Search

In patients with FXI deficiency, the risk of surgery-related bleeding is poorly correlated with plasma FXI activity (FXI:C); the latter can therefore not be used as a reliable predictor of bleeding in surgeries.The aim of this retrospective study was to determine whether thrombin generation assay (TGA) could be used to evaluate the risk of surgery-related bleeding in FXI-deficient patients. TGA parameters were compared to FXI:C values, haemostatic treatments and surgical outcomes.All patients followed at the haemophilia treatment care centre (Lyon, France) with a FXI:C 50IU/dL, and for whom a baseline TGA was performed between January 2014 and December 2019, were included.Among the 175 surgeries reported herein in 49 patients, FXI concentrates were used for 11 (6%) surgeries and fresh frozen plasma was used for five (3%) surgeries; these surgeries were performed in patients with two or three impaired TGA parameters. No haemostatic treatment was prescribed for 119 (68%) surgeries. A surgery-related bleeding occurred in 12 patients during 21 (12%) surgeries. Thrombin generation was significantly reduced or delayed in patients who reported surgery related-bleeding. Among the 34 (68%) surgeries performed without haemostatic treatment in patients with three impaired TGA parameters, a surgery-related bleeding was reported in 44% of cases (15 surgeries out of 34).The present study confirmed that TGA is an interesting laboratory test in FXI deficiency, for determining the bleeding risk and guiding the haemostatic management of surgeries, while taking into account the surgical bleeding risk and the history of bleeding.

The public health policies and sanitary measures taken by governments in various countries to stem the spread of the COVID-19 pandemic (e.g. lockdown, social distancing) have major implications for athletes. The radical changes are challenging and risk causing significant career disruption to athletes, with subsequent negative psychological effects. Thus, the ways athletes cope with such adversity is of critical importance. The present study aimed to identify athletes' coping profiles using a person-centred approach, based on their reported use of multiple coping strategies in response to the impact of the COVID-19 outbreak, and to compare levels of anxiety, stress appraisals, interpersonal coping strategies, and availability and appreciation of the major sources of support across profiles. A total of 526 French athletes competing at national to elite levels answered an online questionnaire during the lockdown. Latent profile analysis results yielded four distinct coping profiles (i.e. self-reliant, engaged, avoidant, active and social). The MANOVA showed that athletes belonging to the four profiles differed on anxiety, stress appraisals, social support, and interpersonal coping. In particular, avoidant copers reported high levels of anxiety, threat, and uncontrollability, and appeared less able to regulate responses to the impact of the COVID-19 outbreak. Using a person-centred approach, the findings could inform the development of more adequate care, support, and intervention for athletes, especially avoidant copers, who were characterized by the least effective coping skills and resources. Accordingly, stress reappraisal and stress mindset interventions could be promising approaches to effectively manage pandemic-related impact during and after the COVID-19 crisis.Highlights The COVID-19 outbreak has major implications for athletes and is causing significant disruption to their careers. Using a person-centred approach, four coping profiles emerge showing athletes' preferred use of several coping strategies in response.The four coping profiles (i.e. self-reliant, engaged, avoidant, active and social) differentiate distinct groups of athletes in relation to anxiety, stress appraisals, social support, and interpersonal coping.Avoidant copers were characterized by the least effective coping skills and social context of coping. Management of the COVID-19 situation may be more problematic for them than other in mitigating its negative psychological effects.Using a person-centred approach, the findings could inform the development of more adequate care, support, and intervention for athletes, especially avoidant copers, who were characterized by the least effective coping skills and resources.

Health of people with severe haemophilia (PwSH) improves thanks to the advancements in haemophilia care, giving them more opportunities in occupational integration. However, there is little literature on the occupational integration of PwSH.The main objective of our study was to assess the occupational integration of PwSH and to compare it with that of the general population. The secondary objective was to study the association between individual characteristics (sociodemographic, clinical and psycho-behavioural) and occupational integration of PwSH.A multicentre, non-interventional, cross-sectional study was conducted in 2018-2020 on PwSH, aged over 18 and under 65 years and included in the FranceCoag registry. Measurements included indicators of occupational integration, sociodemographic, clinical and psycho-behavioural characteristics. The indicators of occupational integration were compared with those of the general population, using indirect standardization. The data of the general population were available from the National Institute of Statistics and Economic Studies (INSEE). Determinants of occupational integration were explored using structural equation modelling.Of 1262 eligible people, 588 were included. PwSH had a lower employment rate than the general population (standardized ratio, .85; 95% CI, .77-.94). There were more PwSH at tertiary education level than expected (standardized ratio, 1.38; 95% CI, 1.17-1.61). HIV infection, poor physical health and mental health concerns were associated with a higher risk of unemployment in PwSH.Employment rate of PwSH is lower than that of the general population despite their higher education level. Target interventions focusing on determinants of difficult occupational integration could be helpful for PwSH.

International audience; The aim of this study was to identify young elite athletes’ personality profiles using a person-centered approach, and to investigate whether the profiles significantly differ in stress and sleep. 260 athletes from a variety of sports completed a questionnaire package to assess neuroticismand conscientiousness traits, stress appraisals (i.e. intensity and directional interpretation of stress, challenge and threat appraisals), and various indicators of sleep (i.e. sleep quality, social jet lag, Ford insomnia response to stress test (FIRST)). A latent profile analysis (LPA) approach was used to identify personality profiles based on the scores of neuroticism and conscientiousness. A multivariate analysis of variance was performed to examine if the athletes belonging to different personality profiles differ on stress appraisals and indicators of sleep.Three profiles emerged: Maladaptive profile (high levels of conscientiousness and neuroticism); Highly adaptive profile (moderate level of conscientiousness and low level of neuroticism); Adaptive profile (high level of conscientiousness and moderate level of neuroticism). Results showed that athletes from the adaptive profile reported significantly lower scores of stress intensity and threat appraisal than those from other profiles. Athletes from the maladaptive profile reported significantly higher levels of FIRST than those from other profiles as well as worse sleep quality and lower levels of challenge appraisal than the athletes from the highly adaptive profile. These results suggest that investigating personality profile may be useful in identifying athletes at higher risk of stress sensitivity and worsening sleep that are likely to benefit from preventive actions (e.g. cognitive behavioural therapy interventions).

