information Center

    Knorr, Ron

    2012-01-01

    Since their introduction to teacher education programs in the 1980s, teacher education cohorts have become a standard scheme of organization in teacher preparation programs. This literature review notes some common characteristics and issues in cohort operations. Cohorts contain a standard academic core, class scheduling, and timeline to program…

  4. 78 FR 64500 - Designation of a Class of Employees for Addition to the Special Exposure Cohort

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-10-29

    ... HUMAN SERVICES Designation of a Class of Employees for Addition to the Special Exposure Cohort AGENCY... addition to the Special Exposure Cohort (SEC) under the Energy Employees Occupational Illness Compensation... included in the Special Exposure Cohort. This designation will become effective on October 30, 2013,...

  5. 76 FR 28436 - Designation of a Class of Employees for Addition to the Special Exposure Cohort

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-05-17

    ... HUMAN SERVICES Designation of a Class of Employees for Addition to the Special Exposure Cohort AGENCY... Cohort (SEC) under the Energy Employees Occupational Illness Compensation Program Act of 2000. On April... other classes of employees included in the Special Exposure Cohort. This designation will...

  6. 75 FR 22409 - Designation of a Class of Employees for Addition to the Special Exposure Cohort

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-04-28

    ... HUMAN SERVICES Designation of a Class of Employees for Addition to the Special Exposure Cohort AGENCY... the Santa Susana Field Laboratory as an addition to the Special Exposure Cohort (SEC) under the Energy... included in the Special Exposure Cohort. This designation will become effective on May 5, 2010,...

  7. 78 FR 64501 - Designation of a Class of Employees for Addition to the Special Exposure Cohort

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-10-29

    ... HUMAN SERVICES Designation of a Class of Employees for Addition to the Special Exposure Cohort AGENCY... addition to the Special Exposure Cohort (SEC) under the Energy Employees Occupational Illness Compensation... Exposure Cohort. This designation will become effective on October 30, 2013, unless Congress...

  8. 77 FR 32641 - Designation of a Class of Employees for Addition to the Special Exposure Cohort

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-06-01

    ... HUMAN SERVICES Designation of a Class of Employees for Addition to the Special Exposure Cohort AGENCY... the Special Exposure Cohort (SEC) under the Energy Employees Occupational Illness Compensation Program... established for one or more other classes of employees included in the Special Exposure Cohort....

  9. 78 FR 18351 - Designation of a Class of Employees for Addition to the Special Exposure Cohort

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-03-26

    ... HUMAN SERVICES Designation of a Class of Employees for Addition to the Special Exposure Cohort AGENCY... addition to the Special Exposure Cohort (SEC) under the Energy Employees Occupational Illness Compensation... of employees included in the Special Exposure Cohort. This designation will become effective on...

  10. 78 FR 64501 - Designation of a Class of Employees for Addition to the Special Exposure Cohort

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-10-29

    ... HUMAN SERVICES Designation of a Class of Employees for Addition to the Special Exposure Cohort AGENCY... Exposure Cohort (SEC) under the Energy Employees Occupational Illness Compensation Program Act of 2000. On... of employees included in the Special Exposure Cohort. This designation will become effective...

  11. 77 FR 40059 - Designation of a Class of Employees for Addition to the Special Exposure Cohort

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-07-06

    ... HUMAN SERVICES Designation of a Class of Employees for Addition to the Special Exposure Cohort AGENCY... as the Fernald Environmental Management Project (FEMP), as an addition to the Special Exposure Cohort... parameters established for one or more classes of employees included in the Special Exposure Cohort....

  12. Counselors-in-Training Perceptions of Cohort Participation: A Q-Sort

    ERIC Educational Resources Information Center

    Glorfield, Cyndia K.

    2011-01-01

    This study explored master's level counselors-in-training perceptions of participation in a cohort model of education. Although the cohort model of education is widely used, research addressing its use in counselor education is scant. Literature regarding the cohort model of education from a variety of higher education programs was reviewed to…

  13. Cohort Differences in Cognitive Aging and Terminal Decline in the Seattle Longitudinal Study

    ERIC Educational Resources Information Center

    Gerstorf, Denis; Ram, Nilam; Hoppmann, Christiane; Willis, Sherry L.; Schaie, K. Warner

    2011-01-01

    Life span researchers have long been interested in how and why fundamental aspects of human ontogeny differ between cohorts of people who have lived through different historical epochs. When examined at the same age, later born cohorts are often cognitively and physically fitter than earlier born cohorts. Less is known, however, about cohort…

