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Guenter Auerswald,1 Claudia Djambas Khayat,2 Oleksandra Stasyshyn,3 Genadi Iosava,4 Irina Romashevskaya,5 Marta Julia López,6 Wilfried Seifert,7 Tobias Rogosch7 1Hess Kinderklinik, Klinikum Bremen-Mitte, Bremen, Germany; 2Hotel Dieu de France Hospital, St Joseph University, Beirut, Lebanon; 3Institute of Blood Pathology and Transfusion Medicine, Academy of Medical Sciences of Ukraine, Lviv, Ukraine; 4Institute for Hematology and Transfusiology, Tbilisi, Georgia; 5Republican Research Centre for Radiation Medicine and Human Ecology, Gomel, Belarus; 6Hematology, Hospital Roosevelt, Guatemala, Guatemala; 7Clinical Development, CSL Behring, Marburg, GermanyCorrespondence: Guenter AuerswaldHess Kinderklinik, Klinikum Bremen-Mitte, Bremen, GermanyTel +49 176-10113362Email guenterauerswald@aol.comPurpose: Formulation V (VONCENTO®) is a plasma-derived high-concentration/low-volume, high-purity von Willebrand factor (VWF)/factor VIII (FVIII) concentrate, originally indicated for von Willebrand disease (VWD) in adults and adolescents. This multicenter, open-label study (SWIFTLY-VWD) evaluated the pharmacokinetics (PK), as well as hemostatic efficacy and safety, of Formulation V in pediatric patients (< 12 years) with severe VWD requiring treatment or prophylaxis of bleedings.Methods: PK investigations were performed following one dose of Formulation V at Day 1 and 180. Nonsurgical bleeds were analyzed, while hemostatic efficacy was graded as excellent/good/moderate/none. Safety assessments included adverse events, and presence of VWF and/or FVIII inhibitors.Results: Formulation V was administered as on-demand (N=13) or prophylaxis therapy (N=4) for 12 months (< 6 years, N=9; 6 to < 12 years, N=8). PK parameters for VWF markers were generally comparable to adults but showed lower VWF:ristocetin cofactor (RCo) exposure. Incidence of major bleeds was lower for prophylaxis (3.3%) than on-demand therapy (27.1%); joint bleeds were also lower (3.3% vs 11.5%, respectively). Investigator-reported excellent/good hemostatic efficacy against nonsurgical bleeds was 100%. No clinically relevant differences in PK, hemostatic efficacy, or safety were observed between age-groups (< 6 years and 6 to < 12 years). Formulation V was well tolerated. Adverse events were mild–moderate and consistent with the adult safety profile. No cases of anaphylactic reactions or angioedema, development of FVIII/VWF inhibitors, thromboembolic events, or viral infections were reported.Conclusion: This study provides evidence for use of Formulation V to treat and prevent bleeding in pediatric patients with severe VWD, and led to the European approval of Formulation V in children.Keywords: von Willebrand disease, clinical trial, pediatrics, prophylaxis, von Willebrand factor-factor VIII concentrate

New therapeutic agents for haemophilia with inhibitors that are in development or already licensed are expected to provide transformative treatment options. Many of these new therapies are not based on simply replacing the missing factor; new strategies include bispecific antibody technology that mimics factor VIII coagulation function (emicizumab), and inhibition of anticoagulant proteins such as tissue factor pathway inhibitor (eg PF-06741086) and antithrombin (eg fitusiran). These agents are administered subcutaneously and should significantly reduce treatment burden and increase the ability to deliver prophylaxis for patients. Limited real-world data and validated practical guidance on these recently licensed/upcoming treatments resulted in the authors convening to discuss recommendations on their use. Emicizumab is currently the only licenced nonfactor therapy; thus, our recommendations focus on this product. Target candidates for emicizumab prophylaxis are difficult-to-treat patients with haemophilia A and inhibitors and/or venous access issues, frequent bleeds and target joints. In case of breakthrough bleeding while receiving emicizumab, patients still require treatment with bypassing agents; the adjunct treatment of choice is recombinant activated factor VII. This treatment is also recommended to prevent bleeds in patients with inhibitors undergoing surgery. Our recommendations on suitable laboratory assays and monitoring new products, as well as the benefit of patient-reported outcomes (such as pain and physical activity levels), are included. We also briefly discuss future treatment options for patients with haemophilia B and inhibitors. Although these nonfactor treatments offer great promise, further data and real-world evidence are needed.

Toshko Lissitchkov,1 Anna Klukowska,2 Evgeny Buevich,3 Irina Maltceva,3 Guenter Auerswald,4 Oleksandra Stasyshyn,5 Wilfried Seifert,6 Tobias Rogosch6 1Specialized Hospital for Active Treatment (SHAT), Sofia, Bulgaria; 2Department of Paediatrics, Haematology and Oncology of Warsaw Medical University, Warsaw, Poland; 3GOUVPO Altaysky State Medical University of Roszdrav, Bernaul, Russian Federation; 4Prof. Hess Kinderklinik, Klinikum Bremen-Mitte, Bremen, Germany; 5Institute of Pathology and Transfusion Medicine AMN, Lviv, Ukraine; 6Clinical Development, CSL Behring, Marburg, GermanyCorrespondence: Toshko LissitchkovSpecialized Hospital for Active Treatment (SHAT) “JOAN PAVEL”, 67A Stoletov Blvd, Sofia 1233, BulgariaTel +35 989 436 9096Email t_lissitchkov@yahoo.comObjective: Plasma-derived von Willebrand factor/factor VIII (pdVWF/FVIII; VONCENTO®, CSL Behring) is a high-concentration, low-volume, high-purity concentrate, which contains a high level of high-molecular-weight multimers and a VWF/FVIII ratio of ∼ 2.4:1. The SWIFT (“Studies with von Willebrand factor/Factor VIII”) program is evaluating pdVWF/FVIII in patients with von Willebrand disease (VWD). The long-term efficacy and safety profile of pdVWF/FVIII was investigated in this multicenter, open-label, extension study.Methods: Pediatric, adolescent, and adult patients with VWD who required treatment of non-surgical bleeds (NSBs), treatment during surgical events or who were receiving prophylaxis and who had completed one of two previous clinical trials of pdVWF/FVIII were included. Efficacy and safety analyses were performed for on-demand (n=10), prophylaxis (n=8), or on-demand and prophylaxis (n=2) treatment in patients pre-treated with pdVWF/FVIII for ≥ 12 months.Results: Seven patients experienced a total of 402 NSBs in the on-demand arm, of which 77 required treatment and nine NSB events in three patients were considered major. Nine patients reported 118 NSBs in the prophylaxis arm, with 96 events requiring treatment and seven patients experiencing 12 major NSB events. Excellent or good hemostatic efficacy was reported by the investigator for 98.7% (on-demand) and 97.9% (prophylaxis) of NSB events treated with pdVWF/FVIII, without relevant differences between subgroups by age. pdVWF/FVIII was well tolerated, and the adverse events seen were mild-moderate and consistent with the safety profile for this product seen in other studies. There were no cases of anaphylactic reactions and angioedema, development of VWF/FVIII inhibitors, thromboembolic events, or viral infections.Conclusion: This contemporary comprehensive development program evaluating pdVWF/FVIII across all ages demonstrates long-term safety and efficacy for treatment and prevention of bleeds in patients with severe VWD, supporting the benefit–risk profile of pdVWF/FVIII.Keywords: von Willebrand disease, hemostatic efficacy, safety, prophylaxis, on-demand, surgery

