Is It Okay to Use Compressed NU-6 Files for Clinical Word Recognition Testing?

PURPOSE: The purpose of this study was to evaluate the impact of file compression on clinically measured word recognition scores obtained using the Northwestern University Test Number Six (NU-6; Auditec recording) materials. METHOD: Participants were 86 adults (N = 170 ears; M age = 65.5). The 25 most difficult words from each of four NU-6 test lists were used to measure word recognition. Two lists were compressed using a freely available Advanced Audio Coding compression algorithm and two were not. Word recognition was measured in each ear using one compressed file and one uncompressed file. Percent correct scores were calculated in each test condition and log transformed for analyses. Clinically meaningful differences between uncompressed and compressed scores were examined using 95% critical difference ranges. The effects of file compression on word recognition scores were examined in the context of multiple potential confounding effects, including age and degree of hearing loss, using linear mixed-effects models (LMMs). RESULTS: Differences between compressed and uncompressed scores in a given ear exceeded the 95% critical difference range in about 7% of cases, approximating the 5% of expected cases occurring due to chance. Likewise, LMM results revealed no significant effect of file compression on clinically measured NU-6 word recognition scores and no significant interactions between compression effects and age or degree of hearing loss. CONCLUSIONS: While the original uncompressed audio files are clearly the most appropriate stimuli for clinical purposes, our study results suggest that file compression, even at an aggressive 64 kilobits per second, does not have a statistically significant, or clinically meaningful, effect on word recognition scores when measured using these Auditec materials.

Modeling Longitudinal Preclinical Tumor Size Data to Identify Transient Dynamics in Tumor Response to Antiangiogenic Drugs.

Experimental evidence suggests that antiangiogenic therapy gives rise to a transient window of vessel normalization, within which the efficacy of radiotherapy and chemotherapy may be enhanced. Preclinical experiments that measure components of vessel normalization are invasive and expensive. We have developed a mathematical model of vascular tumor growth from preclinical time-course data in a breast cancer xenograft model. We used a mixed-effects approach for model parameterization, leveraging tumor size data to identify a period of enhanced tumor growth that could potentially correspond to the transient window of vessel normalization. We estimated the characteristics of the window for mice treated with an anti-VEGF antibody (bevacizumab) or with a bispecific anti-VEGF/anti-angiopoietin-2 antibody (vanucizumab). We show how the mathematical model could theoretically be used to predict how to coordinate antiangiogenic therapy with radiotherapy or chemotherapy to maximize therapeutic effect, reducing the need for preclinical experiments that directly measure vessel normalization parameters.

Pharmacological treatment with L-DOPA may reduce striatal dopamine transporter binding in in vivo imaging studies.

Numerous neurologic and psychiatric conditions are treated with pharmacological compounds, which lead to an increase of synaptic dopamine (DA) levels. One example is the DA precursor L-3,4-dihydroxyphenylalanine (L-DOPA), which is converted to DA in the presynaptic terminal. If the increase of DA concentrations in the synaptic cleft leads to competition with exogenous radioligands for presynaptic binding sites, this may have implications for DA transporter (DAT) imaging studies in patients under DAergic medication. This paper gives an overview on those findings, which, so far, have been obtained on DAT binding in human Parkinson's disease after treatment with L-DOPA. Findings, moreover, are related to results obtained on rats, mice or non-human primates. Results indicate that DAT imaging may be reduced in the striata of healthy animals, in the unlesioned striata of animal models of unilateral Parkinson's disease and in less severly impaired striata of Parkinsonian patients, if animal or human subjects are under acute or subchronic treatment with L-DOPA. If also striatal DAT binding is susceptible to alterations of synaptic DA levels, this may allow to quantify DA reuptake in analogy to DA release by assessing the competition between endogenous DA and the administered exogenous DAT radioligand.

Decades-long changes of the interstellar wind through our solar system.

