Time-to-event estimands and loss to follow-up in oncology in light of the estimands guidance.

Time-to-event estimands are central to many oncology clinical trials. The estimands framework (addendum to the ICH E9 guideline) calls for precisely defining the treatment effect of interest to align with the clinical question of interest and requires predefining the handling of intercurrent events (ICEs) that occur after treatment initiation and "affect either the interpretation or the existence of the measurements associated with the clinical question of interest." We discuss a practical problem in clinical trial design and execution, that is, in some clinical contexts it is not feasible to systematically follow patients to an event of interest. Loss to follow-up in the presence of intercurrent events can affect the meaning and interpretation of the study results. We provide recommendations for trial design, stressing the need for close alignment of the clinical question of interest and study design, impact on data collection, and other practical implications. When patients cannot be systematically followed, compromise may be necessary to select the best available estimand that can be feasibly estimated under the circumstances. We discuss the use of sensitivity and supplementary analyses to examine assumptions of interest.

Radium-223 in women with hormone receptor-positive bone-metastatic breast cancer receiving endocrine therapy: pooled analysis of two international, phase 2, randomized, double-blind, placebo-controlled trials.

BACKGROUND: Most women with advanced breast cancer have skeletal metastases. Radium-223 is an alpha-emitting radionuclide that selectively targets areas of bone metastases. METHODS: Two double-blind, placebo-controlled studies of radium-223 were conducted in women with hormone receptor-positive (HR+), bone-predominant metastatic breast cancer. All patients received endocrine therapy (ET), as a single agent of the investigator's choice (Study A) or exemestane + everolimus (Study B). Patients were randomized to receive radium-223 (55 kBq/kg) or placebo intravenously every 4 weeks for six doses. Accrual was halted following unblinded interim analyses per protocol amendments, and both studies were terminated. We report pooled analyses of symptomatic skeletal event-free survival (SSE-FS; primary endpoint), radiologic progression-free survival (rPFS) and overall survival (OS; secondary), and time to bone alkaline phosphatase (ALP) progression (exploratory). RESULTS: In total, 382 patients were enrolled, and 196 SSE-FS events (70% planned total) were recorded. Hazard ratios (95% confidence intervals) and nominal p values for radium-223 + ET versus placebo + ET were: SSE-FS 0.809 (0.610-1.072), p = 0.1389; rPFS 0.956 (0.759-1.205), p = 0.7039; OS 0.889 (0.660-1.199), p = 0.4410; and time to bone ALP progression 0.593 (0.379-0.926), p = 0.0195. Radium-223- or placebo-related treatment-emergent adverse events were reported in 50.3% versus 35.1% of patients (grade 3/4: 25.7% vs. 8.5%), with fractures/bone-associated events in 23.5% versus 23.9%. CONCLUSIONS: In patients with HR+ bone-metastatic breast cancer, numeric differences favoring radium-223 + ET over placebo + ET for the primary SSE-FS endpoint were suggestive of efficacy, in line with the primary outcome measure used in the underlying phase 2 studies. No similar evidence of efficacy was observed for secondary progression or survival endpoints. Adverse events were more frequent with radium-223 + ET versus placebo + ET, but the safety profile of the combination was consistent with the safety profiles of the component drugs. Clinical trial registration numbers Study A: NCT02258464, registered October 7, 2014. Study B: NCT02258451, registered October 7, 2014.

Safety and activity of anti-mesothelin antibody-drug conjugate anetumab ravtansine in combination with pegylated-liposomal doxorubicin in platinum-resistant ovarian cancer: multicenter, phase Ib dose escalation and expansion study.