Standard treatment of haemophilia A is based on replacing the missing coagulation factor VIII (FVIII) to treat and prevent bleeding episodes. The most challenging complication of FVIII therapy is the development of neutralizing antibodies (inhibitors) that can render treatment ineffective. Eradication of the inhibitor through immune tolerance induction (ITI) remains the most effective strategy for managing these patients. Bypassing agents can be used to help restore haemostasis in inhibitor patients. Several novel agents have recently been developed, such as the FVIII mimetic agent emicizumab, which has been effective in reducing the annualized bleeding rate in haemophilia A patients with inhibitors. When coadministered with repetitive high doses of activated prothrombin complex concentrate (ie >100 U/kg/d for ≥24 hours), emicizumab was associated with thrombotic microangiopathy and thrombosis events. As a consequence the United Kingdom Haemophilia Centres Doctors' Organisation (UKHCDO) issued the first guidance on the treatment of bleeding episodes in patients receiving emicizumab. To build on and extend this work, a panel of German haemophilia specialists met to discuss the UK guidance, review current evidence and provide additional guidance for German healthcare professionals on how to optimize the management of patients with haemophilia A receiving emicizumab. Recommendations are provided on the use of bypassing and other agents to manage breakthrough bleeding, ITI in the emicizumab era, haemostatic support during surgery and issues relating to laboratory monitoring.

BACKGROUND Providing HIV and hepatitis C virus (HCV) testing on an "opt-out" basis is often considered the "gold standard" because it contributes to higher testing rates when compared with "opt-in" strategies. Although rates are crucial, an individual's testing preferences are also important, especially in correctional settings where legal and social factors influence a person's capacity to freely decide whether or not to test. Our study explored factors influencing HIV and HCV testing decisions and individuals' preferences and concerns regarding opt-in vs. opt-out testing at the time of jail entry. METHODS We conducted semistructured interviews to explore individuals' previous testing experiences, reasons to test, understanding of their health care rights, HIV and HCV knowledge, and preferences for an opt-out vs. an opt-in testing script. RESULTS We interviewed 30 individuals detained in the Santa Clara County Jail at intake. Participants reported that their testing decisions were influenced by their level of HIV and HCV knowledge, self-perceived risk of infection and stigma associated with infection and testing, the degree to which they felt coerced, and understanding of testing rights in a correctional setting. Most preferred the opt-in script because they valued the choice of whether or not to be tested. Participants who did prefer the opt-out script did so because they felt that the script was less likely to make people feel "singled out" for testing. CONCLUSIONS Our findings demonstrate that people care about how testing is offered and suggest a need for further research to see how much this influences their decision about whether to test.

OBJECTIVES: Middle adolescent males are a difficult group to recruit for community sexually transmitted infection (STI) prevention research. We describe a process of community engagement, venue-based sampling of 14–17 year-old adolescent males, and compare rates of STIs and STI-risk behaviors by venue. METHODS: Community engagement consisted of (1) informational meetings with organizations, (2) participation in community meetings and events, (3) hiring community members as study personnel, and (4) an adolescent advisory board recruited from the community. Venues were identified and assessed at different times of the day and days of the week using a structured tool. At selected venues, males ages 14–17 were invited to participate in a brief survey and provide a urine sample and an optional anal swab for DNA-based STI testing. RESULTS: Venues were assessed (n=249), and 31 selected for recruitment, including parks, apartment complexes, community events, entertainment venues, a community school, and community programs for LGBT and adjudicated youth. We enrolled 667 participants, average age 15.7 years. Participants reported high rates of sexual and STI risk behaviors, but had low rates of STIs. These rates differed by venue, with more structured venues recruiting youth reporting fewer STI risk behaviors and less structured venues within the highest STI prevalence zip codes recruiting youth reporting more STI risk behaviors. CONCLUSION: Venue-based sampling is a feasible mechanism to target recruitment and enrollment adolescent males with high STI risk behaviors in community settings, with risk profiles varying by setting. IMPLICATIONS AND CONTRIBUTION: Middle adolescent males in high STI prevalence communities are a hidden population. We describe an approach to community engagement and venue-based sampling that is a feasible alternative to institution- and household-based sampling, and then provide data on infection and STI risk behaviors by type of venue.

Factor X deficiency is a rare coagulation disorder that can be hereditary or acquired. The typology and severity of the associated bleeding symptoms are highly heterogeneous, adding to the difficulties of diagnosis and management. Evidence-based guidelines and reviews on factor X deficiency are generally limited to publications covering a range of rare bleeding disorders. Here we provide a comprehensive review of the literature on factor X deficiency, focusing on the hereditary form, and discuss the evolution in disease management and the evidence associated with available treatment options. Current recommendations advise clinicians to use single-factor replacement therapy for hereditary disease rather than multifactor therapies such as fresh frozen plasma, cryoprecipitate, and prothrombin complex concentrates. Consensus in treatment guidelines is still urgently needed to ensure optimal management of patients with factor X deficiency across the spectrum of disease severity.

As is the case across the nation, youth in California experiencing homelessness are often undercounted and overlooked. We Count, California!, a collaboration between the California Homeless Youth Project and the University of California, Berkeley School of Public Health was formed to support California communities in better counting and describing their homeless youth in the 2015 Point-in-Time (PIT) count. Project activities included a series of trainings across the state, provision of seed grants to communities conducting youth-specific count activities, and provision of one-on-one technical assistance to two nonurban, under-resourced pilot sites. Despite considerable increases in the energy, commitment, and funding dedicated to youth counts across California, results of the 2015 PIT count were mixed. In this article, we discuss promising practices, successes, and continuing challenges for youth-inclusive PIT counts. We conclude with recommendations for local initiatives and policy-level interventions for developing a more accurate and inclusive picture of youth homelessness in California and nationwide.

Zusammenfassung Hintergrund Simulationstraining in der minimalinvasiven Chirurgie (MIC) wird zunehmend relevant. Inwieweit das etablierte Lübecker Toolbox-Curriculum (LTB-Curriculum) zum Erlernen von MIC-Basisfertigkeiten die studentische Lehre in der Chirurgie ergänzen kann und mit welcher Akzeptanz, ist unklar. Material und Methoden Seit 04/2015 haben Studierende der Humanmedizin an der Universität zu Lübeck die Möglichkeit, das hoch standardisierte und validierte LTB-Curriculum zu absolvieren. Dieses besteht inhaltlich aus 6 aufeinander aufbauenden Übungen mit definierten Zielvorgaben. Videotutorials erlauben das autodidaktische Training. Der individuelle Trainingsfortschritt wurde laufend dokumentiert wie im Curriculum vorgesehen. Es erfolgte die standardisierte Evaluation über ein für die Evaluation von Lehrveranstaltungen der Universität zu Lübeck etabliertes Onlineportal. Ergebnisse Zwischen 04/2015 und 07/2016 durchliefen 63 Studierende das LTB-Curriculum. Das generelle Interesse an einer chirurgischen Fachdisziplin stieg von im Mittel 1,61 (Standardabweichung [SD] 0,78) vor dem Curriculum auf 1,12 nach dem Curriculum an. Die Anzahl der notwendigen Wiederholungen bis zum Erreichen der Zielvorgaben betrug für die Übungen 1 – 6 im Median 24 (6 – 79), 23 (5 – 61), 7 (5 – 33), 15 (5 – 59), 16 (5 – 50) und 18 (7 – 48). Keiner der 63 Studierenden brach das LTB-Curriculum vorzeitig ab. Im Durchschnitt wurden 4,35 (SD 1,58) Stunden pro Woche aufgewandt und im Mittel eine Gesamtdauer von 4,1 (SD 1,2) Wochen benötigt, um das LTB-Curriculum zu komplettieren. Die Evaluationsergebnisse ergaben eine Gesamtnote von 1,0 (SD 0,17). Der Lernzuwachs, die Didaktik und die Struktur des Trainingsprogramms wurden mit im Mittel 1,0 (SD 0,24), 1,14 (SD 0,36) und 1,0 (SD 0,24) bewertet. Die Relevanz des Curriculums für das weitere Studium und die zukünftige berufliche Tätigkeit wurde im Durchschnitt mit 1,2 (SD 0,45) angegeben. Schlussfolgerung Das Angebot, das strukturierte Lübecker Toolbox-Curriculum zusätzlich zur regulären Lehre absolvieren zu können, wurde von zahlreichen Studierenden angenommen und sehr positiv evaluiert. Die Ergebnisse legen zudem nahe, dass das LTB-Curriculum das Interesse an einer chirurgischen Fachrichtung bei Studierenden steigert. In Zeiten, da die Chirurgie um Nachwuchs bemüht sein muss, erscheint dieser Aspekt relevant.