Introduction With current molecular diagnosis, about 1 to 5% of haemophilia A (HA) patients remain genetically unresolved. In these cases, deep intronic variation or structural variation disrupting the F8 gene could be causal. Aim To identify the causal variation in four genetically unresolved mild-to-severe HA patients using an F8 mRNA analysis approach. Methods Ectopic F8 mRNA analysis was performed in four unrelated HA patients. An in vitro minigene assay was performed in order to confirm the deleterious splicing impact of each variation identified. Results In all probands, mRNA analysis revealed an aberrant splicing pattern, and sequencing of the corresponding intronic region found a deep intronic substitution. Two of these were new variations: c.2113+601G>A and c.1443+602A>G, while the c.143+1567A>G, found in two patients, has previously been reported. The c.1443+602A>G and the c.143+1567A>G variants both led to the creation of a de novo acceptor or donor splice site, respectively. Moreover, the c.143+1567A>G was found in 3/6 patients with genetically unresolved moderate HA registered in our laboratory. Haplotype analysis performed in all patients carrying the c.143+1567A>G variation suggests that this variation could be a recurrent variation. The c.2113+601G>A led to the exonization of a 122-bp antisense AluY element by increasing the strength of a pre-existing cryptic 5' splice site. For each point variation, in vitro splicing analysis confirmed its deleterious impact on splicing of the F8 transcript. Conclusion We identified three deep intronic variations, leading to an aberrant mRNA splicing process as HA causing variation.

Aim For patients with severe haemophilia A, guidelines recommend prophylactic treatment with FVIII, with dose calculations targeting a predetermined FVIII trough level. However, this pharmacokinetic (PK) approach is suboptimal, with some patients experiencing breakthrough bleeds. We aimed to improve FVIII dosing by incorporating the thrombin generation assay, a global haemostasis assay whose main pharmacodynamic (PD) parameter, endogenous thrombin potential (ETP), predicts spontaneous bleeding risk. Methods We performed post hoc combined PK‐PD modelling using data from 66 adults who received human‐cl rhFVIII (Nuwiq®, Octapharma AG) in a phase IIIb study. Time‐to‐event analyses simulated the probability of spontaneous bleeding for different FVIII exposures and baseline ETPs. Results Ninety‐one spontaneous bleeds occurred in 20/66 patients. The relationship between FVIII:C and ETP was non‐linear, and the sigmoid Emax model adequately described the data. Individual PK‐PD Bayesian estimation significantly improved predictive performance. Simulations showed that the mean spontaneous annual bleeding rate decreased with increasing baseline ETP or dosing: with ETP values of 200, 400 and 600 (nmol/L)·min annual bleeding rates were 2.36, 1.25 and 0.66, respectively, on 40 IU/kg human‐cl rhFVIII every 3 days; and annual bleeding rates were 2.09, 1.10, and 0.60, respectively, on 60 IU/kg every 3 days. Conclusion Prophylactic FVIII dosing is more clinically meaningful when incorporating ETP alongside FVIII level. For the first time, FVIII dosing can be personalized with the aim of eliminating spontaneous breakthrough bleeds.

IntroductionDental caries is one of the most common non-communicable diseases in children. The disease management of caries relies on both a preventive individual approach (fluoridation, risk evaluation) and the surgical treatment of established carious lesions. Similar to other non-communicable diseases (obesity, mental diseases, etc), health professionals’ negative perceptions of patients have been shown to affect the quality of disease management. Regarding dental caries in children, some data have indicated the presence of discriminating beliefs and behaviours towards these children and their families in the medical setting. However, oral health stigma related to dental care remains a largely unexplored issue.Methods and analysisThis study presents an exploratory research protocol focusing on the perceptions and attitudes of health professionals towards children with early childhood caries (ECC) and their parents. Semistructured interviews will be conducted among medical and dental health professionals, and verbatim quotations obtained from audio transcriptions will be analysed to identify health professionals’ perceptions of ECC and the influence of these perceptions on clinical care for these children.Ethics and disseminationThe research ethics committee of the Department of Family Medicine at University Lyon 1 approved this protocol. The results will be published in peer-reviewed journals and presented at scientific meetings.Trial registration numberNCT05284279.

The Semmering Base Tunnel in Austria is currently one of the largest tunnel construction sites in Central Europe. Two tunnel tubes, each 27.3 km long, are being built from the portal and three intermediate construction sites. Each access point poses specific challenges, and structural monitoring is a crucial element to ensure both economic and safe construction. In this paper, the authors describe one of the most comprehensive distributed fibre-optic sensing installations on a tunnel construction site worldwide. At the Semmering Base Tunnel, fibre-optic sensing is used at every construction location to monitor tunnel linings, shafts, reinforced earth structures and pipelines. The authors also discuss the challenges posed by the installations and the results of long-term monitoring programmes. The installed monitoring systems will, furthermore, be used throughout the expected 150-year operational lifetime of the tunnel. Unlike conventional sensors, fibre-optic sensors do not comprise electric or moveable components at the measurement location. A longer lifetime can, therefore, be expected for fibre-optic sensors, which makes them promising candidates for condition-based maintenance of civil infrastructure.

Introduction Recombinant FVIIa (rFVIIa) is widely used to manage bleeding risk during and after surgery in patients with haemophilia complicated by inhibitors. In the postoperative period, rFVIIa must be delivered frequently and regularly to maintain haemostasis, considering its short half-life. Preparation and manual administration of bolus doses of rFVIIa at regular intervals may place a strain on available nursing resources. A programmable mini-pump may offer an approach to facilitate regular administration of bolus doses of rFVIIa at specified intervals. Aim To investigate if a mini-pump is a practical and effective way to deliver rFVIIa in the postoperative period. Methods It was first necessary to establish that rFVIIa remains stable and sterile in the mini-pump reservoir for an extended period. Four days after loading the mini-pump under sterile conditions no evidence of bacterial or fungal growth was observed and in vitro procoagulant activity of rFVIIa remained stable. The mini-pump was used to deliver rFVIIa as bolus doses to two patients with inhibitors who had undergone surgery. Nurses were asked to report their satisfaction with the use of the mini-pump using a specific questionnaire. Results Haemostasis was evaluated as excellent in both cases; nurses were satisfied with use of the mini-pump. Conclusion This pilot study shows that intermittent delivery of rFVIIa at fixed intervals using an automated mini-pump offers accurate and reliable administration in the postoperative setting. This approach may reduce burden on nursing staff, potentially minimize the risk of human error and avoid delay in administration of rFVIIa.