  14. Race Differences in Cohort Effects on Non-Marital Fertility in the United States

    ERIC Educational Resources Information Center

    Stockard, Jean; Gray, Jo Anna; O'Brien, Robert; Stone, Joe

    2009-01-01

    We employ newly developed methods to disentangle age, period and cohort effects on non-marital fertility ratios from 1972 through 2002 for black and white women ages 20-44 in the United States. We focus on three cohort factors: family structure, school enrollment and the sex ratio. For both blacks and whites, cohorts with less traditional family…

  15. 34 CFR 668.188 - Preventing evasion of the consequences of cohort default rates.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 34 Education 3 2010-07-01 2010-07-01 false Preventing evasion of the consequences of cohort... Two Year Cohort Default Rates § 668.188 Preventing evasion of the consequences of cohort default rates... institution, the same person (as defined in 34 CFR 600.31) or members of that person's family, directly...

  16. 34 CFR 668.207 - Preventing evasion of the consequences of cohort default rates.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 34 Education 3 2010-07-01 2010-07-01 false Preventing evasion of the consequences of cohort... Cohort Default Rates § 668.207 Preventing evasion of the consequences of cohort default rates. (a... institution, the same person (as defined in 34 CFR 600.31) or members of that person's family, directly...

  17. When a College Class Becomes a Mob: Coping with Student Cohorts

    ERIC Educational Resources Information Center

    Hubbell, Larry; Hubbell, Kelly

    2010-01-01

    This article is a theoretical, experiential and reflective analysis of potential problems that may arise when teaching cohorts of students. Although more often than not teaching cohorts of students can be a fulfilling experience, the authors have, on occasion, taught cohort groups that were challenging. The authors speculate whether this…

  18. 78 FR 18351 - Determination Concerning a Petition To Add a Class of Employees to the Special Exposure Cohort

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-03-26

    ... Cohort AGENCY: National Institute for Occupational Safety and Health (NIOSH), Centers for Disease Control... Richland, Washington, to the Special Exposure Cohort (SEC) under the Energy Employees Occupational...

  19. A cohort study on the mortality of firefighters.

    PubMed Central

    Hansen, E S

    1990-01-01

    This study was set up to investigate the effect of exposure to combustion effluents on the chronic health of firefighters. A cohort of firefighters was followed up through 10 years with regard to cause specific mortality. Comparisons were made with another cohort of civil servants and salaried employees in physically demanding jobs. After a latency of five years, an excess mortality from cancer was seen for persons aged 30 to 74 (standardised mortality ratio (SMR) 173, 95% confidence interval (95% CI) 104-270). A significant increase in lung cancer was seen in the group aged 60 to 74 (SMR 317, 95% CI 117-691), whereas non-pulmonary cancer was significantly increased in the group aged 30 to 49 (SMR 575, 95% CI 187-1341). It is concluded that inhalation of carcinogenic and toxic compounds during firefighting may constitute an occupational cancer risk. An extended use of respiratory protective equipment is advocated. PMID:2271386

  20. Short fiber tremolite free chrysotile mesothelioma cohort revealed.

    PubMed

    Egilman, David; Bird, Tess

    2016-03-01

    In 1995, Dell and Teta published a cohort mortality study of asbestos molding compound workers at a Union Carbide Corporation (UCC) plastics manufacturing plant in Bound Brook, New Jersey. They reported that the factory workers were exposed to "asbestos (mostly chrysotile)," implying that the asbestos used at the Bound Brook plant occasionally contained amphiboles. However, UCC statements and testimony from recent litigation indicate that the Bound Brook plant exclusively used short fiber chrysotile asbestos. These recent documents also point to lower exposures than those reported by Dell and Teta. This chrysotile-only cohort should be included in analyses of chrysotile potency. Am. J. Ind. Med. 59:196-199, 2016. © 2016 Wiley Periodicals, Inc. PMID:26725926

  1. Interactive visual analysis of heterogeneous cohort-study data.

    PubMed

    Angelelli, Paolo; Oeltze, Steffen; Haász, Judit; Turkay, Cagatay; Hodneland, Erlend; Lundervold, Arvid; Lundervold, Astri J; Preim, Bernhard; Hauser, Helwig

    2014-01-01

    Medical cohort studies enable the study of medical hypotheses with many samples. Often, these studies acquire a large amount of heterogeneous data from many subjects. Usually, researchers study a specific data subset to confirm or reject specific hypotheses. A new approach enables the interactive visual exploration and analysis of such data, helping to generate and validate hypotheses. A data-cube-based model handles partially overlapping data subsets during the interactive visualization. This model enables seamless integration of the heterogeneous data and the linking of spatial and nonspatial views of the data. Researchers implemented this model in a prototype application and used it to analyze data acquired in a cohort study on cognitive aging. Case studies employed the prototype to study aspects of brain connectivity, demonstrating the model's potential and flexibility. PMID:25248201