OBJECTIVES: Anetumab ravtansine is an antibody-drug conjugate consisting of a fully human anti-mesothelin monoclonal antibody conjugated to cytotoxic maytansinoid tubulin inhibitor DM4. Mesothelin is highly expressed in ovarian cancer. This phase Ib study determines the safety, pharmacokinetics, and anti-tumor activity of anetumab ravtansine and pegylated liposomal doxorubicin in mesothelin-expressing platinum-resistant ovarian cancer. METHODS: Anetumab ravtansine (5.5 or 6.5 mg/kg) and pegylated liposomal doxorubicin (30 mg/m2) were administered intravenously every 3 weeks to 65 patients with platinum-resistant epithelial ovarian cancer. Mesothelin expression was assessed by central immunohistochemistry. Adverse events, tumor response (RECIST 1.1), and progression-free survival were determined. Biomarker samples were assessed by ELISA and next-generation sequencing. RESULTS: In dose escalation, nine patients received anetumab ravtansine across two doses (5.5 or 6.5 mg/kg). The maximum tolerated dose of anetumab ravtansine was 6.5 mg/kg every 3 weeks and no dose-limiting toxicities were observed. In dose expansion, 56 patients were treated at the maximum tolerated dose. The most common treatment-emergent adverse events of any grade were nausea (47.7%), decreased appetite (43.1%), fatigue (38.5%), diarrhea (32.3%), and corneal disorder (29.2%). In all treated patients the objective response rate was 27.7% (95% CI 17.3% to 40.2%), including one complete (1.5%) and 17 partial responses (26.2%), with median duration of response of 7.6 (95% CI 3.3 to 10.2) months and median progression-free survival of 5.0 (95% CI 3.2 to 6.0) months. In an exploratory analysis of a sub-set of patients (n=19) with high mesothelin expression who received ≤3 prior lines of systemic therapy, the objective response rate was 42.1% (95% CI 20.3% to 66.5%) with a median duration of response of 8.3 (95% CI 4.1 to 12.0) months and median progression-free survival of 8.5 (95% CI 4.0 to 11.4) months. CONCLUSIONS: Anetumab ravtansine and pegylated liposomal doxorubicin showed tolerability and promising clinical activity. These results established the dose schedule and the mesothelin-positive target population of this combination for a phase III study in platinum-resistant ovarian cancer. TRIAL REGISTRATION NUMBER: NCT02751918.

The influence of self-reported noise exposure on 2ƒ1-ƒ2 distortion product otoacoustic emission level, fine structure, and components in a normal-hearing population.

Distortion product otoacoustic emissions (DPOAEs) offer an outcome measure to consider for clinical detection and monitoring outer hair cell dysfunction as a result of noise exposure. This investigation detailed DPOAE characteristics and behavioral hearing thresholds up to 20 kHz to identify promising metrics for early detection of cochlear dysfunction. In a sample of normal-hearing individuals with and without self-reported noise exposure, the DPOAE and hearing threshold measures, as assessed by two questions, were examined. The effects on various auditory measures in individuals aged 10-65 years old with clinically normal/near-normal hearing through 4 kHz were evaluated. Individuals reporting occupational noise exposures (n = 84) and recreational noise exposures (n = 46) were compared to age-matched nonexposed individuals. The hearing thresholds and DPOAE level, fine structure, and component characteristics for the full frequency bandwidth were examined. The data suggest that the DPOAE levels measured using a range of stimulus levels hold clinical utility while fine structure characteristics offer limited use. Under carefully calibrated conditions, the extension to frequencies beyond 8 kHz in combination with various stimulus levels holds clinical utility. Moreover, this work supports the potential utility of the distortion product place component level for revealing differences in cochlear function due to self-reported, casual noise exposure that are not observable in behavioral hearing thresholds.

Impact of Electronic Cigarette Vaping on Cerebral Ischemia: What We Know So Far.