International audience; This study aimed to examine (a) whether subgroups of athletes with different levels of basic psychological need (BPN) satisfaction and frustration emerged; (b) if BPN profile differences existed on sex, years of experience, and number of hours of training; (c) the issue of changes of profiles overtime; and (d) whether athletes belonging to distinct BPN profiles differed on sport burnout and engagement. A sample of 367 adolescent athletes in intensive training centers participated in this study. Results of latent profile transition analyses revealed three profiles at each time points: Fulfilled, autonomy and competence moderately frustrated, and competence and relatedness highly frustrated profiles. Male athletes and athletes with more years of experience were more likely to belong to the autonomy and competence moderately frustrated profile in comparison to the other BPN profiles. Athletes who trained more hours a week were more likely to belong to the fulfilled profile in comparison to the autonomy and competence moderately frustrated profile. Individuals in fulfilled and autonomy and competence moderately frustrated profiles were especially likely to stay in their respective profile at Times 2 and 3, whereas individuals in competence and relatedness highly frustrated profile were less stable in their profile membership. Individuals from the fulfilled profiles reported lower scores of burnout and higher scores of engagement than the athletes from the two other BPN profiles. The opposite pattern of results was observed for the competence and relatedness highly frustrated profile. Overall, a BPN profile approach was found useful in understanding within-person combinations of BPN.

Introduction Lightening the injection burden is commonly believed to improve prophylaxis adherence. Efmoroctocog alfa (rFVIIIFc) is the first recombinant FVIII-Fc fusion protein available in France. This clotting factor with an extended half-life could thus improve medication adherence. Aim The study primarily aimed to assess the real-life impact on prophylaxis adherence of haemophilia A patients, when switching from a standard to an extended half-life FVIII. Methods This study was an observational, monocentre, non-interventional study aiming at assessing haemophilia A patients' real-life adherence during the first-year post-rFVIIIFc prophylaxis initiation. Medication adherence was assessed using two methods: the medication possession ratio (MPR), which is based on the hospital pharmacy dispensing data, and self-reported VERITAS-Pro® questionnaire. Patients on rFVIIIFc prophylaxis for at least 12 months, following a 12-month standard FVIII prophylaxis, were eligible for inclusion. Results In 2019, 47 male patients were undergoing rFVIIIFc prophylaxis in our Hemophilia Center, among which 36 meeting the inclusion criteria. Switching from standard to extended half-life FVIII prophylaxis resulted in increased mean dosing, while the mean number of weekly prophylactic injections (2.6 ± 0.5 vs 1.8 ± 0.3) decreased. Following rFVIIIFc initiation, a non-significant increase in median MPR occurred and the self-reported VERITAS-Pro® questionnaire demonstrated improved adherence to rFVIIIFc prophylaxis. Comparing adherent and non-adherent patients revealed age as the only factor likely to impact adherence (p = .07). Conclusion Our patient cohort exhibited high adherence levels before and after FVIII switching, based on MPR and VERITAS-Pro® questionnaire. The latter is likely a useful tool to quantity prophylaxis adherence from a patient's perspective in daily use.

International audience

The thrombin generation (TG) assay evaluates haemostatic balance, which is influenced by the levels of many coagulation factors and inhibitors. Our objective was to identify the determinant factors of TG in haemophilia A (HA) and haemophilia B (HB) patients and to compare them to those in healthy controls. Coagulation factor and inhibitor levels, and TG, were measured in platelet-poor plasma from 40 patients with HA, 32 patients with HB and 40 healthy subjects. Data were analysed using multiple regression models. In HA patients, factor VIII was a positive determinant of endogenous thrombin potential (ETP) and peak, whereas tissue factor pathway inhibitor (TFPI) and factor V were negative determinants of ETP and peak. In HB patients, FIX was a positive determinant of ETP and peak, FVII being a positive determinant of peak. Antithrombin and protein S (PS) were negative determinants of ETP while FX was a negative determinant of peak. Above all, in HB patients, TFPI was a negative determinant of ETP and peak. In healthy subjects, FVIII was a positive determinant of ETP and peak, whereas FX and protein S were negative determinants of these parameters. TFPI was not a negative determinant of either peak or ETP. In haemophilic patients, the determinant factors of TG are all implicated in FXa generation and inhibition, the crucial determinant factor being TFPI whatever the type of haemophilia, A or B. These findings contribute to the rationale that recently place TFPI as a target for innovative therapies of haemophilia.

Der vorliegende Fall beschreibt die fruhklinische Versorgung eines Patienten mit schwerer Methyl-endioxymetamphetamin-Intoxikation (Ecstasy). Es wird die Historie stimulierender psychotroper Substanzen und die Wirkweise moderner Psychostimulanzien dargestellt. Daten aus dem osterreichischen Drogenbericht zeigen die Verlagerung des Konsums „harter Drogen“ wie z. B. Opioiden hin zu Cannabis und Amphetaminderivaten. Der letale Verlauf im beschriebenen Fall zeigt das hohe Gefahrenpotenzial derartiger Substanzen und weist auf die Notwendigkeit rechtzeitiger, aggressiver intensivmedizinischer Therapie hin.

