Target-mediated clearance and bio-distribution of a monoclonal antibody against the Kunitz–type protease inhibitor 2 domain of Tissue Factor Pathway Inhibitor

Introduction

A humanised monoclonal antibody, concizumab, that binds with high affinity to the Kunitz-type protease inhibitor (KPI) 2 domain of human tissue factor pathway inhibitor (TFPI) is in clinical development. It promotes coagulation by neutralising the inhibitory function of TFPI and may provide a subcutaneous prophylaxis option for patients with haemophilia. We aimed to study biodistribution and pharmacokinetics (PK) of concizumab.

Materials and Methods

Blockage of cellular TFPI by concizumab was measured by tissue factor/Factor VIIa-mediated Factor X activation on human EA.hy926 cells. Biodistribution of concizumab was analysed in rabbits by immunohistology, and the PK was measured in rabbits and rats.

Results and Conclusions

Concizumab bound to cell surface TFPI on EA.hy926 cells and neutralised TFPI inhibition of Factor X activation. The antibody cross-reacted with rabbit TFPI, but not with rat TFPI, allowing for comparative PK studies. PK data in rats described a log-linear profile typical for a non-binding antibody, whereas PK data in rabbits revealed a non-linear, dose-dependent profile, consistent with a target-mediated clearance mechanism. Immunohistology in rabbits during target-saturation showed localisation of the antibody on the endothelium of the microvasculature in several organs. We observed a marked co-localisation with endogenous rabbit TFPI, but a negligible sub-endothelial build-up. Concizumab binds and neutralises the inhibitory effect of cell surface-bound TFPI. The PK profile observed in rabbits is consistent with a TFPI-mediated drug disposition. Double immunofluorescence shows co-localisation of the antibody with TFPI on the endothelium of the microvasculature and points to this TFPI as a putative target involved in the clearance mechanism.     

A case of slipped capital femoral epiphysis results from hypophosphatemic rickets： treatment and midterm follow-up

In this case, a male patient presented with a clinically and radiographieally unstable slipped capital femoral epiphysis （SCFE） as well as slipped calcaneal epiphysis years. Subsequent thorough at the age of 23 work-up revealed that he had some features of rickets and labo- ratory test demonstrated he had hypophos- phatemia （2.3mg/dl）, normocalcemia, normal vi- tamin D metabolite levels, and secondary hy- perparathyroidism.     

Preoperative factors associated with red blood cell transfusion in hip fracture patients

Introduction

Red blood cell (RBC) transfusion is a frequently used treatment in patients admitted with a fractured hip, but the use remains an area of much debate. The aim of this study was to determine preoperative factors associated with the risk of receiving a red blood cell transfusion in hip fracture patients.

Method

The study included 986 consecutive hip fracture patients (aged 60 years or above). The patients were identified from a database of all hip fracture patients admitted to Bispebjerg University Hospital. Data for the database are collected via chart review and data extraction from the hospitals laboratory system, public registries and from the Capital Region Blood Bank Database.

Results

Overall transfusion rate was 58.7 %. The univariate analyses showed that transfusion rate was higher among women (p = 0.004), older patients (p < 0.0001), patients with high ASA scores (p < 0.0001), patients with more severe fractures (p < 0.0001), patients with lower admission haemoglobin levels (p < 0.0001), patients not admitted from own home (p = 0.02) and patients taking aspirin (p = 0.007) or other platelet inhibitors (p = 0.01) on admission. In the multivariate analysis, increasing age, ASA ≥3, being admitted from own home, extracapsular fractures, decreasing admission haemoglobin and use of platelet inhibitors were all significantly associated with the risk of receiving a RBC transfusion.

Conclusion

Several readily available preoperative factors in the form of age, residence, ASA, admission haemoglobin, medication and type of fracture were independently associated with the likelihood of receiving a red blood cell transfusion in patients admitted with a fractured hip.     

Chagas' disease diagnosis: evaluation of several tests in blood bank screening

Blood transfusion is one of the principal routes of transmission of Chagas' disease, a major endemic disease in Latin America. Methods for blood screening are not accurate and may yield false results that lead to high social and economic costs. This study compares two methods of diagnosing Chagas' disease (indirect immunofluorescence and hemagglutination) and several enzyme-linked immunosorbent assays (ELISAs) with regard to specificity and sensitivity, by using human sera with known serologic and parasitologic characteristics, as well as samples with discrepant results on conventional serologic tests. An ELISA using recombinant antigens showed no cross-reactivity with sera that were positive for other diseases. All evaluated ELISAs performed well, and their use may lead to a reduction of more than 50 percent in the number of discordant sera. Further improvements are needed in view of the complexity of the serologic diagnosis of Chagas' disease.     