  2. Systematic review of birth cohort studies in Africa

    PubMed Central

    Campbell, Alasdair; Rudan, Igor

    2011-01-01

    Aim In sub-Saharan Africa, unacceptably high rates of mortality amongst women and children continue to persist. The emergence of research employing new genomic technologies is advancing knowledge on cause of disease. This review aims to identify birth cohort studies conducted in sub-Saharan Africa and to consider their suitability as a platform to support genetic epidemiological studies. Methods A systematic literature review was conducted to identify birth cohort studies in sub-Saharan Africa across the following databases: MEDLINE, EMBASE, AFRO and OpenSIGLE. A total of 8110 papers were retrieved. Application of inclusion/exclusion criteria retained only 189 papers, of which 71 met minimum quality criteria and were retained for full text analysis. Results The search revealed 28 birth cohorts: 14 of which collected biological data, 10 collected blood samples and only one study collected DNA for storage. These studies face many methodological challenges: notably, high rates of attrition and lack of funding for several rounds of study follow up. Population-based ‘biobanks’ have emerged as a major approach to harness genomic technologies in health research and yet the sub-Saharan African region still awaits large scale birth cohort biobanks collecting DNA and associated health and lifestyle data. Conclusion Investment in this field, together with related endeavours to foster and develop research capacity for these studies, may lead to an improved understanding of the determinants of intrauterine growth and development, birth outcomes such as prematurity and low birth weight, the links between maternal and infant health, survival of infectious diseases in the first years of life, and response to vaccines and antibiotic treatment. PMID:23198102

  3. A Cohort Study on Meniscal Lesions among Airport Baggage Handlers.

    PubMed

    Mikkelsen, Sigurd; Brauer, Charlotte; Pedersen, Ellen Bøtker; Alkjær, Tine; Koblauch, Henrik; Simonsen, Erik Bruun; Helweg-Larsen, Karin; Thygesen, Lau Caspar

    2016-01-01

    Meniscal lesions are common and may contribute to the development of knee arthrosis. A few case-control and cross-sectional studies have identified knee-straining work as risk factors for meniscal lesions, but exposure-response relations and the role of specific exposures are uncertain, and previous results may be sensitive to reporting and selection bias. We examined the relation between meniscal lesions and cumulative exposure to heavy lifting in a prospective register-based study with complete follow-up and independent information on exposure and outcome. We established a cohort of unskilled men employed at Copenhagen Airport or in other companies in the metropolitan Copenhagen area from 1990 to 2012 (the Copenhagen Airport Cohort). The cohort at risk included 3,307 airport baggage handlers with heavy lifting and kneeling or squatting work tasks and 63,934 referents with a similar socioeconomic background and less knee-straining work. Baggage handlers lifted suitcases with an average weight of approximately 15 kg, in total approximately five tonnes during a 9-hour workday. The cohort was followed in the National Patient Register and Civil Registration System. The outcome was a first time hospital diagnosis or surgery of a meniscal lesion. Baggage handlers had a higher incidence of meniscal lesions than the referents. Within baggage handlers spline regression showed that the incidence rate ratio was 1.91 (95% confidence interval: 1.29-2.84) after five years as a baggage handler and then decreased slowly to reach unity after approximately 30 years, adjusted for effects of potential confounders. This relation between baggage handling and meniscal lesions was present for work on the apron which involves lifting in a kneeling or squatting position, but not in the baggage hall, which only involves lifting in standing positions. The results support that long-term heavy lifting in a kneeling or squatting position is a risk factor for the development of symptomatic

  4. Alcohol and breast cancer: results from The Netherlands Cohort Study.

    PubMed

    van den Brandt, P A; Goldbohm, R A; van 't Veer, P

    1995-05-15

    Although the results of cohort studies on the association between alcohol and breast cancer are rather consistent, the current evidence is based solely on North American cohorts. Therefore, this association was evaluated in the Netherlands Cohort Study on diet and cancer, conducted since 1986 among 62,573 women aged 55-69 years. After 3.3 years of follow-up (1986-1989), 422 incident breast cancer cases for which there were complete alcohol consumption data were available for analysis. In multivariate case-cohort analyses, the rate ratio for breast cancer in drinkers versus nondrinkers was 1.31 (95 percent confidence interval 1.00-1.71). When separate alcohol intake categories were compared with nondrinking, the rate ratios were 1.30, 1.29, 1.28, and 1.72 for women who consumed < 5, 5-14, 15-29, and > or = 30 g of alcohol per day, respectively (trend p = 0.047). Whereas beer consumption was not associated with breast cancer risk, increased risks were found at higher levels of both wine and liquor consumption. The alcohol-breast cancer association was found to be stronger among women with a history of benign breast disease, women with a history of breast cancer among sister(s), and women with an early menopause, and it varied considerably according to age at first birth. These results support a positive association between alcohol and breast cancer among postmenopausal women. The increased risk was particularly found among women who consumed 30 g or more of alcohol daily. PMID:7741120

