Demographics of patients receiving Intravitreal anti-VEGF treatment in real-world practice: healthcare research data versus randomized controlled trials.

BACKGROUND: While randomized controlled trials (RCTs) are based on strict inclusion/exclusion criteria, non-interventional studies (NISs) might provide additional information to guide management in patients more representative to the real-world setting. The aim of this study was to compare baseline characteristics of patients receiving intravitreal treatment in the NIS OCEAN with those from published RCTs. METHODS: The ongoing OCEAN study enrolled patients treated with ranibizumab for neovascular age-related macular degeneration (nAMD), diabetic macular oedema (DME) or branch/central retinal vein occlusion (B/CRVO). Baseline patient characteristics were compared by indication within the OCEAN cohort. Furthermore, the characteristics were set in reference to those of published RCTs in the same indications. Confidence intervals (CIs) were calculated and assessed for statistically significant differences as indicated by non-overlapping CIs. RESULTS: Patient characteristics in the NIS OCEAN were evaluated for 3,614 patients with nAMD, 1,211 with DME, 204 with BRVO and 121 with CRVO. Between these groups, significant differences in mean age, gender distributions, and mean baseline VA were seen, reflecting known differences between the indications. Compared to the patient characteristics of published RCTs (trials selected by literature search: nAMD: 13 RCTs, DME: 9, RVO: 5), the OCEAN patients' mean age was significantly higher in every indication. The gender distributions across the trials were comparable, with only few differences between OCEAN and the RCTs. Regarding the mean baseline VA, notable differences were found in nAMD and in DME, with VA significantly higher in some RCTs and lower in others. CONCLUSIONS: The described differences underline the complementarity of NISs and RCTs. OCEAN covers a broader spectrum and more variability of patients than do RCTs. As baseline values may have impact on the treatment response (ceiling effect), there is an ongoing need for research in all patient subgroups. Country-specific assessments of patient populations can better reflect the real-world situation. NISs can deliver insights that RCTs may not, as NISs can include non-typical patients, patients with comorbidities, a broader age spectrum and patients of various disease stages. TRIAL REGISTRATION: The NIS OCEAN was registered on www.clinicaltrials.gov (identifier: NCT02194803 ).

Position-dependent accommodative shift of retropupillary fixated iris-claw lenses.

PURPOSE: After implantation of retropupillary fixated iris-claw lenses, changes of the objective refraction can occur depending on the patients' position. The purpose of this study was to evaluate and quantify these changes as well as the influencing factors. METHODS: Within a retrospective study, postoperative refraction visual, acuity and anterior chamber depth after implantation of a retropupillary fixated iris-claw lens (Artisan® / Verisyse®) were measured in 51 eyes (49 patients) depending on their head position. These parameters were determined with the assistance of a mobile auto-refractometer, acoustic biometry, IOL-Master, chart projector and accommodometer in primary position, as well as in forward- and backward-tilted head position. RESULTS: The data analysis indicated a position-dependent change of the anterior chamber depth, which was largest in the backward-tilted head position (median: 4.25 mm/min.: 3.39 mm/max.: 5.37 mm). In comparison to the primary position (4.15 mm), it decreased in a forward-tilted position of the head (4.08 mm). A significant difference in anterior chamber depth was verified for backward- and forward-tilted heads (median: 0.155 mm). Refraction showed a significant difference (0.37 D) between forward- and backward-tilted head position. In comparison to the back-tilted head position (mean: -0.065 D), a smaller spherical equivalent could be demonstrated by bending the head forward (mean: -0.438 D). In addition, no correlation was found between lens movement and other continuous attributes. CONCLUSIONS: Significant changes in anterior chamber depth and refraction due to the iris-claw lens shift were found, depending on head position. The phenomenon of pseudophakic accommodation is explained by pseudo-myopia and pseudo-hyperopia. A considerable influence on visual acuity depending on patients´ head position could not be verified.