The journey of the Sun through the dynamically active local interstellar medium creates an evolving heliosphere environment. This motion drives a wind of interstellar material through the heliosphere that has been measured with Earth-orbiting and interplanetary spacecraft for 40 years. Recent results obtained by NASA's Interstellar Boundary Explorer mission during 2009-2010 suggest that neutral interstellar atoms flow into the solar system from a different direction than found previously. These prior measurements represent data collected from Ulysses and other spacecraft during 1992-2002 and a variety of older measurements acquired during 1972-1978. Consideration of all data types and their published results and uncertainties, over the three epochs of observations, indicates that the trend for the interstellar flow ecliptic longitude to increase linearly with time is statistically significant.

Comparison of two mitotane starting dose regimens in patients with advanced adrenocortical carcinoma.

CONTEXT: Mitotane is the only approved drug for treatment of adrenocortical carcinoma. Its pharmacokinetic properties are not fully elucidated and different dosing regimens have never been compared head to head. OBJECTIVE: The objective of the study was to investigate the relationship between mitotane dose and plasma concentration comparing two dosing regimens. DESIGN/SETTING: This was a prospective, open-label, multicenter trial of a predefined duration of 12 weeks. PATIENTS/INTERVENTIONS: Forty mitotane-naïve patients with metastatic adrenocortical carcinoma were assigned to a predefined low- or high-dose regimen by the local investigator. Thirty-two patients could be evaluated in detail. MAIN OUTCOME MEASURE: The difference in median mitotane plasma levels between both treatment groups was measured. RESULTS: Despite a difference in mean cumulative dose (440 ± 142 g vs 272 ± 121 g), median maximum plasma levels were not significantly different between the two groups [high dose 14.3 mg/L (range 6.3-29.7, n = 20) vs 11.3 mg/L (range 5.5-20.0, n = 12), P = .235]. Ten of 20 patients on the high-dose regimen reached plasma concentrations of 14 mg/L or greater after 46 days (range 18-81 d) compared with 4 of 12 patients on the low-dose regimen after 55 days (range 46-74 d, P = .286). All patients who reached 14 mg/L at 12 weeks displayed a level of 4.1 mg/L or greater on day 33 (100% sensitivity). There were no significant differences in frequency and severity of adverse events. Among patients not receiving concomitant chemotherapy mitotane exposure was higher in the high-dose group: 1013 ± 494 mg/L · d vs 555 ± 168 mg/L · d (P = .080). CONCLUSIONS: The high-dose starting regimen resulted in neither significantly different mitotane levels nor a different rate of adverse events, but concomitant chemotherapy influenced these results. Thus, for mitotane monotherapy the high-dose approach is favorable, whereas for combination therapy a lower dose seems reasonable.

High-risk childhood acute lymphoblastic leukemia in first remission treated with novel intensive chemotherapy and allogeneic transplantation.

Children with acute lymphoblastic leukemia (ALL) and high minimal residual disease (MRD) levels after initial chemotherapy have a poor clinical outcome. In this prospective, single arm, Phase 2 trial, 111 Dutch and Australian children aged 1-18 years with newly diagnosed, t(9;22)-negative ALL, were identified among 1041 consecutively enrolled patients as high risk (HR) based on clinical features or high MRD. The HR cohort received the AIEOP-BFM (Associazione Italiana di Ematologia ed Oncologia Pediatrica (Italy)-Berlin-Frankfurt-Münster ALL Study Group) 2000 ALL Protocol I, then three novel HR chemotherapy blocks, followed by allogeneic transplant or chemotherapy. Of the 111 HR patients, 91 began HR treatment blocks, while 79 completed the protocol. There were 3 remission failures, 12 relapses, 7 toxic deaths in remission and 10 patients who changed protocol due to toxicity or clinician/parent preference. For the 111 HR patients, 5-year event-free survival (EFS) was 66.8% (±5.5) and overall survival (OS) was 75.6% (±4.3). The 30 patients treated as HR solely on the basis of high MRD levels had a 5-year EFS of 63% (±9.4%). All patients experienced grade 3 or 4 toxicities during HR block therapy. Although cure rates were improved compared with previous studies, high treatment toxicity suggested that novel agents are needed to achieve further improvement.

Large mediastinal tumor mass as a prognostic factor in Hodgkin's lymphoma. Is the definition on the basis of a chest radiograph in the era of CT obsolete?