RESUME Une mutation profonde de la cardiologie et de la chirurgie cardiaque est en cours justifiant une reflexion sur la chirurgie cardiaque en 2025. La chirurgie coronarienne s’adressera a des patients avec plus de comorbidites. L’indication des TAVI va s’elargir vers des patients a risque intermediaire entrainant une diminution de la chirurgie de la valve aortique. Les interventions percutanees devront etre realisees dans des centres medico-chirurgicaux au sein d’un « Heart team ». La prise en charge de l’insuffisance cardiaque severe sera en grand developpement avec l’assistance circulatoire mecanique. La chirurgie cardiaque courante de l’adulte devra se faire dans des centres de « proximite » et la chirurgie d’expertise dans des centres de « reference ». L’Academie nationale de medecine recommande d’effectuer des regroupements au sein de la chirurgie elle-meme, de creer des reseaux de chirurgie cardiaque pour realiser les interventions non courantes.

We present the case of an accidental extubation in a prone-positioned patient with a challenging airway because of Klippel-Feil syndrome and previous cervical spine fusions. The surgical procedure was well underway when this occurred, which added substantially to the difficulties produced by this event. We herein highlight the corrective steps we took in our case. We also recommend the need for a comprehensive preoperative briefing with all operating room personnel together with an action plan for how to prevent this particular scenario.

With the development of ambulatory surgery, there may be questions about the legal risk of this procedure. Indeed, the discharge of the patient from the hospital on the same day as the medical treatment raises the problem of monitoring and supervising potential complications, with a substantial delay in medical care, and the anaesthesiologists can be confronted with new areas of liability. This article specifies the French statutory and legal framework of the ambulatory surgery, and shows how the responsibility of the anaesthesiologist can be involved during patient care at all steps. The analysis of judicial precedent shows that the legal risk for the anaesthesiologist also exists in outpatient surgery. Surgery and anaesthesia are medical procedures involving a relatively high risk of damage for the patient. The damage can be attributed to malpractice from one or several health care professionals or to a medical complication (abnormal damage not related to malpractice and independent of past medical history of the patient). In the light of the ongoing and significant development in ambulatory surgery, there may be questions about the legal risk of this procedure. Indeed, the discharge of the patient from the hospital on the same day as the medical treatment raises the problem of monitoring and supervising potential complications, with a substantial delay in medical care. If the patient suffers any damage, the surgeon, the anaesthesiologist and in some cases, the hospital will have to answer in courts: the surgeon for the surgical procedure, the anaesthesiologist for the medical care and the hospital as the liable institution. After having specified the statutory framework of ambulatory surgery, we will see how the responsibility of the anaesthesiologist can be involved during patient care at all steps.

IntroductionSevere haemophilia is a rare disease characterised by spontaneous bleeding from early childhood, which may lead to various complications, especially in joints. It is nowadays possible to avoid these complications thanks to substitutive therapies for which the issue of adherence is major. The transition from adolescence to adulthood in young people with severe haemophilia is a critical period as it is associated with a high risk of lack of adherence to healthcare, which might have serious consequences on daily activities and on quality of life.Methods and analysisWe present the protocol for a cross-sectional, observational, multicentric study to assess the differences between adolescents and young adults with severe haemophilia in France through the transition process, especially on adherence to healthcare. This study is based on a mixed methods design, with two complementary and consecutive phases, comparing data from a group of adolescents (aged 14–17 years) with those from a group of young adults (aged 20–29 years). The quantitative phase focuses on the determinants (medical, organisational, sociodemographic and social and psychosocial and behavioural factors) of adherence to healthcare (considered as a marker of the success of transition). The qualitative phase explores participants’ views in more depth to explain and refine the results from the quantitative phase. Eligible patients are contacted by the various Haemophilia Treatment Centres participating in the French national registry FranceCoag.Ethics and disseminationThe study was approved by the French Ethics Committee and by the French National Agency for Medicines and Health Products Safety (number: 2016-A01034-47). Study findings will be disseminated to the scientific and medical community in peer-reviewed journals and presented at scientific meetings. Results will be popularised to be communicated via the French association for people with haemophilia to participants and to the general public.Trial registration numberNCT02866526; Pre-results.

To understand the mechanisms related to both the onset and correction of severe anaemia after orthopaedic surgery, we analysed all the full blood counts (FBCs) for patients on one orthopaedic ward during a one-year period in an academic hospital.FBCs were screened and the medical records of those patients for whom a postoperative haemoglobin (Hb) concentration below 8 g/dL was recorded at least once were reviewed. The onset of postoperative anaemia was determined by calculating the various time intervals delineated by surgery, the time at which the transfusion threshold was reached and the time at which the lowest Hb level (nadir) and transfusion (if any) occurred.A total of 6573 FBCs drawn from 1255 patients were screened. The medical records of 74 consecutive patients with at least one Hb value8 g/dL were analysed. The postoperative Hb nadir was 7.4 (± 0.6) g/dL (mean - SD). The medians (IQR 25-75) of the calculated intervals were: (surgery - nadir): 72 (48-144) h, (nadir - transfusion): 7 (5-21) h and (transfusion threshold - transfusion): 26 (11-51) h.Delayed transfusion (defined as12 hours between the time at which the transfusion threshold was reached and actual transfusion) was observed in 57% of severely anaemic patients after orthopaedic surgery.

Der 27,3 km lange Semmering-Basistunnel neu ist eines der Schlusselprojekte beim Neu- und Ausbau der osterreichischen Sudstrecke und gleichzeitig Teil des Baltisch-Adriatischen Korridors der EU. Als Vorbereitung fur den Tunnelbau wurden in der Deponie Longsgraben Stutzkonstruktionen und Rampen in Bewehrte-Erde-Bauweise in schwierigem, alpinem Gelande errichtet. Beim systematischen geotechnischen Monitoring wahrend des Baus und nach Fertigstellung der Stutzkonstruktionen kam ein neu entwickeltes System zur faseroptischen Dehnungsmessung zum Einsatz, welches Ruckschlusse auf die Zugkrafte in den Geogittern und damit Einblick in das Tragverhalten dieser Stutzkonstruktionen erlaubt.