Conditions for enhancing the encoding of an elementary motor memory by rTMS.

OBJECTIVE: Motor learning results in changes of movement representation in primary motor cortex (M1) a process involving long-term potentiation (LTP). Pairing motor training with repetitive transcranial magnetic stimulation (rTMS) of M1 enhances the formation of a motor memory. Here we determined the effect of pairing M1 stimulation and the execution of training movements at different times and frequencies on the formation of a motor memory. METHODS: Formation of a motor memory was defined as increases in motor evoked potentials (MEP) of the training agonist (extensor carpi ulnaris muscle, ECU) and increases in peak acceleration of the trained movements that last more than 60min. Training consisted of auditory-paced ballistic wrist extension movements (30min, 0.5Hz) paired with 0.1, 0.25 or 0.5Hz subthreshold rTMS. The rTMS pulse was applied at either the onset, 100ms prior to or 300ms after the onset of training movement related increases in electromyographic (EMG) activity of ECU. This was compared to a Sham condition. RESULTS: Only 0.1Hz rTMS applied at the onset of the training related increase in ECU-EMG activity resulted in increases in MEP amplitudes and peak acceleration when compared to the Sham. CONCLUSIONS: The formation of motor memory is enhanced above the naïve level by co-administration of low frequency rTMS at the time of execution of training movements. SIGNIFICANCE: These results indicate the importance of time and frequency of rTMS in these settings and should be considered in the design of rehabilitation treatment strategies using rTMS.

Differential absorption lidar technique for measurement of the atmospheric pressure profile.

A new two-wavelength lidar technique for remotely measuring the pressure profile using the trough absorption region between two strong lines in the oxygen A band is described. The theory of integrated vertical path, differential ranging, and horizontal path pressure measurements is given with methods to desensitize and correct for temperature effects. The properties of absorption troughs are described and shown to reduce errors due to laser frequency jitter by up to 2 orders of magnitude. A general analysis, including laser bandwidth effects, demonstrates that pressure measurements with an integrated vertical path technique are typically fifty times more accurate than with a differential ranging technique. Simulations show 0.1-0.3% accuracy for ground and Shuttle-based pressure profile and surface pressure experiments.

Effective frequency technique for finite spectral bandwidth effects.

A technique that uses a single effective frequency to represent the effects of finite spectral bandwidth for active and passive measurements centered on an absorption line, a trough region, or a slowly varying spectral feature is described. For Gaussian and rectangular instrumental line shapes, the effective frequency is shown to have a simple form that depends only on the instrumental line shape and bandwidth and not on the absorption line profile. The technique is applicable to a large class of active and passive measurements and simulations in both the laboratory and the atmosphere. Simulations show that the technique yields accuracies better than 0.1% for bandwidths less than 0.2 times the atmospheric linewidth for a rectangular line shape or better than 0.2% for a Gaussian.

Edge technique for high-accuracy Doppler velocimetry.

The edge technique has been used in simple laboratory experiments to demonstrate velocity measurements with an experimental error, standard deviation, as small as 12 cm/s, which represents a Doppler-shift measurement accuracy of 8 parts in 10(10) of the laser frequency. An edge filter with a spectral width 140 times larger than the measurement accuracy achieved is used. The measurements are made in the presence of short-term frequency drifts equivalent to velocities of 5 to 10 m/s, which are eliminated by the differential frequency measurement used in the edge technique. Long-term frequency drifts are compensated for by servo locking the edge to the laser frequency. High accuracy is achieved for a range of locations on the edge from 0.33 to 4.5 fringe half-widths (half-width at half-maximum), a dynamic range greater than 500 times the measurement accuracy.

Theory of the double-edge molecular technique for Doppler lidar wind measurement.