Electronic cigarettes (ECs) are battery-powered nicotine delivery devices that have rapidly gained popularity and attention globally. ECs work by heating a liquid to produce an aerosol that usually contains nicotine, flavoring compounds, and other chemicals, which are inhaled during vaping. EC aerosols are depicted to contain a lower number and overall quantity of harmful toxicants than conventional cigarettes (CCs). However, emerging research indicates that EC aerosols contain harmful ingredients including ultrafine particles, volatile organic compounds, and heavy metals. One common ingredient found in both CCs and ECs is nicotine, which has been shown to be both highly addictive and toxic. Particularly relevant to our current review, there is an enormous amount of literature that shows that smoking-derived nicotine exacerbates ischemic brain damage. Therefore, the question arises: will EC use impact the outcome of stroke? ECs are highly popular and relatively new in the market; thus, our understanding about the long-term effects of EC use on brain are lacking. The current review strives to extrapolate the existing understanding of the nicotine-induced effects of conventional smoking on the brain to the possible effects that ECs may have on the brain, which may ultimately have a potential for adverse stroke risk or severity.

Anetumab ravtansine versus vinorelbine in patients with relapsed, mesothelin-positive malignant pleural mesothelioma (ARCS-M): a randomised, open-label phase 2 trial.

BACKGROUND: Few treatment options exist for second-line treatment of malignant pleural mesothelioma. We aimed to assess the antibody-drug conjugate anetumab ravtansine versus vinorelbine in patients with unresectable locally advanced or metastatic disease overexpressing mesothelin who had progressed on first-line platinum-pemetrexed chemotherapy with or without bevacizumab. METHODS: In this phase 2, randomised, open-label study, done at 76 hospitals in 14 countries, we enrolled adults (aged ≥18 years) with unresectable locally advanced or metastatic malignant pleural mesothelioma, an Eastern Cooperative Oncology Group performance status of 0-1, and who had progressed on first-line platinum-pemetrexed chemotherapy with or without bevacizumab. Participants were prospectively screened for mesothelin overexpression (defined as 2+ or 3+ mesothelin membrane staining intensity on at least 30% of viable tumour cells by immunohistochemistry) and were randomly assigned (2:1), using an interactive voice and web response system provided by the sponsor, to receive intravenous anetumab ravtansine (6·5 mg/kg on day 1 of each 21-day cycle) or intravenous vinorelbine (30 mg/m2 once every week) until progression, toxicity, or death. The primary endpoint was progression-free survival according to blinded central radiology review, assessed in the intention-to-treat population, with safety assessed in all participants who received any study treatment. This study is registered with ClinicalTrials.gov, NCT02610140, and is now completed. FINDINGS: Between Dec 3, 2015, and May 31, 2017, 589 patients were enrolled and 248 mesothelin-overexpressing patients were randomly allocated to the two treatment groups (166 patients were randomly assigned to receive anetumab ravtansine and 82 patients were randomly assigned to receive vinorelbine). 105 (63%) of 166 patients treated with anetumab ravtansine (median follow-up 4·0 months [IQR 1·4-5·5]) versus 43 (52%) of 82 patients treated with vinorelbine (3·9 months [1·4-5·4]) had disease progression or died (median progression-free survival 4·3 months [95% CI 4·1-5·2] vs 4·5 months [4·1-5·8]; hazard ratio 1·22 [0·85-1·74]; log-rank p=0·86). The most common grade 3 or worse adverse events were neutropenia (one [1%] of 163 patients for anetumab ravtansine vs 28 [39%] of 72 patients for vinorelbine), pneumonia (seven [4%] vs five [7%]), neutrophil count decrease (two [1%] vs 12 [17%]), and dyspnoea (nine [6%] vs three [4%]). Serious drug-related treatment-emergent adverse events occurred in 12 (7%) patients treated with anetumab ravtansine and 11 (15%) patients treated with vinorelbine. Ten (6%) treatment-emergent deaths occurred with anetumab ravtansine: pneumonia (three [2%]), dyspnoea (two [1%]), sepsis (two [1%]), atrial fibrillation (one [1%]), physical deterioration (one [1%]), hepatic failure (one [1%]), mesothelioma (one [1%]), and renal failure (one [1%]; one patient had 3 events). One (1%) treatment-emergent death occurred in the vinorelbine group (pneumonia). INTERPRETATION: Anetumab ravtansine showed a manageable safety profile and was not superior to vinorelbine. Further studies are needed to define active treatments in relapsed mesothelin-expressing malignant pleural mesothelioma. FUNDING: Bayer Healthcare Pharmaceuticals.