PURPOSE: The risk factor "large mediastinal tumor mass" is an internationally accepted unfavorable prognostic factor in the staging of Hodgkin's lymphoma (HL). The definition of this risk factor varies considerably between large cooperative study groups. The purpose of the present analysis was to determine to which degree data obtained from chest radiograph (CRX) give the same results as those from CT scans (CT). METHODS: A total of 145 de novo HL patients in early unfavorable and advanced stages were included in this study. A total of 94 patients had a large mediastinal tumor mass according to the guidelines of the German Hodgkin Study Group (GHSG), while 51 had mediastinal lymph node involvement only. The size of mediastinal involvement and the thoracic diameter were measured on CRX and CT. Agreement between CRX and CT was determined by sensitivity and specificity analysis as well as descriptive statistics and correlations. RESULTS: The correlation of the diameters on CRX with those of CT was 0.95 for the tumor size and 0.77 for the thoracic diameter. The diagnostic decision-large mediastinal mass or not-correlated with 0.81 between CRX and CT and was identical in 90.3% of cases. The sensitivity was 0.87 and the specificity 0.96 for CRX, which is considered the current standard. CONCLUSION: The results show that there is a high agreement between the measurements of CRX and CT. Diagnosis of a large mediastinal mass disagreed in 10% of patients. Since the correct diagnosis of this risk factor is decisive for the adequate multimodal treatment choice, CRX should not be omitted.

Evaluation of body fat composition after linagliptin treatment in a rat model of diet-induced obesity: a magnetic resonance spectroscopy study in comparison with sibutramine.

The effects of linagliptin on fat content in diet-induced obese rats were compared with those of the appetite suppressant sibutramine. Female Wistar rats fed a high-fat diet (HFD) for 3 months received vehicle, linagliptin (10 mg/kg) or sibutramine (5 mg/kg) treatment orally, once daily for 6 additional weeks, while continuing the HFD. Magnetic resonance spectroscopy analysis of fat content was performed at baseline and at the end of the 6-week treatment period. Linagliptin treatment profoundly reduced hepatic fat compared with vehicle, with an effect comparable to that of sibutramine. The vehicle-corrected mean change (95% CI) from baseline in hepatic fat and intramyocellular lipid was -59.0% (-104.3%, -13.6%; p = 0.015) and -62.1% (-131.6%, 7.4%; p = 0.073), respectively, for linagliptin compared with -54.3% (-101.5%, -7.1%; p = 0.027) and -72.4% (-142.4%, -2.4%; p = 0.044), respectively, for sibutramine.

Fertility and gonadal function in female survivors after treatment of early unfavorable Hodgkin lymphoma (HL) within the German Hodgkin Study Group HD14 trial.

BACKGROUND: In the HD14 trial, 2×BEACOPPescalated+2×ABVD (2+2) has improved the primary outcome. Compared with 4×ABVD, this benefit might be compromised by more infertility in women. Therefore, we analyzed gonadal function and fertility. PATIENTS AND METHODS: Women≤45 years in ongoing remission at least 1 year after therapy were included. Hormone parameters, menopausal symptoms, measures to preserve fertility, menstrual cycle, pregnancies, and offspring were evaluated. RESULTS: Three hundred and thirty one of 579 women addressed participated (57.2%) and 263 per-protocol treated patients qualified (A=ABVD: 137, B=2+2: 126, mean time after therapy 42 and 43 months, respectively). Regular menstrual cycle after treatment (A: 87%, B: 83%) and time to recovery (≤12 months) were not different. Follicle-stimulating hormone and anti-Muellerian hormone were significantly better in arm A. However, pregnancies after therapy favored arm B (A: 15%, B: 26%, P=0.043) and motherhood rates were equivalent to the German normal population. Multivariate analysis revealed prophylactic use of gonadotropin-releasing hormone (GnRH) analogues as highly significant prognostic factor for preservation of fertility (odds ratio=12.87, P=0.001). Severe menopausal symptoms were frequent in women≥30 years (A: 21%, B: 25%). CONCLUSIONS: Hormonal levels after 2+2 indicate a reduced ovarian reserve. However, 2+2 in combination with GnRH analogues does not compromise fertility within the evaluated observation time.

A comparison of rh-TSH and thyroid hormone withdrawal in patients with differentiated thyroid cancer: preliminary evidence for an influence of age on the subjective well-being in hypothyroidism.