The theory of the double-edge lidar technique for measuring the wind with molecular backscatter is described. Two high-spectral-resolution edge filters are located in the wings of the Rayleigh-Brillouin profile. This doubles the signal change per unit Doppler shift, the sensitivity, and improves measurement accuracy relative to the single-edge technique by nearly a factor of 2. The use of a crossover region where the sensitivity of a molecular- and an aerosol-based measurement is equal is described. Use of this region desensitizes the molecular measurement to the effects of aerosol scattering over a velocity range of +/-100 m/s. We give methods for correcting short-term, shot-to-shot, frequency jitter and drift with a laser reference frequency measurement and methods for long-term frequency correction with a servo control system. The effects of Rayleigh-Brillouin scattering on the measurement are shown to be significant and are included in the analysis. Simulations for a conical scanning satellite-based lidar at 355 nm show an accuracy of 2-3 m/s for altitudes of 2-15 km for a 1-km vertical resolution, a satellite altitude of 400 km, and a 200 km x 200 km spatial resolution.

Edge technique: theory and application to the lidar measurement of atmospheric wind.

The edge technique is a new and powerful method for measuring small frequency shifts. With the edge technique a laser is located on the steep slope of a high-resolution spectral filter, which produces large changes in transmission for small frequency shifts. A differential technique renders the frequency shift measurement insensitive to both laser and filter frequency jitter and drift. The measurement is shown to be insensitive to the laser width and shape for widths that are less than the half-width of the edge filter. The theory of the measurement is given with application to the lidar measurement of wind. The edge technique can be used to measure wind with a lidar by using either the aerosol or molecular backscattered signal. Examples of both measurements are presented. Simulations for a ground-based lidar at 1.06 microm using reasonable instrumental parameters are used to show an accuracy for the vector components of the wind that is better than 0.5 m/s from the ground to an altitude of 20 km for a 100-m vertical resolution and a 100-shot average. For a 20-m vertical resolution and a 10-shot average, simulations show an accuracy of better than 0.2 m/s in the first 2 km and better than 0.5 m/s to 5 km.

Edge technique Doppler lidar wind measurements with high vertical resolution.

We have developed a Doppler lidar system using the edge technique and have made atmospheric lidar wind measurements. Line-of-sight wind profiles with a vertical resolution of 22 m have a standard deviation of 0.40 m /s for a ten-shot average. Day and night lidar measurements of the vector wind have been made for altitudes from 200 to 2000 m. We validated the lidar measurements by comparing them with independent rawinsonde and pilot balloon measurements of wind speed and direction. Good agreement was obtained. The instrumental noise for these data is 0.11 m /s for a 500-shot average, which is in good agreement with the observed minimum value of the standard deviation for the atmospheric measurements. The average standard deviation over 30 mins varied from 1.16 to 0.25 m /s for day and night, respectively. High spatial and temporal resolution lidar profiles of line-of-sight winds clearly show wind shear and turbulent features at the 1 -2-m /s level with a high signal-to-noise ratio and demonstrate the potential of the edge-technique lidar for studying turbulent processes and atmospheric dynamics.

[Psychomotor development of children at risk with special reference to prenatal, intrapartum and postnatal hypoxia]. / Psychomotorische Entwicklung von Risikokindern unter Berücksichtigung prä-, intra- und postnataler Hypoxien.

In a prospective study the psychomotor development of an unselected collective of high risk newborn infants up to the end of the second year of life was examined. The proof of hypoxia was performed with the erythrocytic density test (EDT). The value of EDT showed a decline with the age of life, and it was independent of gestational age or of birthweight only at the first point of determination (cord blood, first or second day of life). Significant connections between the level of light red blood cells and the children's development could not be demonstrated, although the probability to develop psychomotor disabilities increased in the newborn with a positive value of EDT. The diagnostic value of EDT showed the best results for intrapartum and postnatal hypoxia. The highest specificity was calculated with 38.0%, if the sensitivity is 80.0%. In conclusion of these results it's not to be recommended to use the EDT alone for the prediction of individual prognosis of children.

Double-edge molecular measurement of lidar wind profiles at 355 nm.