The discussion of prophylactic therapy in haemophilia is largely focused on joint outcomes. The impact of prophylactic therapy on intracranial haemorrhage (ICH) is less known. This study aimed to analyse ICH in children with haemophilia, with a focus on different prophylaxis regimens and sequelae of ICH. We conducted a multicentre retrospective and prospective study that included 33 haemophilia centres from 20 countries. Inclusion criteria were children and adolescents born between 1993 and 2014, with severe haemophilia A or B without inhibitors. Participants were categorized by prophylaxis regimen: full, partial or none, based on dose and dose frequency of regular infusions. The cohort study included 1515 children: 29 cases of ICH over 8038 patient years were reported. The incidence of ICH in the prophylaxis group, 0·00033 cases of ICH/patient year, was significantly lower compared to the no prophylaxis group, 0·017 cases of ICH/patient year (RR 50·06; P < 0·001) and the partial prophylaxis group, 0·0050 cases of ICH/patient year (RR 14·92; P = 0·007). In the on-demand-group, 8% (2/24) children with ICH died and 33% had long-term sequelae, including intellectual and behavioural problems, paresis and epilepsy. Children on regular, frequent prophylaxis have a low risk of ICH compared to those using non-frequent or no prophylaxis.

Osteosynthesis plate removal is one of the most commonly performed procedures in orthopaedic surgery. Due to technological advances and the quality of increasing osteosynthesis material, more and more locked plates have been implanted over the last 20 years. The aim of this study was to determine whether the complication rate during plate removal differs between conventional and locked plates.In this retrospective cohort study, 620 patients were included and divided into two groups based on the type of plate (locked and conventional). Technical complications during implant removal included screw breakage, destroyed screw head, implant breakage, remaining implant material, refracture, bony or soft tissue overgrowth. The following plate-associated complications were identified: osteosynthesis plate not detachable, plate bent or broken, necessity of special tools or plate loosened. Three types of screw-related complications were observed: screw not detachable, screw broken or screw dislocated.Overall, complications related to the plate or screws were documented in 110 of the 620 cases. These complications occurred in 48 of the 382 cases involving conventional osteosynthesis (7.7% of all removals, 12.6% of all conventional removals) and in 62 of the 238 cases involving locked plate osteosynthesis (10.0% of all removals, 26.1% of all locked plate removals). The statistical analysis showed a significantly higher implant-related complication rate with locked plates compared to the conventional plates (p 0.01).Hardware removal can be a complication-afflicted operation, especially cases involving locked-plate removal should only be performed if a strong indication is evident. Possible benefits of the procedure should be considered carefully, taking the cost-benefit ratio into account.

Joint pain is common in haemophilia and may be acute or chronic. Effective pain management in haemophilia is essential to reduce the burden that pain imposes on patients. However, the choice of appropriate pain-relieving measures is challenging, as there is a complex interplay of factors affecting pain perception. This can manifest as differences in patients’ experiences and response to pain, which require an individualized approach to pain management. Prophylaxis with factor replacement reduces the likelihood of bleeds and bleed-related pain, whereas on-demand therapy ensures rapid bleed resolution and pain relief. Although use of replacement or bypassing therapy is often the first intervention for pain, additional pain relief strategies may be required. There is an array of analgesic options, but consideration should be paid to the adverse effects of each class. Nevertheless, a combination of medications that act at different points in the pain pathway may be beneficial. Nonpharmacological measures may also help patients and include active coping strategies; rest, ice, compression, and elevation; complementary therapies; and physiotherapy. Joint aspiration may also reduce acute joint pain, and joint steroid injections may alleviate chronic pain. In the longer term, increasing use of prophylaxis or performing surgery may be necessary to reduce the burden of pain caused by the degenerative effects of repeated bleeds. Whichever treatment option is chosen, it is important to monitor pain and adjust patient management accordingly. Beyond specific pain management approaches, ongoing collaboration between multidisciplinary teams, which should include physiotherapists and pain specialists, may improve outcomes for patients.

HIV is the leading cause of mortality for youth in sub-Saharan Africa. Youth are more likely than any other age group to be lost to follow-up (LTFU) from care. We investigated the health care-related experiences of youth living with HIV (YLWH) who were LTFU (i.e., had not returned to care for at least 4 months), as well as the perceptions of the community health workers who supported them. Data were collected from two focus group discussions with community health workers (n = 18) who worked with YLWH and 27 semistructured interviews with YLWH (ages 15-21 years) who were LTFU. Attitudes toward health care were presented in the context of a social-ecological model. Respondents highlighted the need for improved youth-oriented services, including youth-friendly clinics and training for care providers about specific needs of YLWH. Researchers should develop and test the impact of these interventions to improve retention of YLWH in care.

BACKGROUND The influenza vaccination rate among older and chronically ill patients in Germany has declined in the past decade in spite of vaccination campaigns. METHODS The influenza vaccination rate among persons with chronic renal disease was studied with the aid of billing data from various Associations of Statutory Health Insurance Physicians (Kassenarztliche Vereinigungen, ASHIPs) in Germany. It was tested in a randomized controlled trial whether a written vaccination appeal, sent by physicians to patients, led to an increase in the vaccination rate. It was tested in a further such trial whether the vaccination rate among patients with renal disease could be improved by an appeal for vaccination that was sent by the ASHIPs to the treating nephrologists. Finally, it was also tested in a prospective interventional study whether the vaccination rate could be improved by an appeal for vaccination sent by a health- insurance carrier directly to the patients. RESULTS In 2012-2017, the vaccination rate among persons with chronically impaired renal function ranged from 41.1% to 46.9%; it ranged from 31.7% to 33.7% in kidney transplant recipients and from 42.7% to 44.7% in dialysis patients. An appeal for vaccination that was sent from physicians to patients raised the vaccination rate by 8.3% in the intervention group compared to the control group (p = 0.03; number needed to treat [NNT]: 13). On the other hand, an appeal for vaccination that was sent to the nephrologists lowered the vaccination rate by 0.8% in the intervention group compared to the control group. Finally, an appeal for vaccination that was sent by the health-insurance fund to the patients raised the vaccination rate by 3.2% (p