Distortion Product Otoacoustic Emission (DPOAE) Growth in Aging Ears with Clinically Normal Behavioral Thresholds.

Age-related hearing loss (ARHL) is a devastating public health issue. To successfully address ARHL using existing and future treatments, it is imperative to detect the earliest signs of age-related auditory decline and understand the mechanisms driving it. Here, we explore early signs of age-related auditory decline by characterizing cochlear function in 199 ears aged 10-65 years, all of which had clinically defined normal hearing (i.e., behavioral thresholds ≤ 25 dB HL from .25 to 8 kHz bilaterally) and no history of noise exposure. We characterized cochlear function by measuring behavioral thresholds in two paradigms (traditional audiometric thresholds from .25 to 8 kHz and Békésy tracking thresholds from .125 to 20 kHz) and distortion product otoacoustic emission (DPOAE) growth functions at f2 = 2, 4, and 8 kHz. Behavioral thresholds through a standard clinical frequency range (up to 8 kHz) showed statistically, but not clinically, significant declines across increasing decades of life. In contrast, DPOAE growth measured in the same frequency range showed clear declines as early 30 years of age, particularly across moderate stimulus levels (L2 = 25-45 dB SPL). These substantial declines in DPOAE growth were not fully explained by differences in behavioral thresholds measured in the same frequency region. Additionally, high-frequency Békésy tracking thresholds above ~11.2 kHz showed frank declines with increasing age. Collectively, these results suggest that early age-related cochlear decline (1) begins as early as the third or fourth decade of life, (2) is greatest in the cochlear base but apparent through the length of the cochlear partition, (3) cannot be detected fully by traditional clinical measures, and (4) is likely due to a complex mix of etiologies.

The importance of loss functions: A note on the evolution of the Toxicity Probability Interval design.

The Toxicity Probability Interval Design by Ji et al. (2007), which was subsequently modified by the mTPI (Ji et al., 2010), proposed a more efficient approach to early-phase dose-finding than conventional designs like 3 + 3. Subsequent authors reported issues with the method, finding that it tends to stay at a dose level when clinical intuition would suggest the toxicity level warrants decrease. Several iterations of refinement proceeded in an effort to address these issues, including the mTPI-2 and the keyboard method, as well as alternative approaches such as the BOIN. This author suggests the reason for these safety issues involves the underlying loss function. The TPI and mTPI used the identify function defined over wide intervals. As explained in this paper, this function and its domain can be problematic as a model of patients' loss experience. Later refinements moved the loss function closer to one more consistent with clinical intuition, and this explains their improved safety performance. Greater attention to quality as defined by fitness for use, including early evaluation of patient-experience and clinical-intuition implications of proposed loss functions, may improve future design efforts.

Walking With Ears: Altered Auditory Feedback Impacts Gait Step Length in Older Adults.