We built a direct-detection Doppler lidar based on the double-edge molecular technique and made the what we believe to be the first molecular-based wind measurements using the eye-safe 355-nm wavelength. Three etalon bandpasses are obtained with step etalons on a single pair of etalon plates. We eliminate long-term frequency drift of the laser and the capacitively stabilized etalon by locking the etalon to the laser frequency. We use a low-angle design to avoid polarization effects. Wind measurements of 1-2-m /s accuracy are obtained to 10-km altitude with 5 mJ of laser energy, a 750-s integration, and a 25-cm telescope. Good agreement is obtained between lidar and rawinsonde measurements.

Airborne and ground based lidar measurements of the atmospheric pressure profile.

The first high accuracy remote measurements of the atmospheric pressure profile have been made. The measurements were made with a differential absorption lidar system that utilizes tunable alexandrite lasers. The absorption in the trough between two lines in the oxygen A-band near 760 nm was used for probing the atmosphere. Measurements of the 2-D structure of the pressure field were made in the troposphere from an aircraft looking down. Also, measurements of the 1-D structure were made from the ground looking up. Typical pressure accuracies for the aircraft measurements were 1.5-2 mbar with a 30-m vertical resolution and a 100-shot average (20 s), which corresponds to a 2-km horizontal resolution. Typical accuracies for the upward viewing ground based measurements were 2.0 mbar for a 30-m resolution and a 100-shot average.

[Perinatal herpes infection. Clinical aspects--therapy--follow-up]. / Die perinatale Herpesinfektion. Klinik--Therapie--Verlauf.

Herpes simplex virus may cause serious infections in neonates. In case of foetal infection in the first trimenon, abortions, stillbirth, prematurity, intrauterine growth retardation (not obligatory) and various malformations may result. Neonatal HSV infection is mostly the consequence of intrapartum virus acquisition during passage through the birth canal. The infection is mostly localised on the skin, at the eyes or the mouth or disseminated with or without HSV meningoencephalitis. It is difficult to establish the diagnosis, because neonatal herpes disease in the early stage is not easy to distinguish from other diseases in the newborn such as RDS, NEC or ICH. Antiviral therapy with aciclovir is the treatment of choice and seems to improve the outcome of neonatal herpes. Prognosis depends on early therapy. Treatment should be initiated in relation to clinical findings, because available diagnostic techniques do not always permit an early detection of the disease.

Laser remote sensing of atmospheric temperature by observing resonant absorption of oxygen.

Measurement of atmospheric temperature through the monitoring of laser energy absorption at the center of an O(2) resonant absorption line near 770 nm has been demonstrated using a dual frequency system. The average temperature of a 1-km path can be determined to better than 1.0 degrees C with a noise level of 0.3 degrees C. An iterative algebraic expression for determining temperature from the measured absorption was developed and shown to be applicable in the troposphere. The effects of pressure and humidity on temperature determination are clear from the algorithm and found to be small near the earth's surface.

Gated photomultiplier response characterization for DIAL measurements.

The characteristics of various detector responses are studied to understand the cause of various systematic biases and to minimize these undesirable effects in measurements of transient signals with large dynamic range. We quantitatively evaluated signal induced bias, gain variation, and the linearity of commonly used gated photomultipliers in the current integrating mode. Analysis of the results indicates that impurity ions inside the photomultiplier tube are the source of the signal induced bias and gain variation. Two different photomultiplier tubes used in this study show significant differences in the magnitude and decay behavior of signal induced bias. We found it can be minimized by using an external amplifier to reduce PMT gain, and by applying a low potential between the cathode and first dynode. The linearity of a photomultiplier tube is also studied over a large dynamic range of input intensities employing a new technique which does not require an absolute calibration. The result of this study shows that the photomultiplier response is linear only for a limited input intensity range below a certain anode current.