  5. Drinking water arsenic in Utah: A cohort mortality study.

    PubMed Central

    Lewis, D R; Southwick, J W; Ouellet-Hellstrom, R; Rench, J; Calderon, R L

    1999-01-01

    The association of drinking water arsenic and mortality outcome was investigated in a cohort of residents from Millard County, Utah. Median drinking water arsenic concentrations for selected study towns ranged from 14 to 166 ppb and were from public and private samples collected and analyzed under the auspices of the State of Utah Department of Environmental Quality, Division of Drinking Water. Cohort members were assembled using historical documents of the Church of Jesus Christ of Latter-day Saints. Standard mortality ratios (SMRs) were calculated. Using residence history and median drinking water arsenic concentration, a matrix for cumulative arsenic exposure was created. Without regard to specific exposure levels, statistically significant findings include increased mortality from hypertensive heart disease [SMR = 2.20; 95% confidence interval (CI), 1.36-3.36], nephritis and nephrosis (SMR = 1.72; CI, 1.13-2.50), and prostate cancer (SMR = 1.45; CI, 1.07-1. 91) among cohort males. Among cohort females, statistically significant increased mortality was found for hypertensive heart disease (SMR = 1.73; CI, 1.11-2.58) and for the category of all other heart disease, which includes pulmonary heart disease, pericarditis, and other diseases of the pericardium (SMR = 1.43; CI, 1.11-1.80). SMR analysis by low, medium, and high arsenic exposure groups hinted at a dose relationship for prostate cancer. Although the SMRs by exposure category were elevated for hypertensive heart disease for both males and females, the increases were not sequential from low to high groups. Because the relationship between health effects and exposure to drinking water arsenic is not well established in U.S. populations, further evaluation of effects in low-exposure populations is warranted. PMID:10210691

  6. Enrollment and response rates in a longitudinal birth cohort.

    PubMed

    Golding, Jean; Birmingham, Karen

    2009-07-01

    For the scientific credibility of study results, longitudinal cohort studies need to invest time, money and creative thought in establishing and maintaining the maximum number of study participants. Although success depends to a large extent on the resources available, much can be achieved by establishing a culture of integrity and enthusiasm among study staff that is conveyed to participants at all times. In this paper we outline various strategies that can be included in order to maximise the response rates. PMID:19490447

  7. Circulating suPAR in Two Cohorts of Primary FSGS

    PubMed Central

    Wei, Changli; Trachtman, Howard; Li, Jing; Dong, Chuanhui; Friedman, Aaron L.; Gassman, Jennifer J.; McMahan, June L.; Radeva, Milena; Heil, Karsten M.; Trautmann, Agnes; Anarat, Ali; Emre, Sevinc; Ghiggeri, Gian M.; Ozaltin, Fatih; Haffner, Dieter; Gipson, Debbie S.; Kaskel, Frederick; Fischer, Dagmar-Christiane; Schaefer, Franz

    2012-01-01

    Overexpression of soluble urokinase receptor (suPAR) causes pathology in animal models similar to primary FSGS, and one recent study demonstrated elevated levels of serum suPAR in patients with the disease. Here, we analyzed circulating suPAR levels in two cohorts of children and adults with biopsy-proven primary FSGS: 70 patients from the North America–based FSGS clinical trial (CT) and 94 patients from PodoNet, the Europe-based consortium studying steroid-resistant nephrotic syndrome. Circulating suPAR levels were elevated in 84.3% and 55.3% of patients with FSGS patients in the CT and PodoNet cohorts, respectively, compared with 6% of controls (P<0.0001); inflammation did not account for this difference. Multiple regression analysis suggested that lower suPAR levels associated with higher estimated GFR, male sex, and treatment with mycophenolate mofetil. In the CT cohort, there was a positive association between the relative reduction of suPAR after 26 weeks of treatment and reduction of proteinuria, with higher odds for complete remission (P=0.04). In the PodoNet cohort, patients with an NPHS2 mutation had higher suPAR levels than those without a mutation. In conclusion, suPAR levels are elevated in geographically and ethnically diverse patients with FSGS and do not reflect a nonspecific proinflammatory milieu. The associations between a change in circulating suPAR with different therapeutic regimens and with remission support the role of suPAR in the pathogenesis of FSGS. PMID:23138488