Factor VIII Inhibitor Bypassing Activity (FEIBA) can effectively achieve haemostasis in haemophilia patients with inhibitors. Further evaluation of FEIBA in surgical settings is of significant interest considering the relatively limited prospective data published to date. The aim of the study is to evaluate the perioperative efficacy and safety of FEIBA in haemophilia patients with inhibitors. Haemophilia patients with inhibitors who underwent surgical procedures and received FEIBA for perioperative haemostatic control were prospectively enrolled in an open-label, noninterventional, postauthorization study [SURgical interventions with FEIBA (SURF)]. Outcome measures included haemostatic efficacy, safety, FEIBA exposure and blood loss associated with the perioperative use of FEIBA. Thirty-five surgical procedures were performed at 19 centres worldwide in patients with congenital haemophilia A, congenital haemophilia B, or acquired haemophilia A. Haemorrhagic risk was severe in 37.1% (13 of 35) of the procedures, moderate in 25.7% (9 of 35) and mild in 37.1% (13 of 35). One moderate risk surgery was excluded from the efficacy analyses because it did not meet all protocol requirements. Haemostasis was judged to be 'good' or 'excellent' in 91.2% (31 of 34) of surgical procedures and 'fair' in 8.8% (3 of 34). Among the 12 adverse events, three were serious adverse events (SAEs), two of which were unrelated to FEIBA therapy; one SAE, a clot in an arteriovenous fistula, was deemed to be possibly related to therapy. This prospective investigation confirms that FEIBA can be safely and effectively used when performing surgical procedures in haemophilia patients with inhibitors.

Introduction Recombinant factor IX fusion protein (rIX-FP) has been developed to improve the pharmacokinetic (PK) profile of factor IX (FIX), allowing maintenance of desired FIX activity between injections at extended intervals, ultimately optimizing haemophilia B treatment. Aim To determine the efficacy and safety of rIX-FP in the perioperative setting. Methods Subjects were adult and paediatric patients with severe to moderately severe haemophilia B (FIX ≤ 2%) participating in three Phase III clinical trials and undergoing a surgical procedure. PK profiles were established prior to surgery for each patient. Haemostatic efficacy was assessed by the investigator for up to 72 h after surgery. Safety measurements during the study included adverse events and inhibitors to FIX. FIX activity was monitored during and after surgery to determine if repeat dosing was required. Results Twenty-one, both major and minor, surgeries were performed in 19 patients. Haemostatic efficacy was rated as excellent (n = 17) or good (n = 4) in all surgeries. A single preoperative dose maintained intraoperative haemostasis in 20 of 21 surgeries. Nine major orthopaedic surgeries were conducted in eight patients with a mean of 7 (range: 6–12) rIX-FP injections during surgery and the 14-day postoperative period. Median rIX-FP consumption for orthopaedic surgeries was 87 IU kg−1 preoperatively and 375 IU kg−1 overall. No subject developed inhibitors to FIX or antibodies to rIX-FP. Conclusion Recombinant factor IX fusion protein was well tolerated and effectively maintained haemostasis during and after surgery. Stable FIX activity was achieved with a prolonged dosing interval and reduced consumption compared to conventional or currently available long-acting recombinant FIX.

Background and Objectives Total knee replacement (TKR) is the treatment of choice in case of end-stage knee arthropathy, the main complication of haemophilia. We report here a retrospective evaluation of 72 total knee replacement in 51 haemophilia A and B patients using continuous infusion of factor concentrates (CIFC). Materials and Methods Patients were evaluated on the basis of the following efficacy and safety criteria: range of motion, surgery-related blood loss by three different methods, factor consumption and occurrence of short and long term complications. Results Kaplan–Meier analysis showed a removal-free survival of TKRs of 88.4% 10 years after surgery. Most patients were satisfied with their prosthesis and described pain relief and improved mobility and better quality of life after surgery. The long term follow-up showed a mean range of motion at 86° with a flexion deformity of 4°. The blood loss differed significantly according to the method used for measurement. No life-threatening bleeding occurred. Twenty six haematomas (36.1%) and 2 haemarthroses (2.7%) occurred in 38.8% of cases during the first three postoperative weeks, with no significant impact on the orthopaedic outcome. The average factor consumption during hospitalization was 79 IU/kg/day for patients with haemophilia A and 99 IU/kg/day for patients with haemophilia B. Infections occurred in 4.1% of patients. One patient with severe haemophilia A developed an inhibitor. Conclusions The multidisciplinary approach and the homogeneous management of our large cohort allowed the achievement of excellent functional results. Our results confirmed previously reported data on the safety and efficacy of CIFC in situations requiring intensive factor replacement, such as TKR surgery.

All the files of complications of regional anaesthesias requiring an expertise for a Regional Commission for Conciliation and Compensation for medical accidents (CRCI) between 2003 and 2008 were analyzed. The objective was to estimate the homogeneity of the appointed experts, their opinions and the opinions of the CRCI. Querying the database, shared by the National Office for Compensation for Medical Accidents (ONIAM) and the CRCI, and identified 40 files corresponding to the selection criteria. The expertise carried out involved an anaesthetist in 27 cases, always registered, either on the national list of the experts in medical accidents, or on one list of court-appointed experts. Conversely, in 13 cases, no specialist performing himself the technique in question was involved in the expertise, and sometimes the expert was registered on any list. Mostly, the non-specialists do not conclude to medical malpractice. This was not the case in a single file, where the anaesthetist sought and obtained the addition of an anaesthetist in a new expertise, which concluded differently. Damages assessed were highly variable, but the given evidence provided to understand why. The CRCI have generally followed the opinions of the experts, except in a few cases where the evidence allowed a different opinion without requiring a new expertise. In conclusion, the abnormalities in the appointment of experts do not seem to have had consequences in terms of damage assessment, but may alter the balance between causes faulty and not faulty, in favour of the latter.