Owing to the heterogeneity in the clinical phenotype of haemophilia A and B, it is now recognized that disease severity (based on factor VIII/IX activity) may no longer be the most appropriate guide for treatment and that a 'one-size-fits-all' approach is unlikely to achieve optimal therapy. Based on the present literature and consensus views of a group of experts in the field, this article highlights key gaps in the understanding of the diverse relationships between bleeding phenotype and factors such as joint health, genetic susceptibility, laboratory parameters, quality of life and management of pain. Early prophylaxis is a potential 'gold standard' therapy and issues surrounding inhibitor development, variations in its clinical use and long-term outcomes are discussed. Comprehensive treatment should be individualized for all patients (including those with mild or moderate haemophilia and carriers). Wherever possible all patients should be given prophylaxis. However, adult patients with a milder haemophilia phenotype may be candidates for ceasing prophylaxis and switching to on-demand treatment. Regardless, all treatment (on-demand and prophylaxis) should be tailored towards both the patient's personal needs and their clinical profile. In addition, as the associations between risk factors (psychosocial, condition-related and treatment-related) and clinical features are unique to each patient, an individualized approach is required to enable patients to alter their behaviour in response to them. The practical methodologies needed to reach this goal of individualized haemophilia care, and the health economic implications of this strategy, are ongoing topics for discussion.

Die Freiheit des Arztberufs wird durch die Bemuhungen des Gesetzgebers, stets neue Regelungen in das Vertragsarztrecht zu implementieren, bedroht. Praxisaufkaufregelungen und das Antikorruptionsgesetz stellen nur zwei Beispiele dar, welche die wirtschaftlichen Bedingungen fur niedergelassene Vertragsarzte gefahrden konnen. Nicht nur Niederlassungswillige, sondern auch bereits Niedergelassene werden dadurch verunsichert. Um auch zukunftig am Markt bestehen zu konnen, ist eine Bundelung von Ressourcen erforderlich.

Introduction In haemophilia, recurrent joint bleeds are responsible for the development of chronic joint damage, because blood induces biochemical changes in joint structures. Joint degeneration is a long process, and structural damage is often preceded by joint dysfunction, which is represented by quantitative and qualitative changes in the contraction pattern of muscles around the joints. Muscle function in patients with haemophilia is still poorly investigated. Aim The aim of this 2-year prospective study was to assess the changes in muscle function of lower limbs in a group of patients affected with haemophilia in San Jose, Costa Rica. Methods Muscle function of lower limbs was assessed by means of surface electromyography (sEMG) accomplished at study enrolment and after 2 years of follow-up. Gluteus medius, vastus medialis, biceps femoris, gastrocnemius and tibialis anterior were examined. All patients underwent concurrent clinical examination using Haemophilia Joint Health Score (HJHS). Results Sixty patients aged 2-43 years with severe haemophilia underwent clinical and sEMG evaluation. Thirty-two patients (53%) had target joints. sEMG parameters were altered in all patients and were not correlated to the presence of target joints and/or an abnormal HJHS. Muscle function deterioration was observed after 2 years of follow-up despite an unmodified HJHS. Conclusions Muscle function of lower limbs as detected by means of sEMG was impaired in patients with haemophilia irrespective of the presence of overt joint damage. sEMG is a simple and sensitive assessment tool able to detect muscle dysfunction and so favouring the implementation of early rehabilitation therapy.

The standard therapy for patients with haemophilia is prophylactic treatment with replacement factor VIII (FVIII) or factor IX (FIX). Patients who develop inhibitors against FVIII/FIX face an increased risk of bleeding, and the likelihood of early development of progressive arthropathy, alongside higher treatment‐related costs. Bypassing agents can be used to prevent and control bleeding, as well as the recently licensed prophylaxis, emicizumab, but their efficacy is less predictable than that of factor replacement therapy. Antibody eradication, by way of immune tolerance induction (ITI), is still the preferred management strategy for treating patients with inhibitors. This approach is successful in most patients, but some are difficult to tolerise and/or are unresponsive to ITI, and they represent the most complicated patients to treat. However, there are limited clinical data and guidelines available to help guide physicians in formulating the next treatment steps in these patients. This review summarises currently available treatment options for patients with inhibitors, focussing on ITI regimens and those ITI strategies that may be used in difficult‐to‐treat patients. Some alternative, non‐ITI approaches for inhibitor management, are also proposed, Supported by a grant from Novo Nordisk Health Care AG, in compliance with international guidelines for good publication practice.

Perioperative bleeding is a major concern in patients with factor VII (FVII) deficiency. Evaluating data of 95 FVII-deficient patients undergoing 110 surgical procedures (61 major, 49 minor), we assessed the impact of type of surgery, bleeding phenotype and FVII coagulant activity (FVII:C) levels on perioperative replacement therapy (RT). Compared to those with higher FVII:C levels, patients with

In children with severe haemophilia A, inhibitors to factor VIII (FVIII) usually develop during the first 50 treatment exposure days and are classified as low or high titre depending on the peak inhibitor titre being greater or less than 5 Bethesda units/mL (BU/mL). Classification of the inhibitor may change with time, as some low-titre inhibitors progress to high titre following re-exposure to FVIII concentrate. The aim of this study was to investigate potential risk factors for such a progression in children with severe haemophilia A and newly diagnosed inhibitors. This study was a follow-up study of the PedNet Registry and included 260 children with severe haemophilia A and inhibitors born between 1990 and 2009 and recruited consecutively from 31 haemophilia centres. Clinical and laboratory data were collected from the date of each child's first positive inhibitor test for at least 3 years. At the time of first positive inhibitor test, 49% (n = 127) had low-titre inhibitors, with 50% of them progressing to high titre and only 25% maintaining low titres. The FVIII gene (F8) mutation type was known in 247 patients (95%), and included 202 (82%) null mutations. The progression to high-titre inhibitors was associated with null F8 mutations (odds ratio [OR]: 2.6; 95% confidence interval [CI]: 1.0–6.5), family history of inhibitors (OR: 7.2; 95% CI: 1.8–28.4) and the use of high-dose immune tolerance induction, defined as ≥100 IU FVIII concentrate/kg/d (OR: 3.9; 95% CI: 1.5–10.0). These results suggest that high-dose immune tolerance induction should be avoided as the initial strategy in patients who develop low-titre FVIII inhibitors.