  8. Circulating suPAR in two cohorts of primary FSGS.

    PubMed

    Wei, Changli; Trachtman, Howard; Li, Jing; Dong, Chuanhui; Friedman, Aaron L; Gassman, Jennifer J; McMahan, June L; Radeva, Milena; Heil, Karsten M; Trautmann, Agnes; Anarat, Ali; Emre, Sevinc; Ghiggeri, Gian M; Ozaltin, Fatih; Haffner, Dieter; Gipson, Debbie S; Kaskel, Frederick; Fischer, Dagmar-Christiane; Schaefer, Franz; Reiser, Jochen

    2012-12-01

    Overexpression of soluble urokinase receptor (suPAR) causes pathology in animal models similar to primary FSGS, and one recent study demonstrated elevated levels of serum suPAR in patients with the disease. Here, we analyzed circulating suPAR levels in two cohorts of children and adults with biopsy-proven primary FSGS: 70 patients from the North America-based FSGS clinical trial (CT) and 94 patients from PodoNet, the Europe-based consortium studying steroid-resistant nephrotic syndrome. Circulating suPAR levels were elevated in 84.3% and 55.3% of patients with FSGS patients in the CT and PodoNet cohorts, respectively, compared with 6% of controls (P<0.0001); inflammation did not account for this difference. Multiple regression analysis suggested that lower suPAR levels associated with higher estimated GFR, male sex, and treatment with mycophenolate mofetil. In the CT cohort, there was a positive association between the relative reduction of suPAR after 26 weeks of treatment and reduction of proteinuria, with higher odds for complete remission (P=0.04). In the PodoNet cohort, patients with an NPHS2 mutation had higher suPAR levels than those without a mutation. In conclusion, suPAR levels are elevated in geographically and ethnically diverse patients with FSGS and do not reflect a nonspecific proinflammatory milieu. The associations between a change in circulating suPAR with different therapeutic regimens and with remission support the role of suPAR in the pathogenesis of FSGS. PMID:23138488

  9. A Cohort Study on Meniscal Lesions among Airport Baggage Handlers

    PubMed Central

    Mikkelsen, Sigurd; Brauer, Charlotte; Pedersen, Ellen Bøtker; Alkjær, Tine; Koblauch, Henrik; Simonsen, Erik Bruun; Helweg-Larsen, Karin; Thygesen, Lau Caspar

    2016-01-01

    Meniscal lesions are common and may contribute to the development of knee arthrosis. A few case-control and cross-sectional studies have identified knee-straining work as risk factors for meniscal lesions, but exposure-response relations and the role of specific exposures are uncertain, and previous results may be sensitive to reporting and selection bias. We examined the relation between meniscal lesions and cumulative exposure to heavy lifting in a prospective register-based study with complete follow-up and independent information on exposure and outcome. We established a cohort of unskilled men employed at Copenhagen Airport or in other companies in the metropolitan Copenhagen area from 1990 to 2012 (the Copenhagen Airport Cohort). The cohort at risk included 3,307 airport baggage handlers with heavy lifting and kneeling or squatting work tasks and 63,934 referents with a similar socioeconomic background and less knee-straining work. Baggage handlers lifted suitcases with an average weight of approximately 15 kg, in total approximately five tonnes during a 9-hour workday. The cohort was followed in the National Patient Register and Civil Registration System. The outcome was a first time hospital diagnosis or surgery of a meniscal lesion. Baggage handlers had a higher incidence of meniscal lesions than the referents. Within baggage handlers spline regression showed that the incidence rate ratio was 1.91 (95% confidence interval: 1.29–2.84) after five years as a baggage handler and then decreased slowly to reach unity after approximately 30 years, adjusted for effects of potential confounders. This relation between baggage handling and meniscal lesions was present for work on the apron which involves lifting in a kneeling or squatting position, but not in the baggage hall, which only involves lifting in standing positions. The results support that long-term heavy lifting in a kneeling or squatting position is a risk factor for the development of symptomatic