Resume Le comite d’ethique de la Societe francaise d’anesthesie et de reanimation (Sfar) a ete sollicite par l’agence de la biomedecine sur la question des prelevements d’organes apres arret des therapeutiques actives (ATA). Ce type de prelevement est autorise et pratique aux Etats-Unis, au Canada, au Royaume-Uni, aux Pays-Bas et en Belgique. Les trois premiers pays ont redige des recommandations concernant ce type de prelevement. Ces recommandations fixent pour l’essentiel une procedure ou une conduite a tenir operationnelle, une fois l’ATA valide. Le comite a deliberement cadre sa reflexion selon un champ plus large et global que celui qui prevaut dans l’approche anglo-saxonne. Cette analyse qui envisage toutes les etapes d’un tel prelevement, nous a conduits a emettre des reserves quant a l’applicabilite de ce type de prelevement a tout patient chez qui une decision d’ATA aurait ete validee. Dans un souci de coherence par rapport aux pratiques du prelevement d’organes chez des patients en mort encephalique qui prevalent en France, nous avons souligne la necessite de n’envisager l’ATA-M3, pour le moment, que chez les patients cerebro-leses chez qui un tres mauvais pronostic neurologique pouvait etre predit avec un niveau de certitude eleve, au moyen d’examens paracliniques. Dans notre esprit, les elements de preuve doivent etre fixes et assumes par la collectivite, representee par l’agence de biomedecine, et pas par le medecin en charge du malade. Ils doivent etre opposables au cas ou l’on s’interrogerait sur la qualite de la pronostication neurologique. Ce texte a ete endosse par le conseil d’administration de la Sfar.

Harlequin ichthyosis (HI) is a rare disorder of defective lipid transport resulting in severe epidermal hyperkeratosis producing large plate-like scales. Although mortality is high, improved treatments have allowed some with HI to survive into their third and fourth decades. However, until this case, there have been no known reports of pregnancy followed by birth of a healthy neonate to a mother with HI. We report one of the only approximately 25 known current HI survivors worldwide unique in having carried a pregnancy to full term and outline challenges for the anesthesiologist during labor and delivery.

RESUME L’Academie nationale de medecine souhaite appeler la societe a porter une attention toute particuliere a la situation des personnes handicapees du fait d’un handicap congenital physique, organique, consequence d’une anomalie du developpement. Pour la plupart, causes et mecanismes demeurent incertains (facteurs genetiques et epigenetiques, embryopathies, foetopathies...). Le handicap physique malformatif revet des formes tres diverses, tres personnelles a chaque personne handicapee. Ce fait explique en partie la dispersion de la perception qu’a d’eux la societe. Elle conduit souvent a leur meconnaissance. Par ailleurs l’intelligence normale de ces handicapes physiques peut donner a penser que leur handicap est moins lourd, tant pour eux-memes que pour leur entourage. La diversite des handicaps d’origine congenitale physiques organiques et la « rarete » de chacun d’entre eux, ne confere aux petites associations a la creation desquelles ils ont pu donner lieu, qu’une tres faible representativite aupres des decideurs en matiere de sante publique. De ce fait ces handicaps sont certainement ceux auxquels la societe s’est le moins interessee. Cependant nombre de ces anomalies du developpement sont en fait incurables, au sens propre du terme, c’est-a-dire irreparables ad integrum. Ces personnes en supportent avec courage, leur vie durant, les sequelles et souvent aussi les soins qu’ils imposent. L’absence de donnees epidemiologiques a longtemps conduit a meconnaitre la diversite des situations vecues notamment par les personnes adultes et plus encore les personnes vieillissantes. Heureusement desormais expressement identifies et repertories dans la base de donnees ORPHANET et dans le cadre du plan Handicaps rares et maladies rares, ces anomalies du developpement beneficient depuis peu de la mise en place du reseaudes Centres de reference labellises regionaux et des Centres de competence, de proximite qui leur sont associes. L’Academie Nationale Medecine formule ici quelques recommandations concernant les modalites nouvelles de cette prise en charge medicale qui ne suffit pas a repondre a l’attente des personnes handicapees physiques congenitales. Elles ne demandent qu’a etre inserees dans la societe comme tout autre personne, pour peu que la societe les y accepte et consente a faciliter non pas leur assistance mais leur integration.

It has been reported that thrombin generation test (TGT) may be a useful tool to monitor recombinant factor VIIa (rFVIIa). However, TGT does not reflect the stability of fibrin clot and its resistance to fibrinolysis which are crucial. Using whole-blood thromboelastography (TEG) and tissue plasminogen activator (tPA), we developed an in-vitro model to assess fibrin clot stability. Fibrin fibres were thicker in haemophiliacs compared with controls (P < 0.0001). After addition of rFVIIa 90 μg kg(-1), the diameter of fibrin fibres was dramatically decreased (P = 0.006). TEG-tPA assay showed a dose-dependent improvement of clot stability in the presence of rFVIIa. These data demonstrate a significant correlation between fibrin clot structure and its stability (P = 0.001). We also showed a correlation between thrombin generating capacity and clot resistance to fibrinolysis. Despite this overall correlation, a relatively large spreading around a general trend was observed, suggesting that the two assays bring complementary information on the haemostatic effect of rFVIIa.

The statistical process control required under International Organization for Standardization 15189 as well as economic considerations necessitates having robust methods that do not need systematic recalibration for each series of analyses. Using the concrete example of one-stage clotting factor VIII assay, we assessed the analytic variability specifically linked to changing factor VIII deficient plasma vials. The study used freeze-dried (Instrumentation Laboratory, Siemens, Stago and T-Coag) and frozen (Affinity Biologicals and Precision Biologic) factor VIII deficient plasmas. On the most widely recognized acceptability criteria and methods (i.e. those of Kallner et al. and Kasper et al.), the Stago and Instrumentation Laboratory plasmas require systematic recalibration at each vial changeover.

Coagulation factor VIII was assayed around the critical concentration of 80 U/dl, which is optimal for postoperative haemostasis in haemophiliac patients, in order to assess the use of Bayesian logic in interpreting internal quality control results during a change of reagent or control batch. A mathematical model based on Bayesian inference, requiring no preliminary control-plan phase, was compared with a classical approach, which necessarily involves performing a preliminary phase. Tsiamyrtzis and Hawkins' Bayesian model proved applicable to rapid statistical control of factor VIII assay, detecting shift at least as efficiently as classical approaches, which depend on running the kind of costly and controversial preliminary control phase recommended by Shewhart.

