Simoctocog Alfa (Nuwiq) in Previously Untreated Patients with Severe Haemophilia A: Final Results of the NuProtect Study.

INTRODUCTION: FVIII inhibitor development is the most serious contemporary treatment complication in haemophilia A, particularly in previously untreated patients (PUPs). No inhibitors developed in clinical trials in previously treated patients treated with simoctocog alfa (Nuwiq), a fourth-generation recombinant FVIII produced in a human cell line. METHODS: The NuProtect study investigated the immunogenicity of simoctocog alfa in PUPs. NuProtect was a prospective, multinational, open-label, non-controlled, phase III study. PUPs with severe haemophilia A (FVIII:C <1%) of any age and ethnicity were treated with simoctocog alfa for 100 exposure days or a maximum of 5 years. Patients were true PUPs without prior exposure to FVIII concentrates or blood components. Inhibitor titres were measured with the Nijmegen-modified Bethesda assay; cut-off for positivity was 0.6 BU mL-1 (≥0.6 to <5 low-titre, ≥5 high titre). RESULTS: A total of 108 PUPs with a median age at first treatment of 12.0 months (interquartile range: 8.0-23.5) were treated with simoctocog alfa. F8 mutation type was known for 102 patients (94.4%) of whom 90 (88.2%) had null F8 mutations and 12 (11.8%) had non-null mutations. Of 105 PUPs evaluable for inhibitor development, 28 (26.7%) developed inhibitors; 17 high titre (16.2%) and 11 low titre (10.5%). No PUPs with non-null F8 mutations developed inhibitors. CONCLUSION: In the NuProtect study, the rate of inhibitor development in PUPs with severe haemophilia A treated with simoctocog alfa was lower than the rate reported for hamster-cell-derived recombinant factor VIII products in other recent clinical trials. No inhibitors were reported in PUPs with non-null F8 mutations.

Stratum corneum occlusion induces water transformation towards lower bonding state: a molecular level in vivo study by confocal Raman microspectroscopy.

OBJECTIVE: It is conventionally understood that occlusive effects are the retention of excessive water in the stratum corneum (SC), the increase of SC thickness (swelling) and a decrease of the transepidermal water loss. However, the influence of occlusion on water binding properties in the SC is unknown. METHODS: The action of plant-derived jojoba and almond oils, as well as mineral-derived paraffin oil and petrolatum topically applied on human skin, is investigated in vivo using confocal Raman microspectroscopy. To understand the oils' influence on the SC on the molecular level, the depth-dependent hydrogen bonding states of water in the SC and their relationship to the conformation of keratin, concentration of natural moisturizing factor (NMF) molecules and lipid organization were investigated. RESULTS: A significant SC swelling was observed only in petrolatum-treated skin. The water concentration was increased in oil-treated skin in the intermediate SC region (40-70% SC depth). Meanwhile, the amount of free, weakly and tightly bound water increased, and strongly bound water decreased in the uppermost SC region (0-30% SC depth). The NMF concentration of oil-treated skin was significantly lower at 50-70% SC depth. The lateral organization of lipids in oil-treated skin was lower at 0-30% SC depth. The secondary structure of keratin was changed towards an increase of ß-sheet content in mineral-derived oil-treated skin and changed towards an increase of α-helix content in plant-derived oil-treated skin. CONCLUSION: The occlusive properties can be summarized as the increase of free water and the transformation of water from a more strongly to a more weakly hydrogen bonding state in the uppermost SC, although some oils cause insignificant changes of the SC thickness. The accompanied changes in the keratin conformation at the intermediate swelling region of the SC also emphasize the role of keratin in the SC's water-transporting system, that is the water in the SC transports intercellularly and intracellularly in the intermediate swelling region and only intercellularly in the uppermost non-swelling region. Bearing this in mind, almond, jojoba and paraffin oils, which are not occlusive from the conventional viewpoint, have an occlusion effect similar to petrolatum on the SC.