Auditory feedback may provide the nervous system with valuable temporal (e. g., footstep sounds) and spatial (e.g., external reference sounds) information that can assist in the control of upright walking. As such, hearing loss may directly contribute to declines in mobility among older adults. Our purpose was to examine the impact of auditory feedback on the control of walking in older adults. Twenty older adults (65-86 years) with no diagnosed hearing loss walked on a treadmill for three sound conditions: Baseline, Ear Plugs, and White Noise. We hypothesized that in response to reduced temporal auditory feedback during the Ear Plugs and White Noise conditions, participants would adapt shorter and faster steps that are traditionally believed to increase mechanical stability. This hypothesis was not supported. Interestingly, we observed increases in step length (p = 0.047) and step time (p = 0.026) during the Ear Plugs condition vs. Baseline. Taking longer steps during the Ear Plugs condition may have increased ground reaction forces, thus allowing participants to sense footsteps via an occlusion effect. As a follow-up, we performed a Pearson's correlation relating the step length increase during the Ear Plugs condition to participants' scores on a clinical walking balance test, the Functional Gait Assessment. We found a moderate negative relationship (rho = -0.44, p = 0.055), indicating that participants with worse balance made the greatest increases in step length during the Ear Plugs condition. This trend suggests that participants may have actively sought auditory feedback with longer steps, sacrificing a more mechanically stable stepping pattern. We also hypothesized that reduced spatial localization feedback during the Ear Plugs and White Noise conditions would decrease control of center of mass (COM) dynamics, resulting in an increase in lateral COM excursion, lateral margin of stability, and maximum Lyapunov exponent. However, we found no main effects of auditory feedback on these metrics (p = 0.580, p = 0.896, and p = 0.056, respectively). Overall, these results suggest that during a steady-state walking task, healthy older adults can maintain walking control without auditory feedback. However, increases in step length observed during the Ear Plugs condition suggest that temporal auditory cues provide locomotor feedback that becomes increasingly valuable as balance deteriorates with age.

Approximation rates for neural networks with general activation functions.

We prove some new results concerning the approximation rate of neural networks with general activation functions. Our first result concerns the rate of approximation of a two layer neural network with a polynomially-decaying non-sigmoidal activation function. We extend the dimension independent approximation rates previously obtained to this new class of activation functions. Our second result gives a weaker, but still dimension independent, approximation rate for a larger class of activation functions, removing the polynomial decay assumption. This result applies to any bounded, integrable activation function. Finally, we show that a stratified sampling approach can be used to improve the approximation rate for polynomially decaying activation functions under mild additional assumptions.

Extended high frequency hearing and speech perception implications in adults and children.

Extended high frequencies (EHF), above 8 kHz, represent a region of the human hearing spectrum that is generally ignored by clinicians and researchers alike. This article is a compilation of contributions that, together, make the case for an essential role of EHF in both normal hearing and auditory dysfunction. We start with the fundamentals of biological and acoustic determinism - humans have EHF hearing for a purpose, for example, the detection of prey, predators, and mates. EHF hearing may also provide a boost to speech perception in challenging conditions and its loss, conversely, might help explain difficulty with the same task. However, it could be that EHF are a marker for damage in the conventional frequency region that is more related to speech perception difficulties. Measurement of EHF hearing in concert with otoacoustic emissions could provide an early warning of age-related hearing loss. In early life, when EHF hearing sensitivity is optimal, we can use it for enhanced phonetic identification during language learning, but we are also susceptible to diseases that can prematurely damage it. EHF audiometry techniques and standardization are reviewed, providing evidence that they are reliable to measure and provide important information for early detection, monitoring and possible prevention of hearing loss in populations at-risk. To better understand the full contribution of EHF to human hearing, clinicians and researchers can contribute by including its measurement, along with measures of speech in noise and self-report of hearing difficulties and tinnitus in clinical evaluations and studies.

Assessing the Impact of COVID-19 on the Clinical Trial Objective and Analysis of Oncology Clinical Trials-Application of the Estimand Framework.

Abstract-Coronavirus disease 2019 (COVID-19) outbreak has rapidly evolved into a global pandemic. The impact of COVID-19 on patient journeys in oncology represents a new risk to interpretation of trial results and its broad applicability for future clinical practice. We identify key intercurrent events (ICEs) that may occur due to COVID-19 in oncology clinical trials with a focus on time-to-event endpoints and discuss considerations pertaining to the other estimand attributes introduced in the ICH E9 addendum. We propose strategies to handle COVID-19 related ICEs, depending on their relationship with malignancy and treatment and the interpretability of data after them. We argue that the clinical trial objective from a world without COVID-19 pandemic remains valid. The estimand framework provides a common language to discuss the impact of COVID-19 in a structured and transparent manner. This demonstrates that the applicability of the framework may even go beyond what it was initially intended for.