One of the most erroneous and repeated assertion in the history of pharmacology for anaesthetists is to say that "the curare was introduced in Europe by Sir Walter Raleigh under the name of ourari". On the contrary, the names to be reminded are: Lawrence Keymis for the first citation of the word ourari, Jose Gumilla for the word curare and the description of its effects, Charles-Marie de La Condamine for the import of the first known samples. The mistake was initiated by Alexander von Humboldt and developed by the physiologist Munter, a student of Johannes Muller, quoted by Claude Bernard. The repetition of this error was facilitated by the world diffusion of Claude Bernard's work.

Resume Le syndrome de Mendelson est une complication majeure de la pratique de l’anesthesie. Le present article presente les donnees detaillees concernant ce syndrome obtenues au cours de l’etude realisee conjointement par la Societe francaise d’anesthesie et de reanimation (Sfar) et le Centre d’epidemiologie sur les causes medicales de deces (CepiDC) sur la mortalite anesthesique. Les methodes et les principaux resultats des deux enquetes ont ete prealablement publies. Brievement, la premiere enquete (1996) a permis d’estimer le nombre annuel et les caracteristiques des anesthesies realisees en France (denominateur). La seconde enquete a consiste a recueillir des informations a partir des certificats de deces de l’annee 1999 (numerateur). Apres une analyse globale des deces en rapport avec l’anesthesie, une investigation complementaire a ete menee pour etudier en detail les deces en rapport avec un syndrome de Mendelson. Quatre-vingt-trois deces ont ete rapportes a un syndrome de Mendelson, soit un cinquieme des deces totalement ou partiellement imputables a l’anesthesie pour un taux annuel d’un pour 221 368 anesthesies generales, soit 4,5 × 10−6 (IC 95 % : 0,8 × 10−6–14 × 10−6). Il s’agissait de patients dans un etat clinique grave (ASA ≥ 3 : 92 %), tres âges et souvent operes dans un contexte d’urgence digestive. Deux deces sont survenus a l’occasion d’une coloscopie et aucun en situation obstetricale. L’inhalation est survenue a l’induction dans tous les cas, sauf un. L’analyse des pratiques retrouve une non-conformite aux regles dans la presque totalite des cas. Les anesthesistes–reanimateurs francais doivent s’engager de facon volontariste dans des actions de formation medicale continue sur ce theme, de facon a optimiser leurs pratiques.

Taking the specific case of coagulation factor VIII assay, we determined the characteristics of an internal quality control panel assuring control of the assay method for all of the critical factor VIII concentrations. The precision of the assay method was determined on six control materials C1-C6, with expected factor VIII levels of 1, 5, 30, 50, 80 and 150 U/dl, respectively. Given that, when two control levels correlate statistically, the information provided by one of them is redundant, we used correlation and principal components analysis to define a priori adequate and inadequate control panels. For each of these panels, we calculated the number of runs required, using Hotelling's method, to detect a shift expressed on C1 and impacted on C2, C3, C4, C5 and C6 in relation to the correlation phenomena among the six levels. The C1/C6 panel proved to be as informative in this regard as the complete panel for a 1 U/dl shift simulated on C1 and impacted on other levels too. These correlation phenomena allow the biologist to implement fewer control levels than there are critical concentrations needing to be explored in the internal quality control plan.

Intrathecal morphine is a widely used method for postoperative pain relief after major abdominal surgery. The aim of this randomized, double-blinded study was to compare intrathecal morphine and intravenous PCA morphine for postoperative analgesia and recovery course after major colorectal surgery in elderly patients.After written informed consent, patients70 years of age were prospectively and randomly assigned to receive either preoperative intrathecal morphine (0.3 mg) and postoperative patient-controlled (PCA) intravenous morphine (IT morphine) or PCA alone (group control). Results are presented as mean +/- SD (95% confidence interval).Twenty-six patients successfully completed the study in each group. In the IT morphine group, rate of awakening was delayed. Pain intensity and daily intravenous morphine consumption were significantly reduced 1 and 2 days after surgery in the IT morphine group (P.01). Mental function (assessed by Mini Mental State and Digit Symbol Substitution Test) was similar in both groups. Episodes of postoperative delirium/confusion occurred similarly in both groups. Time to ileus resolution and time to ambulation without assistance did not differ between the 2 groups. The duration of hospitalization was 8.4 +/- 1.7 (7-11) days and 7.9 +/- 2.0 (6-9.9) days for control and IT morphine, respectively (nonstatistical difference). Patients in the IT morphine group had longer time to awakening from anesthesia and experienced more sedation.Intrathecal morphine, as compared with intravenous PCA morphine alone, improves immediate postoperative pain and reduces parenteral morphine consumption but does not improve postoperative recovery in elderly patients after major colorectal surgery.

Vasopressin administration may be a promising therapy in the management of various shock states. In laboratory models of cardiac arrest, vasopressin improved vital organ blood flow, cerebral oxygen delivery, the rate of return of spontaneous circulation, and neurological recovery compared with epinephrine (adrenaline). In a study of 1219 adult patients with cardiac arrest, the effects of vasopressin were similar to those of epinephrine in the management of ventricular fibrillation and pulseless electrical activity; however, vasopressin was superior to epinephrine in patients with asystole. Furthermore, vasopressin followed by epinephrine resulted in significantly higher rates of survival to hospital admission and hospital discharge. The current cardiopulmonary resuscitation guidelines recommend intravenous vasopressin 40 IU or epinephrine 1mg in adult patients refractory to electrical countershock. Several investigations have demonstrated that vasopressin can successfully stabilize hemodynamic variables in advanced vasodilatory shock. Use of vasopressin in vasodilatory shock should be guided by strict hemodynamic indications, such as hypotension despite norepinephrine (noradrenaline) dosages0.5 mug/kg/min. Vasopressin must never be used as the sole vasopressor agent. In our institutional routine, a fixed vasopressin dosage of 0.067 IU/min (i.e. 100 IU/50 mL at 2 mL/h) is administered and mean arterial pressure is regulated by adjusting norepinephrine infusion. When norepinephrine dosages decrease to 0.2 microg/kg/min, vasopressin is withdrawn in small steps according to the response in mean arterial pressure. Vasopressin also improved short- and long-term survival in various porcine models of uncontrolled hemorrhagic shock. In the clinical setting, we observed positive effects of vasopressin in some patients with life-threatening hemorrhagic shock, which had no longer responded to adrenergic catecholamines and fluid resuscitation. Clinical employment of vasopressin during hemorrhagic shock is experimental at this point in time.

