Validation of a predictive model for identifying an increased risk for recurrence in adolescents and young adults with a first provoked thromboembolism.

BACKGROUND: To develop and validate a predictive model to determinate patients at increased risk to suffer from recurrence following a first provoked deep vein thrombosis (VTE). METHODS: Predictive variables, i.e. male sex [1 point], inherited thrombophilia (IT) status (none [0 points], single [1 point], combined variants [2 points]), blood group non-0, and age at first VTE onset were included into a risk assessment model, which was derived in 511 patients and then validated in 509 independent subjects. RESULTS: VTE recurrence risk score (maximum 4 points, range 0-3) was below two for patients scored as low-risk (LRS) and ≥2 for patients at high-risk (HRS). Within a median time of 3 years after withdrawal of anticoagulation (AC) recurrence rate in LRG (derivation) was 11.8% versus 26.0% in HRS (p < 0.001). In the validation cohort within 2.2 years the recurrence rate was 9.8% in LRS versus 30.1% in HRS (p < 0.001). In multivariable analysis adjusted for age at first VTE and blood group the recurrent risk in HRS was significantly increased compared with the LRS (derivation: hazard/95% confidence interval: 3.7/1.75-7.91; validation: 4.7/2.24-9.81; combined 5.2/1.92-13.9). Model specificity (sensitivity) was 79.0% (52.0%) in the derivation cohort compared with 78.0% (43.0%) in the validation group. In conclusion, in the prediction model presented here the risk of VTE recurrence was associated with male gender and combined ITs. Based on the negative predictive value calculated the model may identify patients with a first provoked VTE not being at risk for recurrence.

Spatial Ventilation Inhomogeneity Determined by Electrical Impedance Tomography in Patients With Chronic Obstructive Lung Disease.

The aim of this study was to examine whether electrical impedance tomography (EIT) could determine the presence of ventilation inhomogeneity in patients with chronic obstructive lung disease (COPD) from measurements carried out not only during conventional forced full expiration maneuvers but also from forced inspiration maneuvers and quiet tidal breathing and whether the inhomogeneity levels were comparable among the phases and higher than in healthy subjects. EIT data were acquired in 52 patients with exacerbated COPD (11 women, 41 men, 68 ± 11 years) and 14 healthy subjects (6 women, 8 men, 38 ± 8 years). Regional lung function parameters of forced vital capacity (FVC), forced expiratory volume in 1 s (FEV1), forced inspiratory vital capacity (FIVC), forced inspiratory volume in 1 s (FIV1), and tidal volume (V T ) were determined in 912 image pixels. The spatial inhomogeneity of the pixel parameters was characterized by the coefficients of variation (CV) and the global inhomogeneity (GI) index. CV and GI values of pixel FVC, FEV1, FIVC, FIV1, and VT were significantly higher in patients than in healthy subjects (p ≤ 0.0001). The ventilation distribution was affected by the analyzed lung function parameter in patients (CV: p = 0.0024, GI: p = 0.006) but not in healthy subjects. Receiver operating characteristic curves showed that CV and GI discriminated patients from healthy subjects with an area under the curve (AUC) of 0.835 and 0.852 (FVC), 0.845 and 0.867 (FEV1), 0.903 and 0.903 (FIVC), 0.891 and 0.882 (FIV1), and 0.821 and 0.843 (VT), respectively. These findings confirm the ability of EIT to identify increased ventilation inhomogeneity in patients with COPD.

Hearing requires otoferlin-dependent efficient replenishment of synaptic vesicles in hair cells.

Inner hair cell ribbon synapses indefatigably transmit acoustic information. The proteins mediating their fast vesicle replenishment (hundreds of vesicles per s) are unknown. We found that an aspartate to glycine substitution in the C(2)F domain of the synaptic vesicle protein otoferlin impaired hearing by reducing vesicle replenishment in the pachanga mouse model of human deafness DFNB9. In vitro estimates of vesicle docking, the readily releasable vesicle pool (RRP), Ca(2+) signaling and vesicle fusion were normal. Moreover, we observed postsynaptic excitatory currents of variable size and spike generation. However, mutant active zones replenished vesicles at lower rates than wild-type ones and sound-evoked spiking in auditory neurons was sparse and only partially improved during longer interstimulus intervals. We conclude that replenishment does not match the release of vesicles at mutant active zones in vivo and a sufficient standing RRP therefore cannot be maintained. We propose that otoferlin is involved in replenishing synaptic vesicles.