We aimed to investigate the subjective well-being in patients with differentiated thyroid cancer after hormone withdrawal. Since this might be confounded by psycho-oncological processes unrelated to hypothyroidism we intended to minimize such factors by only including patients with a history of uneventful follow-up examinations for several years. We investigated 67 patients applying the General Health Questionnaire (GHQ-12) at 3 time points t1, t2, and t3. The time point t2 represented an intensified follow-up examination 5 years after thyroidectomy, which was performed either on hormone withdrawal (49 patients) or using rh-TSH (18 patients). The time points t1 and t3 took place during follow-up examinations 6 months before and after t2 in a euthyroid state. Additionally, we assessed the impact of age, gender, family status, and education on the GHQ-12 score at all 3 time points. Within the hormone withdrawal group the analyses demonstrated a significant difference between t1 and t2 as well as t3 and t2. Additionally, there was a significant negative correlation of age with GHQ-12 sum scores at t2, but not at t1 or t3. Subgroup analyses at t2 indicated that the subjective well-being in younger patients was more impaired compared to elderly patients. The between-group analysis showed no significant differences. However, concerning the age effect there was a significant difference between the subgroup of young hypothyroid patients and the total rh-TSH group at t2. We demonstrated preliminary evidence for an influence of age on the subjective well-being in hypothyroidism suggesting that younger subjects are subjectively more impaired by hypothyroidism than elderly ones.

Reversal of imbalance between kynurenic acid and 3-hydroxykynurenine by antipsychotics in medication-naïve and medication-free schizophrenic patients.

The association between the pro-inflammatory state of schizophrenia and increased tryptophan degradation into kynurenine has been reported. However, the relationship between metabolites from subdivisions of the kynurenine pathway, kynurenic acid and 3-hydroxykynurenine, remains unknown. The present study tested the relationship between these kynurenine metabolites in the plasma of medication-naïve (n=35) or medication-free (n=18) patients with schizophrenia at admission and following 6-week antipsychotic treatment compared to healthy controls (n=48). The plasma concentrations of kynurenic acid (nmol/l) were lower (difference=-8.44 (-13.22 to -3.65); p=0.001) and of 3-hydroxykynurenine (nmol/l) were higher (difference=11.24 (8.11-14.37); p<0.001) in the patients compared with the healthy controls. The kynurenic acid/kynurenine (difference=-2.75 (-5.115 to -0.336); p=0.026) and kynurenic acid/3-hydroxykynurenine (difference=-1.08 (-1.431 to -0.729); p<0.001) ratios were also lower in the patients. After the 6-week treatment, the patients' plasma kynurenic acid levels (difference=3.85 (-0.23 to 7.94); p=0.064) showed a trend towards an increase, whereas plasma 3-hydroxykynurenine levels (difference=22.41 (19.76-25.07); p<0.001) decreased. As a consequence, the kynurenic acid/3-hydroxykynurenine ratio (difference=-4.41 (-5.51 to -3.3); p<0.001) increased. Higher initial plasma kynurenic acid levels on admission or increased kynurenic acid/kynurenine ratio after treatment were associated with reduction of clinical symptoms scores upon discharge although higher kynurenic acid/kynurenine on admission may induce higher positive symptoms score. In contrast, higher 3-hydroxykynurenine is associated with lower positive symptoms score. These results indicate that there is an imbalance in the kynurenine pathway in schizophrenia. The 6-week antipsychotic treatment may partially reverse the imbalance in kynurenine metabolism and that in turn induces clinical response.

In vivo imaging neurotransmitter function. The rat 6-hydroxydopamine model and its relevance for human Parkinson's disease.

This article gives an overview of those small animal imaging studies which have been conducted on neurotransmitter function in the rat 6-hydoxydopamine (6-OHDA) model of Parkinson's disease, and discusses findings with respect to the outcome of clinical studies on Parkinsonian patients.

Clinical evaluation of a new hearing aid anti-cardioid directivity pattern.