Summary. In haemophilia patients with inhibitor, elective orthopaedic surgery is usually performed under recombinant activated factor VII (rFVIIa). We report here the case of a severe haemophilia A patient with a high inhibitor who needed a bilateral total knee arthroplasty. Recombinant FVIIa was previously shown to be ineffective for the treatment of muscle and joint bleedings, and he had a history of excessive postoperative bleeding under activated prothrombin complex concentrate (APCC). Thrombin generation test (TGT) was used to assess the efficacy of Factor Eight Inhibitor Bypassing Activity (FEIBATM). Insufficient correction of thrombin-generating capacity was observed after administration of 75 U kg−1 FEIBATM. In a multidisciplinary environment, a bilateral total knee arthroplasty was performed using a protocol combining immunoadsorption of inhibitors preoperatively associated with FVIII replacement during a first phase followed by FEIBATM when the inhibitor reappeared. To our knowledge this is the first direct application of TGT in the management of haemophilia patients with inhibitor, which indicated that a sequential use of immunoadsorption, FVIII and FEIBATM was the most appropriate treatment to perform this major elective surgery. This case demonstrates that this combined protocol can be safely used to cover major surgery in inhibitor patients. In addition, it also suggests that TGT may have a major contribution in the decision-making process of the most adapted therapy for the treatment of such high-risk patients.

The commercial production of complex pharmaceutical proteins from human origin in plants is currently limited through differences in protein N-glycosylation pattern between plants and humans. On the one hand, plant-specific alpha(1,3)-fucose and beta(1,2)-xylose residues were shown to bear strong immunogenic potential. On the other hand, terminal beta(1,4)-galactose, a sugar common on N-glycans of pharmaceutically relevant proteins, e.g., antibodies, is missing in plant N-glycan structures. For safe and flexible production of pharmaceutical proteins, the humanisation of plant protein N-glycosylation is essential. Here, we present an approach that combines avoidance of plant-specific and introduction of human glycan structures. Transgenic strains of the moss Physcomitrella patens were created in which the alpha(1,3)-fucosyltransferase and beta(1,2)-xylosyltransferase genes were knocked out by targeted insertion of the human beta(1,4)-galactosyltransferase coding sequence in both of the plant genes (knockin). The transgenics lacked alpha(1,3)-fucose and beta(1,2)-xylose residues, whereas beta(1,4)-galactose residues appeared on protein N-glycans. Despite these significant biochemical changes, the plants did not differ from wild type with regard to overall morphology under standard cultivation conditions. Furthermore, the glyco-engineered plants secreted a transiently expressed recombinant human protein, the vascular endothelial growth factor, in the same concentration as unmodified moss, indicating that the performed changes in glycosylation did not impair the secretory pathway of the moss. The combined knockout/knockin approach presented here, leads to a new generation of engineered moss and towards the safe and flexible production of correctly processed pharmaceutical proteins with humanised N-glycosylation profiles.

In the months of winter 2002-2004, three cases of non-traumatic cardiac arrest occurred in the skiing area of the Stubaier Gletscher in Tyrol, Austria. All patients were initially resuscitated by ski patrol members, including the use of an automated external defibrillator (AED). Two of the patients were alive at hospital admission, one patient was discharged from hospital without neurological damage. The article describes the chain of survival in a high-alpine area, the installation of a modified public-access-defibrillation (PAD) system in a skiing area, and the prerequisites necessary for a successful PAD-program far away from an organized emergency medical system.

A National Confidential Inquiry was conducted among death certificators and anaesthetists. A sample of 3700 death certificates from the year 1999 were randomised, after selection of words relating to anaesthesia, surgery, obstetrics, endoscopy, procedural complications, and violent death, with different ratios according to the words and the age; 500 additional certificates relating to deaths in hospital were evaluated to verify the exhaustive nature of the mention of procedures in the certificates. The certificator was sent a simplified form each time the role of the procedure in death could not be excluded (response rate 97%). The anaesthetist was offered a peer review whenever the role of the anaesthetic procedure could not be ruled out (uptake rate 97%). An expert committee analysed the (anonymized) files to determinate the mechanism of the accident and its relationship to anaesthesia. The mortality rates were estimated from the 1996 "Anaesthesia in France" survey. The annual rates of deaths that were totally or partially related to anaesthesia were respectively 7 (CI95%: 2-12) and 47 (31-63) per million. These mortality rates increased with comorbidity, from 4 per million in patients of ASA physical status class 1 to 554 per million in class 4. Similarly, these rates increased with age, from 7 per million in patients less than 45 years old, to 32 in older patients. Most accidents were of ventilatory (38%: airway management: 6%, aspiration pneumonitis: 9%), cardiac (31%: ischaemia: 25%, including anaemia-related), and vascular origin (30%: hemorrhage: 12%, vasodilation by spinal anaesthesia: 6%, anaphylaxis: 3%). The main surgical procedures involved were orthopaedic (50%: hip fracture, haemorrhagic surgery) and digestive (24%: occlusion, peritonitis). INSERM had previously collected data on complications associated with anaesthesia between 1978 and 1982: the annual rates of deaths that were totally or partially related to anaesthesia were respectively 76 and 263 per million. Compared to these previous data, the anaesthesia-related mortality rate fell ten-fold over the last two decades, while the number of anaesthetic procedures at least doubled. In addition, the number of procedures involving old people and patients with poor physical status was multiplied by four. It seems logical to attribute these results to safety and practice guidelines published after the previous inquiry. Progress remains to be made: the present rate of 1/145000 will serve as a basis for systematic analysis of accidents.