The Association Between Physiological Noise Levels and Speech Understanding in Noise.

OBJECTIVES: Traditionally, elevated hearing thresholds have been considered to be the main contributors to difficulty understanding speech in noise; yet, patients will often report difficulties with speech understanding in noise despite having audiometrically normal hearing. The purpose of this cross-sectional study was to critically evaluate the relationship of various metrics of auditory function (behavioral thresholds and otoacoustic emissions) on speech understanding in noise in a large sample of audiometrically normal-hearing individuals. DESIGN: Behavioral hearing thresholds, distortion product otoacoustic emission (DPOAE) levels, stimulus-frequency otoacoustic emission levels, and physiological noise (quantified using OAE noise floors) were measured from 921 individuals between 10 and 68 years of age with normal pure-tone averages. The quick speech-in-noise (QuickSIN) test outcome, quantified as the signal-to-noise ratio (SNR) loss, was used as the metric of speech understanding in noise. Principle component analysis (PCA) and linear regression modeling were used to evaluate the relationship between the measures of auditory function and speech in noise performance. RESULTS: Over 25% of participants exhibited mild or worse degree of SNR loss. PCA revealed DPOAE levels at 12.5 to 16 kHz to be significantly correlated with the variation in QuickSIN scores, although correlations were weak (R = 0.017). Out of all the metrics evaluated, higher levels of self-generated physiological noise accounted for the most variance in QuickSIN performance (R = 0.077). CONCLUSIONS: Higher levels of physiological noise were associated with worse QuickSIN performance in listeners with normal hearing sensitivity. We propose that elevated physiological noise levels in poorer speech in noise performers could diminish the effective SNR, thereby negatively impacting performance as seen by poorer QuickSIN scores.

A randomized, double-blind, comparison of radium-223 and placebo, in combination with abiraterone acetate and prednisolone, in castration-resistant metastatic prostate cancer: subgroup analysis of Japanese patients in the ERA 223 study.

BACKGROUND: ERA 223 compared concurrent abiraterone acetate/prednisolone (AAP) plus radium-223 with AAP plus placebo in men with chemotherapy-naïve asymptomatic or mildly symptomatic metastatic castration-resistant prostate cancer (mCRPC) and bone metastases. We report data from a subgroup of Japanese patients in ERA 223. METHODS: Patients were randomized to radium-223 (55 kBq/kg) or placebo once every 4 weeks (max. 6 cycles), and also received oral abiraterone acetate 1000 mg once daily plus prednisone/prednisolone 5 mg twice daily during and after radium-223/placebo treatment, until a symptomatic skeletal event (SSE). The primary endpoint was SSE-free survival (SSE-FS); overall survival (OS) was a secondary endpoint. RESULTS: Of 806 patients randomized in ERA 223, 114 patients (57 per arm) were enrolled in Japan. SSE-FS was not improved significantly in the radium-223 arm [25.5 months, 95% CI 20.6-not estimated (NE)] compared with the placebo arm (28.7 months, 95% CI 19.7-NE) (HR = 0.907, 95% CI 0.501-1.642). OS and other secondary endpoints were not improved significantly in the radium-223 arm. The incidence of fracture was 23% and 11% in the radium-223 and placebo arms, respectively. The incidence of death was 32% and 36%, respectively. CONCLUSIONS: In the Japanese ERA 223 subgroup, concurrent treatment with AAP and radium-223 did not significantly improve SSE-FS and increased the incidence of fracture, similar to outcomes achieved in the overall population, while an increased incidence of death was not evident. The combination of radium-223 with AAP is not recommended in Japanese patients with asymptomatic or mildly symptomatic mCRPC and bone metastases. CLINICAL TRIAL REGISTRATION: Clinical trial registration no: NCT02043678.