胎儿和新生儿同种异体免疫性血小板减少症:进展与持续性争议

胎儿和新生儿同种异体免疫性血小板减少症(AIT)是引起胎儿和新生儿严重血小板减少的最常见原因.母亲针对源自父亲的胎儿血小板抗原的IgG抗体,在妊娠早期就可通过胎盘,通常导致胎儿严重血小板减少.由于一些血小板减少症临界值(50、100或150×109/L)的不同,他们的发生率亦各不相同.但在多数未经选择的人群中,AIT影响1/1 000到1/2 000活产数.在新生儿病房,临床确诊的重症AIT很罕见,可能只有1:10 000分娩数.     

The Geriatric Depression Scale and the Cornell Scale for Depression in Dementia. A validity study

The study is a validation study of two psychogeriatric depression rating scales, The Geriatric Depression Scale (GDS) and the Cornell Scale for Depression in Dementia (CSDD). The sensitivity and specificity, and the convergent and criterion validity of the two scales as well as the inter-rater reliability of the CSDD are reported. Two independent clinicians using the ICD-10 for depression and dementia, the Clinical Global Impression (CGI), the Hamilton Depression rating scale 17-items and the Mini-Mental-State Examination (MMSE), interviewed each patient or control subject. One hundred forty-five persons of 65 years or more of age were included, 73 were depressed only, 36 depressed and demented; 36 persons were control subjects, 11 of these were demented. The inter-rater reliabilities were high or very high equalling perfect correlation. There was very high convergent validity between the screening tools and the severity scales; the shorter versions of the GDS (15-, 10- or four-item version) had lower though still almost perfect correlations. The criterion validity in the total population showed the CSDD as the better scale with sensitivity and specificity of 93% and 97% with a cut-off value of ≥6. The GDS versions had sensitivities and specificities ranging from 82% to 90% and 75% to 94% respectively with cut-off values ≥9, 4, 3 and 1. The CSDD retained its validity and specificity as a screening tool for depression in a population of demented, while the GDS versions all diminished in validity. The GDS and the CSDD are both valid screening tools for depression in the elderly; however, the CSDD alone seems to be equally valid in populations of demented and non-demented.     

Sleep efficiency and neurophysiological patterns in middle‐aged men are associated with cognitive change over their adult life course

Disrupted sleep is a contributing factor to cognitive ageing, while also being associated with neurodegenerative disorders. Little is known, however, about the relation of sleep and the gradual cognitive changes over the adult life course. Sleep electroencephalogram (EEG) patterns are potential markers of the cognitive progress. To test this hypothesis, we assessed sleep architecture and EEG of 167 men born in the Copenhagen Metropolitan Area in 1953, who, based on individual cognitive testing from early (~18 years) to late adulthood (~58 years), were divided into 85 subjects with negative and 82 with positive cognitive change over their adult life. Participants underwent standard polysomnography, including manual sleep scoring at age ~58 years. Features of sleep macrostructure were combined with a number of EEG features to distinguish between the two groups. EEG rhythmicity was assessed by spectral power analysis in frontal, central and occipital sites. Functional connectivity was measured by inter‐hemispheric EEG coherence. Group differences were assessed by analysis of covariance (p < 0.05), including education and severity of depression as potential covariates. Subjects with cognitive decline exhibited lower sleep efficiency, reduced inter‐hemispheric connectivity during rapid eye movement (REM) sleep, and slower EEG rhythms during stage 2 non‐REM sleep. Individually, none of these tendencies remained significant after multiple test correction; however, by combining them in a machine learning approach, the groups were separated with 72% accuracy (75% sensitivity, 67% specificity). Ongoing medical screenings are required to confirm the potential of sleep efficiency and sleep EEG patterns as signs of individual cognitive progress.     

Temporal trends in hip fracture incidence,mortality, and morbidity in Denmark from 1999 to 2012

Background and purpose — While development in hip fracture incidence and mortality is well examined, none has yet looked at the temporal trends regarding prevalence of co-morbidities. Therefore we investigated changes in incidence of first hip fracture, co-morbidity prevalence, 30?day- and 1-year mortality in hip fracture patients in the Danish population during the period 1999 to 2012.

Patients and methods — Patients >18 years admitted with a fractured hip in Denmark between 1996 and 2012 were identified with data for the period 1999–2012 being analyzed regarding prevalence of co-morbidities, incidence, and mortality.

Results — 122,923 patients were identified. Incidence in the whole population declined but sex-specific analysis showed no changes for men. For the whole study population, 30-day and 1-year mortality remained unchanged. Age at time of first hip fracture also remained unchanged. Of the included co-morbidities a decrease in prevalence of malignancy and dementia in women was found while there was an increase in the prevalence of all remaining co-morbidities, except hemi- or paraplegia for both sexes, rheumatic diseases for women, and for men diabetes with complications, myocardial infarction, AIDS/HIV, and malignancy.

Interpretation — While hip fracture incidence declined for women it was unchanged for men; likewise, 30-day and 1-year mortality rates together with age at first fracture remained unchanged. When these results are compared with the relatively large increase in the prevalence of co-morbidities, it does not seem likely that the increased disease burden is affecting either the incidence or the mortality.