  10. Drinking water arsenic in Utah: A cohort mortality study.

    PubMed

    Lewis, D R; Southwick, J W; Ouellet-Hellstrom, R; Rench, J; Calderon, R L

    1999-05-01

    The association of drinking water arsenic and mortality outcome was investigated in a cohort of residents from Millard County, Utah. Median drinking water arsenic concentrations for selected study towns ranged from 14 to 166 ppb and were from public and private samples collected and analyzed under the auspices of the State of Utah Department of Environmental Quality, Division of Drinking Water. Cohort members were assembled using historical documents of the Church of Jesus Christ of Latter-day Saints. Standard mortality ratios (SMRs) were calculated. Using residence history and median drinking water arsenic concentration, a matrix for cumulative arsenic exposure was created. Without regard to specific exposure levels, statistically significant findings include increased mortality from hypertensive heart disease [SMR = 2.20; 95% confidence interval (CI), 1.36-3.36], nephritis and nephrosis (SMR = 1.72; CI, 1.13-2.50), and prostate cancer (SMR = 1.45; CI, 1.07-1. 91) among cohort males. Among cohort females, statistically significant increased mortality was found for hypertensive heart disease (SMR = 1.73; CI, 1.11-2.58) and for the category of all other heart disease, which includes pulmonary heart disease, pericarditis, and other diseases of the pericardium (SMR = 1.43; CI, 1.11-1.80). SMR analysis by low, medium, and high arsenic exposure groups hinted at a dose relationship for prostate cancer. Although the SMRs by exposure category were elevated for hypertensive heart disease for both males and females, the increases were not sequential from low to high groups. Because the relationship between health effects and exposure to drinking water arsenic is not well established in U.S. populations, further evaluation of effects in low-exposure populations is warranted. PMID:10210691

  11. Cohort Profile: The Hawai’i Family Study of Cognition

    PubMed Central

    Onoye, Jane MM; Hishinuma, Earl S; McArdle, John J; Zonderman, Alan B; Takeshita, Junji

    2014-01-01

    Intergenerational longitudinal studies over the lifespan provide valuable information for understanding the contexts and dynamic relations among cognition, family and health in adults and the elderly. The Hawai‘i Family Study of Cognition (HFSC), initiated in the early 1970s, included a cohort of over 6500 individuals representing over 1800 families of parents and their offspring. The HFSC gathered data on cognitive, personality, biological and other psychosocial variables, and provided novel information on the nature of cognitive abilities, especially on family issues. Some families were reassessed with short-term retesting in the 1970s. A select sample of offspring and their siblings and spouses were re-measured in the 1980s. Decades later, a 40-year follow-up of the original HFSC cohort was facilitated by the availability of contemporary tracking and tracing methods and internet-based testing. A subgroup of the original HFSC participants was re-contacted and retested on contemporary cognitive as well as socio-demographic and health measures. In this paper, we describe the original HFSC cohort and the design and methodology of the re-contact and retest studies of the HFSC, plans for expanding the re-contact and retesting, as well as directions for future research and collaborations. The Principal Investigator may be contacted for more information regarding the application, review and approval process for data access requests from qualified individuals outside the project. PMID:24639439

  12. Quarantine, Isolation, and Cohorting: From Cholera to Klebsiella

    PubMed Central

    Riccio, Lin M.; Campbell, Kristin Turza; Politano, Amani D.; Sawyer, Robert G.

    2012-01-01

    Abstract Background Isolation is defined as the separation of persons with communicable diseases from those who are healthy. This public health practice, along with quarantine, is used to limit the transmission of infectious diseases and provides the foundation of current-day cohorting. Methods Review of the pertinent English-language literature. Results Mass isolation developed during the medieval Black Death outbreaks in order to protect ports from the transmission of epidemics. In the mid-1800s, infectious disease hospitals were opened. It now is clear that isolation and cohorting of patients and staff interrupts the transmission of disease. Over the next century, with the discovery of penicillin and vaccines against many infectious agents, the contagious disease hospitals began to close. Today, we find smaller outbreaks of microorganisms that have acquired substantial resistance to antimicrobial agents. In the resource-limited hospital, a dedicated area or region of a unit may suffice to separate affected from unaffected patients. Conclusion Quarantine, or cohorting when patients are infected with the same pathogen, interrupts the spread of infections, just as the contagious disease hospitals did during the epidemics of the 18th and 19th centuries. PMID:22472002