OBJECTIVE: The purpose of this research was to evaluate a new directional hearing aid algorithm which automatically adapts to an anti-cardioid pattern in background noise when a speech signal originates from behind the hearing aid user. DESIGN: Using the hearing-in-noise-test (HINT) in the soundfield, with the sentences delivered adaptively from the back (180°) and the standard HINT competing noise from the front (0°; 72 dB SPL), the participants were tested for three different hearing aid conditions: omnidirectional, conventional adaptive directional, and adaptive directional with the anti-cardioid algorithm enabled. STUDY SAMPLE: Adults (n = 21) with bilaterally symmetrical downward sloping sensorineural hearing loss; experienced hearing aid users and aided bilaterally for experimental testing. RESULTS: Results revealed a significant effect for the hearing aid microphone setting (p < .0001), with a HINT mean RTS of 4.2 dB for conventional adaptive directional, -0.1 dB for omnidirectional, and -5.7 dB when the anti-cardioid algorithm was active. This was a large effect size (Cohen's f2). CONCLUSION: The findings suggest that the signal classification system steered the algorithm correctly, and that when implemented, the anti-cardioid polar pattern resulted in an improvement in speech recognition in background noise for this listening situation.

Slit-lamp-adapted fourier-domain OCT for anterior and posterior segments: preliminary results and comparison to time-domain OCT.

PURPOSE: To evaluate the diagnostic potential of a slit-lamp (SL)-adapted Fourier-domain (= spectral radar, SR) optical coherence tomography (OCT)-SL-SR-OCT-instrument as an in vivo imaging device for use in examinations of the anterior and posterior segments. MATERIALS AND METHODS: In a pilot study, 88 eyes from 70 healthy volunteers and patients were examined using a prototype Fourier-domain SL-SR-OCT system. Results were compared to those from the following commercially available systems: the 1310-nm SL-OCT (Heidelberg Engineering, Heidelberg, Germany) for anterior segment and the Stratus OCT (Zeiss Meditec, Jena, Germany) for posterior segment imaging. Our SL-SR-OCT provides 1025 axial scans, 5000 Hz line-scan frequency, scan length of up to 8 mm, axial depth in air of 3.5 mm, and resolution of 9 mum. For posterior visualization, a hand-held 78-diopter ophthalmoscopic lens was used. RESULTS: Our SL-SR-OCT system allowed simultaneous scanning with direct biomicroscopic and SL imaging of anterior and posterior segment structures. Anatomical structures and pathological changes were displayed with high resolution and excellent contrast. Measurements of corneal and retinal thickness were possible. In comparison to images obtained by the SL-OCT, our SL-SR-OCT boasted a higher resolution, thus providing more clinically relevant details of the corneal epithelium, internal structure of filtering blebs, etc. Complete imaging of the chamber angle was limited, however, due to the backscattering properties of the sclera at 830 nm. For posterior segment imaging, excellent delineation of the macula and optic nerve head details, with a distinct portrayal of macular pathology and retinal edema, was possible with SL-SR-OCT. CONCLUSION: SL-SR-OCT enables detailed imaging of physiological and pathological anterior and posterior segment structures. As a multi-purpose device, it offers a wide spectrum of applications, with high-quality OCT-imaging, in a comfortable setting without the need to move the patient.

No protection of the ovarian follicle pool with the use of GnRH-analogues or oral contraceptives in young women treated with escalated BEACOPP for advanced-stage Hodgkin lymphoma. Final results of a phase II trial from the German Hodgkin Study Group.

BACKGROUND: The reduction of treatment-related toxic effects is the main goal in the current trials of the German Hodgkin Study Group (GHSG). In this regard, the protection of the ovarian reserve in young women is very important. Therefore, the GHSG investigated the use of gonadotropin-releasing hormone-analogues (GnRH-a) and oral contraceptives (OC) in young women with advanced-stage Hodgkin lymphoma (HL). PATIENTS AND METHODS: Women (18-40 years) were randomly assigned either to receive daily OC or monthly GnRH-a during escalated combination therapy with bleomycin, etoposide, adriamycin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPPesc). Hormonal levels were determined at baseline, during therapy, and at follow-up. RESULTS: The study was closed prematurely after an interim analysis of 12 patients in arm A (OC) and 11 in arm B (GnRH-a), 9 and 10 are assessable for the primary end point. Women's median age was 25 years in both arms. The anti-Mullerian hormone level after at least 12 months was reduced in all patients. For the entire study cohort, the respective ovarian follicle preservation rate was 0% (95% confidence interval 0% to 12%). CONCLUSION: We observed no protection of the ovarian reserve with hormonal co-treatment during BEACOPPesc. This result supports efforts of ongoing trials to reduce chemotherapy intensity and toxicity. Alternative strategies for the protection of fertility must be offered to young female HL patients before the start of BEACOPPesc therapy.