Difficulties at the beginning of the learning curve in minimally invasive surgery (MIS) can well be overcome by simulation outside the operating room. Despite a great number of available devices, standardized, structured, and validated training curricula for video simulators are scarce. The Lubeck Toolbox (LTB) video trainer provides six training modules and online video tutorials. Proficiency levels for the tasks were defined by performance analysis of MIS experts (n = 15). Mean values of the best performed repetitions were set as benchmarks for a validation study with n = 30 MIS novices and the learning curves calculated. The novices performed a cholecystectomy on a pig organ model before and after the curriculum which were analyzed using the GOALS score. Benchmarks defined by expert performance for the task Nos. 1 to 6 were 72 s (± 8) (Pack Your Luggage), 49 s (± 9) (Weaving), 66 s (± 10) (Chinese Jump Rope), 89 s (± 28) (Triangle Cut), 138 s (± 44) (Hammer Cut), and 98 (± 22) (Suturing). The median numbers of required repetitions by the novices to reach the proficiency level were n = 42 (7–80), n = 26 (9–55), n = 32 (14–77), n = 44 (15–59), n = 19 (6–68), and n = 26 (15–60). These values were all located at the beginning of the plateau phase of the learning curves. GOALS score improved significantly after completion of the curriculum (18.0 (± 2.6) vs. 10.9 (± 1.6), p

Introduction Inhibitory antibodies to factor VIII occur in about 30% of previously untreated patients (PUPs) and are the most serious complication of haemophilia A. It is unclear why some patients develop inhibitors and others do not. Aims The Early Prophylaxis Immunologic Challenge (EPIC) study was designed to test the hypothesis that inhibitor incidence in PUPs with severe or moderately severe haemophilia A could be reduced when a once-weekly FVIII prophylaxis starts with 25 IU kg−1 rAHF-PFM before 1 year of age and immunological danger signals are minimized. Methods These signals were minimized by avoiding: surgery; the first FVIII infusion during severe bleeding or an infection; central venous access devices and administering vaccinations intramuscularly 3–4 days before or after FVIII. Results Eight of the 19 treated subjects (42.1%) developed confirmed inhibitors. Eleven of the 19 treated subjects were PUPs without any prior exposure to FVIII. Three of them (27.3%) developed a confirmed inhibitor together with FVIII-binding antibodies. The study was stopped because the likelihood to reach the primary objective was minimal, a decision endorsed by the data safety monitoring board. Conclusion Because of early termination, the EPIC study hypothesis could not be corroborated. Nonetheless, our data analyses indicate that the current definition of an inhibitor only based on plasma inhibitor activity ≥0.6 BU mL−1 may not always reflect the presence of FVIII-neutralizing antibodies. The findings of this study teach us that low-level inhibitor activity results need in addition a confirmatory test and/or the assessment of the therapeutic response.

Prophylaxis is now an established treatment standard in haemophilia in Western Europe and the US with multiple studies demonstrating the clinical benefits of prophylaxis over on-demand treatment. In Western Europe in particular, prophylactic use of factor VIII (FVIII) is high as a result of the findings from the early prophylaxis studies and adherence to national guidelines. Unfortunately, prophylaxis has not yet been implemented on a worldwide basis. The introduction of prophylaxis by haemophilia treatment centres in Bremen, Frankfurt and Munich, as recommended in German guidelines, has significantly improved outcomes for our young haemophilia patients. In the Frankfurt centre, a decreasing rate of inhibitors has been observed since prophylaxis was started early, dosing was individualized, and the importance of treatment continuity was recognized. The centres in Munich and Bremen have explored the possibility of further reducing inhibitor rates using early tolerization - a new prophylaxis regimen that introduces low FVIII doses administered once weekly as soon as a bleeding tendency is observed - with excellent results. All three centres avert the induction of immunological danger signals by avoiding the use of central venous catheters, postponing vaccination wherever possible and not undertaking elective surgery during the early FVIII exposure days. The benefits of using this approach have been confirmed by the remarkably low rates of inhibitors in previously untreated patients reported at these centres. Hopefully, as we and others explore new prophylaxis regimens for our paediatric patients, we can work towards the goal of one day overcoming this serious complication of haemophilia treatment.

Introduction A paucity of data exists on the incidence, diagnosis and treatment of bleeding in women with inherited factor VII (FVII) deficiency. Aim Here we report results of a comprehensive analysis from two international registries of patients with inherited FVII deficiency, depicting the clinical picture of this disorder in women and describing any gender-related differences. Methods A comprehensive analysis of two fully compatible, international registries of patients with inherited FVII deficiency (International Registry of Factor VII deficiency, IRF7; Seven Treatment Evaluation Registry, STER) was performed. Results In our cohort (N = 449; 215 male, 234 female), the higher prevalence of mucocutaneous bleeds in females strongly predicted ensuing gynaecological bleeding (hazard ratio = 12.8, 95% CI 1.68–97.6, P = 0.014). Menorrhagia was the most prevalent type of bleeding (46.4% of patients), and was the presentation symptom in 12% of cases. Replacement therapies administered were also analysed. For surgical procedures (n = 50), a receiver operator characteristic analysis showed that the minimal first dose of rFVIIa to avoid postsurgical bleeding during the first 24 hours was 22 μg kg−1, and no less than two administrations. Prophylaxis was reported in 25 women with excellent or effective outcomes when performed with a total weekly rFVIIa dose of 90 μg kg−1 (divided as three doses). Conclusion Women with FVII deficiency have a bleeding disorder mainly characterized by mucocutaneous bleeds, which predicts an increased risk of ensuing gynaecological bleeding. Systematic replacement therapy or long-term prophylaxis with rFVIIa may reduce the impact of menorrhagia on the reproductive system, iron loss and may avoid unnecessary hysterectomies.

Retrospective, single centre cohort study. To determine factors associated with ventilator weaning success and failure in patients with acute spinal cord injury (SCI); determine length of time and attempts required to wean from the ventilator successfully and determine the incidence of pneumonia. BG Klinikum Hamburg, Level 1 trauma centre, SCI Department, Germany. From 2010 until 2017, 165 consecutive patients with cervical SCI, initially dependent on a ventilator, were included and weaned discontinuously via tracheal cannula. Data related to anthropometric details, neurological injury, respiratory outcomes, and weaning parameters were prospectively recorded in a database and retrospectively analysed. Seventy-nine percent of all patients were successfully weaned from ventilation. Average duration of the complete weaning process was 37 days. Ninety-one percent of the successfully weaned patients completed this on first attempt. Age (>56 years), level of injury (C4 and/or above), vital capacity ( 25 kg/m2), and chronic obstructive pulmonary disease (COPD) significantly decreased the chance of successful weaning. These factors also correlated with a higher number of weaning attempts. High level of injury, older age, and reduced vital capacity also increased the duration of the weaning process. Patients with low vital capacity and concurrent therapy with Baclofen and Dantrolene showed higher rates of pneumonia. We conclude that mentioned factors are associated with weaning outcome and useful for clinical recommendations and patient counselling. These data further support the complexity of ventilator weaning in the SCI population due to associated complications, therefore we recommend conducting weaning of patients with SCI on intensive or intermediate care units (ICU/IMCU) in specialised centres.

Recent advancements in almost all aspects of hemophilia treatment have vastly improved patient care and management, and new and emerging treatments hold the promise of further progress. However, there remains a scarcity of data on long-term outcomes in hemophilia, particularly among those patients with inhibitors, for whom no validated outcome assessment tools are currently available. At the 15th Zurich Haemophilia Forum, an expert panel reviewed the most important outcome measures in inhibitor patients and considered the challenges associated with assessing outcomes in this population. A framework for outcome assessment in inhibitor patients incorporates traditional hemophilia outcome measures, such as bleed frequency and mortality, alongside measures of health, functioning, disability, social participation, quality of life, and economic considerations. It is important to remember that inhibitor patients differ in their clinical needs, perspectives, and priorities according to age, inhibitor status, degree of joint disease, and activity levels; as a result, the relative importance of different outcome measures will change throughout an inhibitor patient's life. Challenges inherent in measuring long-term outcomes in inhibitor patients include the small number of known patients, the subjective nature of many outcome assessment tools, and the risk of overburdening patients with repeated requests to complete questionnaires or participate in studies. Therefore, there is an urgent need to reach consensus on the most important and appropriate assessment tools for measuring outcomes in this population. These tools should ideally be standardized, easily applied, and internationally applicable in order to collect and generate quality outcome data.