[The status of biological risk factors and the optimality concept in diagnosis of early childhood developmental disorders]. / Die Stellung biologischer Risikofaktoren und des Optimalitätskonzeptes in der Diagnostik frühkindlicher Entwicklungsstörungen.

In a prospective study the psychomotor development up to the end of the second year of life of 409 preterm and term newborn infants was examined in order to identify which optimality score might be associated with disturbances of normal childlike development. Significant connections between 24 and 55 risk factors and the mortality could be demonstrated, but only 3 factors (sex, apgar, acidosis) exert influence on psychomotor development. The risk loading of the collective was high, not one of the children showed an optimal score. Decreased patients possessed a stronger reduced optimality than survivors. The optimality concept is not suitable for the prediction of later disturbed development of children, because the items are unspecific. The marker of hypoxia, the erythrocytic-density-test, as well as the neuron-specific enolase showed better diagnostic values than the optimality concept.

[Intracerebral hemorrhage and its sequelae in high risk newborn infants in relation to oxygen deficiency status]. / Intrazerebrale Blutungen und ihre Folgezustände bei Risikoneugeborenen in Abhängigkeit von Sauerstoffmangelzuständen.

In a prospective study 325 risk newborn infants were examined by means of ultrasound scanning. Children with and without intracerebral haemorrhages were classified, according to pre-, intra-, and postnatal periods of oxygen privation. For the characterization of short-term hypoxia the blood-gas analysis was used for the ascertainment of longtime hypoxia the erythrocytic-density-test (EDT). In dependence on PO2-values less than or equal to 5 kPa intracerebral haemorrhages of variable states increased significantly (p = 0.01). Evaluating the results of erythrocytic-density-test it may be concluded that the prenatal hypoxia has the greatest influence on the rate of intracerebral bleedings. Thus only 37.5% of our patients with prenatal hypoxia remained free of haemorrhages, in contrast of 70.2% of children without deficiency of oxygen.

Theory of the double-edge technique for Doppler lidar wind measurement.

The theory of the double-edge technique is described by a generalized formulation that substantially extends the capabilities of the edge technique. It uses two edges with opposite slopes located about the laser frequency. This doubles the signal change for a given Doppler shift and yields a factor of 1.6 improvement in the measurement accuracy compared with the single-edge technique. Use of two high-resolution edge filters reduces the effects of Rayleigh scattering on the measurement by as much as an order of magnitude and allows the signal-to-noise ratio to be substantially improved in areas of low aerosol backscatter. We describe a method that allows the Rayleigh and aerosol components of the signal to be independently determined. The effects of Rayleigh scattering are then subtracted from the measurement, and we show that the correction process does not significantly increase the measurement noise for Rayleigh-to-aerosol ratios as high as 10. We show that for small Doppler shifts a measurement accuracy of 0.4 m/s can be obtained for 5000 detected photons, 1.2 m/s for 1000 detected photons, and 3.7 m/s for 50 detected photons for a Rayleigh-to-aerosol ratio of 5. Methods for increasing the dynamic range to more than +/-100 m/s are given.

[Intracerebral hemorrhage and neuron-specific enolase in premature and full-term infants--a clinical study]. / Intrazerebrale Blutungen und neuronenspezifische Enolase bei Früh- und Termingeborenen--Eine klinische Studie.

In a prospective study 199 risk newborn infants were examined by means of cerebral ultrasound scanning and after this the influence of diagnosed intracerebral events on the concentration of neuron-specific enolase (NSE) was determined. The NSE may be valid as an indicator of intracerebral damage. A significant relationship between increased concentration of NSE and intracerebral haemorrhage of type II could be found only for the NSE-1 (determination from cordblood or from blood of the first or second day of life). The same relationship results for intracranial cystic rebuildings, destructions and enlargements of ventricles. The diagnostic tests of NSE-1 for intracerebral haemorrhages don't prove with a validity of 57.4% high prognostic value. Not until a NSE-1-level of 16.0 micrograms/l a predictive value of the positive test of 100% was calculated.