Statistically derived factors of varied importance to audiologists when making a hearing aid brand preference decision.

PURPOSE: To determine the amount of importance audiologists place on various items related to their selection of a preferred hearing aid brand manufacturer. RESEARCH DESIGN: Three hundred forty-three hearing aid-dispensing audiologists rated a total of 32 randomized items by survey methodology. RESULTS: Principle component analysis identified seven orthogonal statistical factors of importance. In rank order, these factors were Aptitude of the Brand, Image, Cost, Sales and Speed of Delivery, Exposure, Colleague Recommendations, and Contracts and Incentives. While it was hypothesized that differences among audiologists in the importance ratings of these factors would dictate their preference for a given brand, that was not our finding. Specifically, mean ratings for the six most important factors did not differ among audiologists preferring different brands. A statistically significant difference among audiologists preferring different brands was present, however, for one factor: Contracts and Incentives. Its assigned importance, though, was always lower than that for the other six factors. CONCLUSIONS: Although most audiologists have a preferred hearing aid brand, differences in the perceived importance of common factors attributed to brands do not largely determine preference for a particular brand.

Cardiac signal extraction in patients with Implantable Cardioverter Defibrillators.

According to the guidelines the indication for Implantable Cardioverter Defibrillator (ICD) implantation is based on the ejection fraction. However, only a fraction of patients with implanted ICD shows live threatening arrhythmic events followed by adequate shocks. For this reason, further research is needed to find a more sensitive risk stratificator for patients prone to ventricular tachycardia or fibrillation. Unfortunately, standard prospective studies are time consuming. An alternative approach is to perform retrospective studies on patients with already implanted ICDs. So far, an implanted ICD is an exclusion criterion for Magnetic Field Imaging (MFI) studies. To overcome this problem several Blind Source Separation (BSS) algorithms have been tested to find out whether it is possible to separate the disturbances from the cardiac signals, in spite of the extreme difference in amplitude. Not all the methods are able to separate cardiac signal and disturbances. Temporal Decorrelation source Separation (TDSEP) is found to be superior both from a separation and performing point of view. For the first time it is possible to extract cardiac signals from measurements disturbed by an ICD, offering the possibility for a QRS-fragmentation analysis in patients with already implanted ICDs.

Neural traffic as voxel-based measure of cerebral functional connectivity in fMRI.

To access functional connectivity by in vivo brain imaging voxel-by-voxel, we developed a novel approach named neural traffic (NT). NT depicts the intensity of functional connectivity on a voxel-by-voxel basis in the whole brain. Functional magnetic resonance imaging (fMRI) experiments were carried out on eight individuals during either hearing or viewing words. The blood oxygen level dependant (BOLD) signal was taken as measure of neural activity. For each voxel, functional connectivity with all other brain voxels was determined by calculating Pearson correlation coefficients at two connectivity thresholds (r=0.35 and 0.65). Then, NT images were derived by counting the number of suprathreshold connections for each individual voxel. Calculations based on random networks indicate that statistically reliable NT images can be derived in individuals. With regard to group analysis, at r=0.35 NT images are similar though not identical with the first component of principal component analysis (PCA), displaying a widespread but not ubiquitous pattern of functionally connected cortical areas. At r=0.65, NT group images display functional connectivity confined to circumscribed cortical regions which reach beyond the corresponding primary sensory areas, their known associated areas and the default network. In conclusion, NT goes beyond the approach of correlating the BOLD signal with the external stimulus-presentation time course by computing linear functional connectivity between all brain voxels based on any BOLD time course. First results demonstrate that the NT approach is likely - on an individual base - to reveal novel cortical and subcortical connectivities involved in stimulus processing.