Patients with haemophilia A (and their physicians) may be reluctant to switch factor VIII (FVIII) concentrates, often due to concerns about increasing the risk of inhibitors; this reluctance to switch may contribute to patients missing the clinical benefits provided by the arrival of new factor VIII products. This topic was explored at the Eleventh Zurich Haemophilia Forum. Clinical scenarios for which product switching may be cause for concern were discussed; when there is a clinical need, there are no absolute contraindications to switching, but some patients (e.g. previously untreated patients and those undergoing elective surgery) may require more careful consideration. Both patient and physician surveys indicate that the reluctance to switch, and the fear of inhibitor development, does not appear to be evidence based. The evaluation of more recent data did not support previous studies suggesting that particular products (e.g. recombinant vs. plasma-derived and full length vs. B-domain modified) may be associated with increased risk. In addition, data from three national product switches showed that switching was not associated with increased inhibitor risk, but highlighted the need for regular inhibitor testing and for a centralised, unbiased database of inhibitor incidence. To conclude, current evidence does not suggest that switching products significantly influences inhibitor development.

Although effective therapies for haemophilia have been available for decades, the prevention and treatment of joint disease remain major clinical concerns for all haemophilia patients. Early identification of joint disease is vital to initiate or modify treatment, and prevent arthropathy. However, there remains a need for more sensitive and accurate methods, which may also detect improvement in patient outcome with new therapies or different prophylaxis regimens. These topics were explored at the Ninth Zürich Haemophilia Forum. A summary of our shared views on the limitations of current assessment methods, and the potential advantages of more recently developed tools, is provided. Ultrasonography enables more frequent routine monitoring and the early detection of joint disease. In addition, serological markers may provide suitable biomarkers of early arthropathy. To prevent arthropathy, in our opinion, prophylaxis is key to prevent joint bleeds and subsequent initiation of the 'vicious circle of joint disease'. However, issues remain, including when prophylaxis should be started, stopped, and if it is efficacious for inhibitor patients. Once joint bleeding has occurred, enhanced on-demand treatment should be considered. For more advanced stages of joint disease, the issues regarding the treatment options available are explored. Radiosynovectomy should be performed to treat chronic synovitis, and may prevent the need for elective orthopaedic surgery (EOS). Ultimately, however, EOS can be considered once all other treatment options have been explored. While, bypassing agents have facilitated the use of EOS in inhibitor patients, a multidisciplinary approach and careful surveillance is required for good patient outcome.

Purpose Abstinence is a core pregnancy and sexually transmitted infection (STI) prevention strategy. We explore the attitudinal, behavioral, and family contexts relating to abstinence and the decision to delay sex among adolescent boys. Methods Adolescent boys ages 14–17 years were recruited from community sites using a venue-based sampling method. All eligible boys at venues were invited to participate in an electronic survey. Question items included sexual behaviors, attitudes related to sex, relationships, masculine values, and family contextual items. Results We enrolled 667 participants, mean age 15.7 years, of diverse ethnicity. A total of 252 were abstinent (38%). Abstinent participants were younger and less likely to report non-coital behaviors, and reported lower conventional masculine values. Among abstinent participants, 62% planned to delay sex, whereas 38% anticipated sex in the next year. Participants with lower conventional masculine values and more religious or moral motivations for abstinence were more likely to plan to delay sex. Conclusions Abstinence among boys is common, even in high–STI risk communities. For these boys, abstinence appears to be a complex behavioral decision influenced by demographic, behavioral, attitudinal, and contextual factors such as age, race, non-coital sexual behaviors, and masculine values. Understanding the attitudes and contexts of abstinence, including plans to delay sex, can inform the development of public health programs for early fatherhood and STI prevention.

WOS: 000319897700018, PubMed: 23403322, Because of the very short half-life of factor VII, prophylaxis in factor VII deficiency is considered a difficult endeavor. The clinical efficacy and safety of prophylactic regimens, and indications for their use, were evaluated in factor VII-deficient patients in the Seven Treatment Evaluation Registry. Prophylaxis data (38 courses) were analyzed from 34 patients with severe factor VII deficiency (10 years. No thrombosis or new inhibitors occurred. In conclusion, a subset of patients with factor VII deficiency needed prophylaxis because of severe bleeding. Recombinant activated factor VII schedules based on "frequent" administrations (three times weekly) and a 90 mu g/kg total weekly dose were effective. These data provide a rationale for long-term, safe prophylaxis in factor VII deficiency., Novo Nordisk and charities; Novo Nordisk A/SNovo Nordisk, This work was supported by institutional research organizations and unrestricted funding from Novo Nordisk and charities, administered by the Internal Medicine Department of the University of L'Aquila. GM, as coordinator of the International FVII Study Group and the STER, collected the financial support. Editorial assistance to the authors during the preparation of this manuscript was provided by Sharon Eastwood (medical writer, PAREXEL) and financially supported by Novo Nordisk A/S, in compliance with international guidelines for good publication practice.

Inhibitor development against von Willebrand factor, factor VIII or factor IX is one of the most severe complications of treating patients with von Willebrand's disease (VWD), haemophilia A or haemophilia B respectively. Continuous infusion of factor concentrate has been implicated as a risk factor for inhibitor development. This prospective study investigated inhibitor development after continuous infusion of factor concentrate for surgical procedures in subjects with VWD or a severe form of haemophilia (factor activity

Introduction Hemophilia patients with inhibitors have frequent bleeding episodes and often develop hemophilic arthropathy which is in contradistinction to non-inhibitor patients for whom prophylaxis prevents joint disease. Recently, two prospective trials have demonstrated that secondary prophylaxis with bypassing agents in inhibitor patients offers benefit by reducing bleeding episodes. This report describes the clinical experience of secondary prophylaxis in a large population of inhibitor patients. Patients/Methods This retrospective, observational study was performed by abstracting data from medical records of patients in whom secondary prophylaxis with rFVIIa was prescribed. Data were collected by professional medical record abstractors and included patient demographics, dosing regimens, bleeding events, and healthcare resource utilization. Data analysis was descriptive and included sensitivity analyses. Results Data from 86 patients from 14 countries were collected. The primary outcome measure (% reduction in bleeding) was 46% (95% CI, -54.0 to − 38.2) in patients with at least one bleeding episodes prior to starting prophylaxis and 52% (95% CI, -60.7 to − 43.3) in patients with at least one bleeding episode per month prior to starting prophylaxis. A variety of subanalyses were performed, including among age and bleed location; the results for pediatric patients, adults, target and non-target joint bleeds categorizations were similar to the overall primary outcome. Conclusions The results in this large observational study are similar to those from the previously reported prospective study of prophylaxis with rFVIIa in inhibitor positive patients, although this study represents a more typical inhibitor population who utilized prophylaxis in the clinical setting. As such, prophylaxis should be considered a potentially effective therapy in hemophilia patients with inhibitors.