OBJECTIF: Il est généralement entendu que les effets occlusifs consistent en la rétention d'un excès d'eau dans la couche cornée (stratum corneum, SC), l'augmentation d'épaisseur de la SC (gonflement) et une diminution de la perte d'eau trans-épidermique. Cependant, l'influence de l'occlusion sur les propriétés de fixation de l'eau dans le SC est inconnue. MÉTHODES: L'action des huiles de jojoba et d'amande d'origine végétale, ainsi que des huiles de paraffine et de pétrolatum d'origine minérale appliquées topiquement sur la peau humaine est étudiée in vivo à l'aide de la microspectroscopie Raman confocale. Pour comprendre l'influence des huiles sur le SC au niveau moléculaire, on a étudié les états de liaison hydrogène de l'eau dans le SC en fonction de la profondeur et leur relation avec la conformation de la kératine, la concentration des molécules du facteur naturel d'hydratation (NMF) et l'organisation des lipides. RÉSULTATS: Un gonflement significatif de le SC n'a été observé que dans la peau traitée au pétrolatum. La concentration en eau a été augmentée dans la peau traitée au pétrolatum dans la région SC intermédiaire (40-70% de profondeur du SC). En meme temps, la quantité d'eau libre, faiblement et fortement liée augmentait, tandis que l'eau fortement liée diminuait dans la région SC supérieure (0-30% de profondeur du SC). La concentration en NMF de la peau traitée à l'huile était plus basse d´une manière significative à 50-70% de profondeur du SC. L'organisation latérale des lipides dans la peau huilée était plus basse à une profondeur du SC de 0 à 30 %. La structure secondaire de la kératine a été modifiée pour augmenter la teneur en feuillet-ß dans les peaux huilées d'origine minérale et pour augmenter la teneur en hélice α dans les peaux huilées d'origine végétale. CONCLUSION: Les propriétés occlusives peuvent être résumées comme l'augmentation de l'eau libre et la transformation de l'eau d'un état de liaison hydrogène plus fort à un état de liaison hydrogène plus faible dans le SC supérieure, bien que certaines huiles provoquent des changements insignifiants de l'épaisseur de la SC. Les modifications de la conformation de la kératine dans la zone de gonflement intermédiaire du SC soulignent également le rôle de la kératine dans le système de transport de l'eau du SC, c'est-à-dire que l'eau est transportée du SC de manière intercellulaire et intracellulaire dans la zone de gonflement intermédiaire et seulement de manière intercellulaire dans la zone non gonflée la plus élevée. En considérant cela, les huiles d'amande, de jojoba et de paraffine, qui ne sont pas occlusives du point de vue conventionnel, ont un effet d'occlusion similaire à celui du pétrolatum sur le SC.

Meta-analysis demonstrates lack of association between the ACE gene I/D polymorphism and obstructive sleep apnea-hypopnea syndrome occurrence and severity.

Published data on a possible association between the angiotensin-converting enzyme (ACE) gene I/D polymorphism and obstructive sleep apnea-hypopnea syndrome (OSAHS) occurrence and its severity risk are inconclusive. We performed a meta-analysis of case-control studies published in English or Chinese. Thirteen studies, totaling 1361 cases and 1373 controls, were investigated for association of the ACE I/D polymorphism with OSAHS. We also made a study of ACE I/D with OSAHS severity risk, including 879 mild/moderate OSAHS patients and 357 severe OSAHS patients. A random-effects model was used, irrespective of between-study heterogeneity. Study quality was assessed in duplicate. Overall, the ACE I/D polymorphism was not significantly associated with an increase in OSAHS risk [odds ratio (OR) = 1.21; 95% confidence interval (95%CI) = 0.88-1.65; P = 0.24]. In subgroup analysis by ethnicity, comparison of alleles I with D demonstrated a 58% (nonsignificantly) increased risk for OSAHS in Chinese (OR = 1.58; 95%CI = 0.92-2.70; P = 0.09). We also found that there was no significant association between ACE I/D and OSAHS severity risk. No publication biases were observed. This meta-analysis suggests that there is no significantly increased risk for OSAHS occurrence or severity associated with the ACE I/D polymorphism.

A review of inherited platelet disorders with guidelines for their management on behalf of the UKHCDO.

The inherited platelet disorders are an uncommon cause of symptomatic bleeding. They may be difficult to diagnose (and are likely to be under-diagnosed) and pose problems in management. This review discusses the inherited platelet disorders summarising the current state of the art with respect to investigation and diagnosis and suggests how to manage bleeding manifestations with particular attention to surgical interventions and the management of pregnancy.

[Pharmacokinetic and clinical studies of cefotiam in the perinatal period].

Patients, who had undergone cesarean sections, and those who had experienced premature rupture of membranes, received cefotiam (CTM) and the clinical efficacy and the safety for mothers and fetuses were investigated. At the same time, pharmacokinetic analysis was done to study the maternal fetal transfer. Following results were observed. In cases of premature rupture of membranes, the maternal-fetal transfer ratio after intravenous administrations of CTM was 50.3% at a dosage of 1 g. Maternal and fetal serum concentrations of CTM were maintained higher levels than the MIC80 (0.78 micrograms/ml) against major pathogens excluding anaerobic of gynecologic-obstetric infections and were maintained up to 5.87 hours and 6.15 hours in mothers and fetuses, respectively. The CTM was administered once every 12 hours at a dosage of 1 g to 38 cases up to the 3rd or 4th day of puerperium after the rupture of membranes. Also, the CTM was administered up to times of delivery to another 20 cases, in one of which the fetus developed pneumonia. The maternal-fetal prophylactic effect was recognized in 98.3% (57/58) of cases. Forty-three cesarean section cases received CTM at a dosage level of 1 g by one-hour intravenous drip infusion in the following manner: after surgery to the 4th day, twice a day; from the 5th to the 7th day, once a day. Postoperative prophylactic effect against infection was achieved in all the cases. In 1 case, a slight transient elevation in the maternal GOT was observed. Neonatal jaundice with total bilirubin levels higher than 15.0 mg/dl was observed in 19 neonates (32.8%) in the group in which premature rupture of the membranes had occurred. However, the cause/effect relationship between CTM and the total bilirubin levels is unclear. The maternal-fetal transition of CTM was excellent, and the safety toward the fetus and neonate was high. When an antimicrobial activity and pharmacokinetics are considered, CTM will be a useful drug in the treatment of perinatal infections.