  13. High fertility regions in Bangladesh: a marriage cohort analysis.

    PubMed

    Islam, Sabina; Islam, Mohammad Amirul; Padmadas, Sabu S

    2010-11-01

    Bangladesh represents one of the few countries in south Asia where the pace of fertility decline has been unprecedented over the last three decades. Although there has been significant reduction in fertility levels at the national level, regional variations continue to persist, especially in Sylhet and Chittagong where the total fertility rates are well above the country average. Using data from three consecutive Bangladesh Demographic and Health Surveys (BDHSs) this paper assesses how fertility patterns in Sylhet and Chittagong differ from the rest of Bangladesh through a marriage cohort analysis of the parity progression ratios, and examines the factors determining the transition rates to higher parity in these two regions. Three cohorts of women are identified: those married during 1965-1974, 1975-84 and 1985-94. The results show that the probability that a woman from the recent cohort in Sylhet or Chittagong who had a third birth will have a fourth birth is nearly twice that of her counterpart in other regions. Social characteristics such as education, occupation, religion and residence have no effect on fertility in Sylhet and Chittagong. Additional period-specific analyses using the 2007 BDHS data show that women in Sylhet are considerably more likely to have a third or fourth birth sooner than those in other divisions, especially Khulna. The findings call for specific family planning policy interventions in Sylhet and Chittagong ensuring gender equity, promoting female education and delaying entry into marriage and childbearing. PMID:20868540

  14. Patterns of experienced aging with a Finnish cohort.

    PubMed

    Heikkinen, R L

    A cohort study of eighty-year old residents in Jyväskylä (pop. 66,000), central Finland, was carried out in 1990 as part of the EVERGREEN-project. A total of 262 persons born in 1910 were interviewed in the cohort study. The survey data produced a fairly accurate picture of the respondents' objective situation. In order to shed further light on how the respondents felt about growing old, tape recorded narrative stories were collected from a subsample of twenty persons (10 women and 10 men). The stories revealed the subjective meanings and evaluations attached by the individuals concerned to their own aging. Being members of the same culture and the same age cohort, they also shared the same way of perceiving themselves and the surrounding world. It became obvious that there existed some kind of boundary conditions for the experience of aging. The model of boundary conditions for the experience of aging was developed on the basis of the narratives. PMID:1305147

  15. 2004 update of dosimetry for the Utah Thyroid Cohort Study.

    PubMed

    Simon, Steven L; Anspaugh, Lynn R; Hoffman, F Owen; Scholl, Alan E; Stone, Mary B; Thomas, Brian A; Lyon, Joseph L

    2006-02-01

    In the 1980s, individual thyroid doses and uncertainties were estimated for members of a cohort of children identified in 1965 in Utah and Nevada who had potentially been exposed to fallout from the Nevada Test Site. That reconstruction represented the first comprehensive assessment of doses received by the cohort and was the first large effort to assess the uncertainty of dose on an individual person basis. The data on dose and thyroid disease prevalence during different periods were subsequently used in an analysis to determine risks of radiogenic thyroid disease. This cohort has received periodic medical follow-up to observe changes in disease frequency and to reassess the previously reported radiation-related risks, most recently after a Congressional mandate in 1998. In a recent effort to restore the databases and computer codes used to estimate doses in the 1980s, various deficiencies were found in the estimated doses due to improperly operating computer codes, corruption of secondary data files, and lack of quality control procedures. From 2001 through 2004, the dosimetry system was restored and corrected and all doses were recalculated. In addition, two parameter values were updated. While the mean of all doses has not changed significantly, many individual doses have changed by more than an order of magnitude. PMID:16435919

  16. Findings from longitudinal cohort studies: Gothenburg and Jerusalem.

    PubMed

    Stessman, J; Hammerman-Rozenberg, R; Svanborg, A

    1996-08-01

    The longitudinal study of age-homogeneous cohorts is a powerful tool to elucidate age-related changes and to attempt to distinguish normal aging from the effects of disease. Many influences, such as the effect of changing lifestyle, medical practices and environmental factors with time must be considered when designing and interpreting such studies. Cross-cultural differences manifest in comparing different studies must also be accounted for, but alternately provide a tool to distinguish between endogenous and exogenous factors influencing human aging. The first stage of the longitudinal study of 70 year olds in Gothenburg, Sweden, a cross-sectional survey performed in 1971, is compared to a similar cross-sectional survey performed in Jerusalem in 1991 as part of a projected longitudinal study. The similarities between the two cohorts with regard to living conditions, functional independence and disease prevalence are striking. There are also significant contrasts that reflect the 20 years that elapsed between the execution of the two studies, as well as the cultural and social differences. In particular, the ethnic diversity of the Jerusalem population, hailing from 40 separate countries, is emphasized. The comparison of these two studies highlights many of the principles critical to the role of longitudinal cohort studies in gerontology. PMID:8816868