Little research has explored the link between the behavioural effects of testosterone use among transmen and HIV risk. We conducted a mixed methods study to explore testosterone use among transmen and the behavioural effects on HIV risk. A sample of 122 transmen from San Francisco participated in a cross-sectional quantitative survey and 14 transmen participated in 2 focus group discussions. Most participants (81.9%) were currently taking hormones. Participants attributed testosterone use to new sexual behaviours among 69% of transmen, changes in sexual attraction (49%), and increased frequency of sexual activity (72%). Among current testosterone users, 3.3% had cisgender men as partners before starting testosterone, whereas after starting testosterone, 25.4% did. Similarly, 4.1% had a transgender woman as a sexual partner before starting testosterone and 13.9% after starting testosterone. Findings suggest that testosterone's side effects were associated with transmen's desires for sex with cisgender men who have sex with men. The reported increase in attraction to and sex with partners from populations with a high HIV prevalence may have important implications for HIV risk among transmen, especially as the availability of transgender health services may draw transmen to a context in which HIV prevalence is high.

Introduction: Maintaining haemostasis in surgery is challenging for hereditary rare bleeding disorders in which multi-coagulation-factor concentrates are the only therapeutic option. Hereditary factor X (FX) deficiency affects 1:500 000 to 1:1 000 000 individuals, and no specific replacement FX concentrate has been available. A high-purity, plasma-derived FX concentrate (pdFX) has been developed for patients with hereditary FX deficiency. Aim: Our objective was to assess the safety and efficacy of pdFX in subjects with FX deficiency undergoing surgery. Methods: Subjects with hereditary mild-to-severe FX deficiency (basal plasma FX activity [FX:C] 50 IU/dL until the subject was no longer at risk of bleeding due to surgery. Efficacy of pdFX was assessed by blood loss during surgery, requirement for blood transfusion, postoperative bleeding from the surgical or other sites, and changes in haemoglobin levels. Safety was assessed by adverse events (AEs), development of inhibitors, and clinically significant changes in laboratory parameters. Results: Five subjects (aged 14-59 years) underwent 7 surgical procedures (4 major and 3 minor). Treatment duration was 1-15 days. For each procedure, pdFX treatment was assessed as “excellent” in preventing bleeding and achieving haemostasis. No blood transfusions were required, no AEs related to pdFX were observed, and no clinically significant trends were found in any laboratory parameters. Conclusion: These data demonstrate that pdFX is safe and effective as replacement therapy in 5 subjects with mild-to-severe FX deficiency undergoing surgery on 7 occasions.

SummaryThe burden of disease in haemophilia patients has wide ranging implications for the family and to society. There is evidence that having a current inhibitor increases the risk of morbidity and mortality. Morbidity is increased by the inability to treat adequately and its consequent disabilities, which then equates to a poor quality of life compared with non-inhibitor patients. The societal cost of care, or `burden of inhibitors’, increases with the ongoing presence of an inhibitor. Therefore, it is clear that successful eradication of inhibitors by immune tolerance induction (ITI) is the single most important milestone one can achieve in an inhibitor patient. The type of factor VIII (FVIII) product used in ITI regimens varies worldwide. Despite ongoing debate, there is in vitro and retrospective clinical evidence to support the use of plasma-derived VWF-containing FVIII concentrates in ITI regimens in order to achieve early and high inhibitor eradication success rates.

The introduction of clotting factor concentrates led to major advances in hemophilia care. Rather than simply providing an alternative to plasma-derived concentrates, the introduction in the 1990s of recombinant concentrates added value to replacement therapy particularly with respect to prophylaxis and immune-tolerance induction. While the safety of plasma-derived concentrates has improved considerably, these concentrates may still pose an infectious risk through as-yet unknown pathogens and poor impurity constituent characterization. Recombinant concentrates are increasingly used because of their benefits in pathogen safety, convenience and the potential for unfettered supply. Yet worldwide they remain accessible only to a limited number of patients due to fear of the potential for inhibitor development, overestimation of their costs and underestimation of their benefits. This article reviews the characteristics and properties of recombinant FVIII concentrates to help physicians and patient representatives promote the right of access of patients to the safest products.

SummaryWe report a prospective trial of 55 previously untreated patients (PUPs) and minimally treated patients (MTPs) with severe/moderately severe haemophilia A (baseline factor VIII [FVIII] ≤2%) treated with a single FVIII replacement product. It was the objective of this study to evaluate the immunogenicity, efficacy, and safety of rAHF-PFM (Advate®). Ondemand or prophylactic treatment regimens were determined at the discretion of the investigator. rAHF-PFM was also permitted for perioperative management. There were 633 bleeding episodes (BEs), including 517 treated, and 466 rated for efficacy. Haemostatic efficacy was considered excellent/good in 93% of 466 rated treatments. Of 517 treated BEs, 463/517 (90%) were managed with one (356/517 [69%]) or two infusions (107/517 [21%]). There were 27 surgeries. Intraoperative (n=22) and postoperative (n=25) haemostatic efficacies were considered excellent or good in 100% of rated surgeries. Related serious adverse events (SAEs) were inhibitor development in 16/55 (29.1%) subjects who received at least one infusion of rAHF-PFM. Nonserious, related adverse events (AEs) were few in number (14 in eight subjects). The odds ratio (OR [95% Confidence Interval, CI]) of developing inhibitors was significantly higher in subjects with a family history of inhibitor (4.95 [1.29–19.06]), non-Caucasian ethnicity (4.18, [1.18–14.82]), and intensive treatment at high dose (4.5 [1.05–19.25]) within ≤20 exposure days (EDs). In conclusion, rAHF-PFM was safe and effective for the management and perioperative coverage of PUPs/MTPs with severe/moderately severe haemophilia A. This report supports previous findings from studies in which family history of inhibitor, non-Caucasian ethnicity, and high intensity treatment were associated with high risk of inhibitor development.

For hemophilia patients with inhibitors, immune tolerance induction (ITI) may help to restore clinical response to factor (F) VIII or FIX concentrates. Several ITI regimens and protocols exist; however, despite 30 yr of progressive investigation, the ITI evidence base relies mainly on observational data. Expert opinion, experience, and interpretation of the available evidence are therefore valuable to support clinical decision-making. At the Sixth Zurich Haemophilia Forum, an expert panel considered recent data and consensus to distill key practice points relating to ITI. The panel supported current recommendations that, where feasible, ITI should be offered early to children and adults (ideally ≤ 5 yr of inhibitor detection) when inhibitor titers are

A group of international physicians committed to the unique care of pediatric hemophilia patients form the International Network for Pediatric Hemophilia (INPH). The main objectives of the group center on scientific studies, educational presentations and networking. By joining together on an international level, large hemophilia centers with extensive experience in the clinical care of children with hemophilia perform and publish scientifically valid studies. Annual meetings of the group include invited speakers who present hot topics or new developments in this therapeutic area for the purpose of educating the group on cutting edge research. Furthermore, since members have experience in pediatric treatment from different parts of the world, current practices as well as new trends can be discussed and shared among the group. The Fifth Annual INPH meeting was held in Buenos Aires, Argentina, on July 8–9, 2010 and focused on the topics of prophylaxis treatment and immune tolerance induction in the clinical care of children with hemophilia. The meeting is structured around roundtable discussions on the members’ current research and clinical activities, project reports of INPH study initiatives, followed by invited educational presentations with interactive discussions.