  17. Cohort Profile: The Manitoba Follow-up Study (MFUS).

    PubMed

    Tate, Robert B; Cuddy, T Edward; Mathewson, Francis A L

    2015-10-01

    The Manitoba Follow-up Study (MFUS) is Canada's longest running study of cardiovascular disease and ageing. The MFUS cohort consists of 3983 men recruited from the Royal Canadian Air Force at the end of World War II. At entry to the study, 1 July 1948, their mean age was 31 years, with 90% between ages 20 and 39 years. All study members were free of clinical evidence of ischaemic heart disease. The protocol of MFUS was to obtain routine medical examinations from these men at regular intervals over time. The research goal of the study was to examine the role that any abnormalities detected on routine electrocardiograms from apparently healthy men might play in the prediction of subsequent diagnoses of cardiovascular disease. Over the course of 65 years, about 35% of the cohort has documented evidence of ischaemic heart disease. The research focus was expanded in 1996 to explore the roles of physical, mental and social functioning in support of healthy and successful ageing. On 1 July 2013, 429 original cohort members were alive with a mean age of 92 years. Collaborative research with others outside the in-house team is welcomed. PMID:25064641

  18. Retrospective Cohort Study of a Microelectronics and Business Machine Facility

    PubMed Central

    Silver, Sharon R.; Pinkerton, Lynne E.; Fleming, Donald A.; Jones, James H.; Allee, Steven; Luo, Lian; Bertke, Stephen J.

    2015-01-01

    Objectives We examined health outcomes among 34,494 workers employed at a microelectronics and business machine facility 1969–2001. Methods Standardized mortality ratio (SMR) and standardized incidence ratios were used to evaluate health outcomes in the cohort and Cox regression modeling to evaluate relations between scores for occupational exposures and outcomes of a priori interest. Results Just over 17% of the cohort (5,966 people) had died through 2009. All cause, all cancer, and many cause-specific SMRs showed statistically significant deficits. In hourly males, SMRs were significantly elevated for non-Hodgkin’s lymphoma and rectal cancer. Salaried males had excess testicular cancer incidence. Pleural cancer and mesothelioma excesses were observed in workers hired before 1969, but no available records substantiate use of asbestos in manufacturing processes. A positive, statistically significant relation was observed between exposure scores for tetrachloroethylene and nervous system diseases. Conclusions Few significant exposure–outcome relations were observed, but risks from occupational exposures cannot be ruled out due to data limitations and the relative youth of the cohort. PMID:24375784

  19. Cohort and duration patterns among Asian immigrants: Comparing trends in obesity and self-rated health

    PubMed Central

    Ro, Annie; Geronimus, Arline; Bound, John; Griffith, Derek; Gee, Gilbert

    2015-01-01

    Many studies, but not all, suggest that immigrant health worsens with duration of residence in the U.S. Cohort effects may explain the inconsistent findings; not only are cohort effects confounded with duration, but the timing of entry into the US may also create qualitatively different migration experiences. The present study tests for duration and cohort patterns among Asian immigrants to the United States across six year-of-entry cohorts (pre-1980, 1981-1985, 1986-1990, 1991-1995, 1996-2000, 2001-2005). Data come from the Asian American sample (n=44,002) from the 1994-2009 waves of the National Health Interview Survey. The data show cohort differences for self-rated health, such that more recent cohorts showed improved baseline health compared to older cohorts. After accounting for cohorts, there was no significant change in self-rated health by duration. Older cohorts actually showed improving self-rated health with longer duration. Obesity showed the opposite pattern; there were no differences across cohorts, but duration in the United States correlated with higher obesity. These results imply that immigrant health is not simply an issue of duration and adaptation, but underscore the utility of considering cohorts as broader contexts of migration. Collectively, the results encourage future research that more carefully examines the etiological mechanisms that drive immigrant health. PMID:25879262

  20. Case-cohort design in practice – experiences from the MORGAM Project

    PubMed Central

    Kulathinal, Sangita; Karvanen, Juha; Saarela, Olli; Kuulasmaa, Kari

    2007-01-01

    When carefully planned and analysed, the case-cohort design is a powerful choice for follow-up studies with multiple event types of interest. While the literature is rich with analysis methods for case-cohort data, little is written about the designing of a case-cohort study. Our experiences in designing, coordinating and analysing the MORGAM case-cohort study are potentially useful for other studies with similar characteristics. The motivation for using the case-cohort design in the MORGAM genetic study is discussed and issues relevant to its planning and analysis are studied. We propose solutions for appending the earlier case-cohort selection after an extension of the follow-up period and for achieving maximum overlap between earlier designs and the case-cohort design. Approaches for statistical analysis are studied in a simulation example based on the MORGAM data. PMID:18053196