Excessive bleeding represents a major complication of surgical interventions and its control is especially relevant in patients with Congenital Bleeding Disorders (CBD). In factor VII (FVII) deficiency, scanty data on surgery is available to guide treatment strategies. The STER (Seven Treatment Evaluation Registry) is a multi-centre, prospective, observational, web-based study protocol providing the frame for a structured and detailed data collection. Inhibitor occurrence was checked in a centralized fashion. Forty-one surgical operations (24 'major' and 17 'minor') were performed in 34 subjects with a carefully characterized FVII deficiency under the coverage of recombinant activated Factor VII (rFVIIa). Bleeding occurred during three major interventions of orthopaedic surgery, but rFVIIa was given at very low dose in each case. An antibody to FVII was observed in one patient who underwent a multiple dental extraction. No thromboses were reported during the 30-d follow up period. Replacement therapy with rFVIIa proved effective when suitable doses were used, which, during the period of maximum bleeding risk (the day of operation), were calculated (Receiver Operated Characteristic analysis) to be of at least 13 μg/kg/body weight per single dose and no less than three administrations. This indication is important especially in the case of major surgery.

Few studies document incidence of injection drug use among homeless youth. We followed a cohort of 70 street-recruited homeless youth in San Francisco, California who had never injected drugs for six months in 2004-5. We examined initiation of injection drug use and its predictors, informed by prior ethnographic findings. Data were analyzed using exact logistic regression. 11.4% of youth initiated injection drug use. Having no high school education, being over 21 years old, and being in disequilibrium predicted initiation. Limitations, implications and suggestions for future research are noted. Funding was provided by the National Institute for Child Health and Development.

Summary. The most problematic complication of haemophilia A treatment is the development of inhibitors to FVIII. The highest risk of developing inhibitors is during the first 20 exposure days (EDs). If the patient can be brought through this high risk period without inhibitor development, the subsequent risk is low. Therefore, as a pilot project, we developed a prophylaxis regimen for the first 20‐50 EDs specifically designed to induce tolerance to the administered FVIII and to minimize inhibitor development by avoiding immunological danger signals. Twenty-six consecutive previously untreated patients (PUPs) with severe haemophilia A were treated with the new prophylaxis regimen and the incidence of inhibitor development in this group was compared with that in a historical control group of 30 consecutive PUPs treated with a standard joint protection prophylaxis regimen (40‐50 IU kg )1 , three times a week). There were no significant differences between the study and control groups in patient-related inhibitor risk factors such as ethnicity (all Caucasian), severity of haemophilia (all

SummaryRecombinant activated factor VII (rFVIIa; Novo Seven®) is, besides other indications, authorised for the treatment of bleeding episodes in patients with hereditary haemophilia A or B and inhibitors. Based on the results of three clinical studies, marketing authorisation was granted for the single dose of 270 μg/kg body weight rFVIIa for the treatment of mild-to-moderate bleeding episodes in patients with haemophilia A or B with inhibitors in March 2007. Thereupon, an expert group analysed the relevance of this additional treatment option for clinical routine. Compared with the repeated application of 90 μg/kg body weight rFVIIa, quality of life may be improved if the single dose of 270 μg/kg body weight rFVIIa reduces the number of injections. The single dose has a benefit for those patients who require several rFVIIa applications or who do not respond adequately to low doses. Moreover, patients with poor venous access or who fear injections or reject them (especially children) may benefit from the single dose. The prescription of 270 μg/kg body weight rFVIIa as a single dose instead of multiple dosing of 90 μg/kg body weight is basically an individual and indication-related decision.

Haemophilia patients with inhibitors characteristically have impaired joint function and reduced health-related quality of life (HRQoL). This analysis examined whether secondary prophylaxis with recombinant activated factor VII (rFVIIa) improves HRQoL vs. conventional on-demand therapy in patients with haemophilia with inhibitors and frequent bleeds. After a 3-month preprophylaxis period, 22 patients received daily rFVIIa prophylaxis (90 or 270 microg kg(-1)) for 3 months, followed by 3 months' postprophylaxis. Days of hospitalization, absence from school/work and mobility aids requirements were recorded. HRQoL was assessed by EuroQoL (EQ-5D) questionnaire, visual analogue scale (VAS), derived Time to Trade-Off (TTO) scores and Quality Adjusted Life Years (QALYs). rFVIIa prophylaxis significantly (P < 0.0001) reduced bleeding frequency vs. prior on-demand therapy. Hospitalization (5.9% vs. 13.5%; P = 0.0026) and absenteeism from school/work (16.7% vs. 38.7%; P = 0.0127) decreased during prophylaxis; these effects tended to be maintained during postprophylaxis. HRQoL (evaluated by EQ-5D) tended to improve during and after rFVIIa prophylaxis. Notably, pain decreased and mobility increased in 40.9% and 27.3% of patients, respectively, at the end of the postprophylaxis period vs. preprophylaxis. Median VAS score increased from 66 to 73 (P = 0.048), and TTO scores suggested better HRQoL (0.62 vs. 0.76; P = 0.054) during postprophylaxis than preprophylaxis. Small to moderate changes in effect sizes were reported for VAS and TTO scores. Median QALYs were 0.68 (VAS) and 0.73 (TTO). Reductions in bleeding frequency with secondary rFVIIa prophylaxis were associated with improved HRQoL vs. on-demand therapy.

Among a cohort of 237 sexually active females aged 14-19 years recruited from community venues in a predominantly Latino neighborhood in San Francisco, California, the authors examined the relation between gang exposure and pregnancy incidence over 2 years of follow-up between 2001 and 2004. Using discrete-time survival analysis, they investigated whether gang membership by individuals and partners was associated with pregnancy incidence and determined whether partnership characteristics, contraceptive behaviors, and pregnancy intentions mediated the relation between gang membership and pregnancy. Pregnancy incidence was determined by urine-based testing and self-report. Latinas represented 77% of participants, with one in five born outside the United States. One quarter (27.4%) became pregnant over follow-up. Participants' gang membership had no significant effect on pregnancy incidence (hazard ratio = 1.25, 95% confidence interval: 0.54, 3.45); however, having partners who were in gangs was associated with pregnancy (hazard ratio = 1.90, 95% confidence interval: 1.09, 3.32). The male partner's perceived pregnancy intentions and having a partner in detention each mediated the effect of partner's gang membership on pregnancy risk. Increased pregnancy incidence among young women with gang-involved partners highlights the importance of integrating reproductive health prevention into programs for gang-involved youth. In addition, high pregnancy rates indicate a heightened risk for sexually transmitted infections.

ZusammenfassungEin Problem in der Therapie der Hämophilie ist die Entwicklung von Antikörpern gegen den zugeführten Faktor VIII. Patienten mit Antikörpern sind bei spontanen Blutungen, Operationen oder Traumata besonders gefährdet. Ist die Immuntoleranztherapie mit hohen i.v.-Dosen von Faktor VIII nicht erfolgreich, kommt eine Behandlung mit rekombinantem Faktor VIIa oder aktiviertem Prothrombinkomplex in Betracht. Dieser Artikel fasst die Daten dreier Patienten mit einer schweren Form der Hämophilie A und einer Intron- 22-Inversion im FVIII-Gen, die Antikörper gegen FVIII entwickelt haben, zusammen.Die Gabe von rFVIIa erwies sich bei diesen Patienten nicht nur als effektiv, sondern auch als sicher. Darüber hinaus zeigte sich unter der prophylaktischen Therapie mit rFVIIa in individueller Dosierung von 180 bis 270 μg/kg Körpergewicht einmal pro Tag eine deutliche Reduktion der spontanen Blutungsereignisse (Target Joints, Muskulatur, andere Lokalisation). Die verminderte Blutungsfrequenz führte zum Rückgang der Gelenk-und Muskelschmerzen und verhalf den jungen Patienten zu größerer Mobilität und deutlich besserer Lebensqualität.