Effect of Middle-Ear Pathology on High-Frequency Ear Canal Reflectance Measurements in the Frequency and Time Domains.

The effects of middle-ear pathology on wideband acoustic immittance and reflectance at frequencies above 6-8 kHz have not been documented, nor has the effect of such pathologies on the time-domain reflectance. We describe an approach that utilizes sound frequencies as high as 20 kHz and quantifies reflectance in both the frequency and time domains. Experiments were performed with fresh normal human temporal bones before and after simulating various middle-ear pathologies, including malleus fixation, stapes fixation, and disarticulation. In addition to experimental data, computational modeling was used to obtain fitted parameter values of middle-ear elements that vary systematically due to the simulated pathologies and thus may have diagnostic implications. Our results demonstrate that the time-domain reflectance, which requires acoustic measurements at high frequencies, varies with middle-ear condition. Furthermore, the extended bandwidth frequency-domain reflectance data was used to estimate parameters in a simple model of the ear canal and middle ear that separates three major conductive pathologies from each other and from the normal state.

Evaluation of the psychometric properties and minimally important difference of the MD Anderson Symptom Inventory for malignant pleural mesothelioma (MDASI-MPM).

BACKGROUND: Symptom assessment requires psychometrically validated questionnaires that are easy to use, relevant to the disease, and quick to administer. The MD Anderson Symptom Inventory for malignant pleural mesothelioma (MDASI-MPM) was adapted from the general (core) MDASI to assess the severity of cancer-related and treatment-related symptoms specific to patients with this condition. The MDASI-MPM includes the 13 core MDASI symptoms, which are experienced by most cancer patients, and 6 MPM-specific items developed via qualitative interviewing, a method favored by the US Food and Drug Administration for instrument item generation and development. Qualitative interviewing that summarizes the item generation and development for the MDASI-MPM is detailed in a separate report. The psychometric study reported here was the next step in developing the validation dossier for the MDASI-MPM. RESULTS: In this secondary analysis of data from a Phase II trial, 248 patients provided MDASI-MPM data at multiple timepoints during therapy. Over time, fatigue, pain, shortness of breath, feeling of malaise, and muscle weakness were consistently the worst symptoms reported; symptoms interfered most with work and general activity and least with relations with others. Cronbach coefficient alpha values for all MDASI-MPM subscales were at least 0.88 at baseline and 0.91 during treatment, indicating good internal consistency reliability. Intraclass correlations of at least 0.86 for all MDASI-MPM subscales administered a cycle apart (n = 82) were indicative of good test-retest reliability. Correlations between MDASI-MPM subscales and LCSS-Meso scores were at least 0.70 (P < 0.001 for all comparisons). Patients with good performance status had significantly lower scores than did patients with poor performance status (all P < 0.05), supporting evidence for known-group validity and sensitivity. Effect-size differences were 0.69 and higher, indicating medium-to-large effects. The minimally important difference in the MDASI-MPM subscales ranged from 1.0 to 1.5 points on a 0-10 scale. CONCLUSIONS: Symptoms specific to a particular cancer, treatment method, or treatment site can be added to the core MDASI to create a tailored, "fit for purpose" instrument. We found the MDASI-MPM to be a valid, reliable, and responsive (sensitive) instrument for assessing the severity of symptoms of patients with MPM and their interference in patients' daily functioning.

Evanescent waves in simulated ear canals: Experimental demonstration and method for compensation.

Evanescent waves emerge from a small sound source that radiates into a waveguide with a larger cross-sectional area, but unlike planar waves, do not propagate far from the source. Evanescent waves thus contaminate in-ear calibration of acoustic stimuli. Measurements with an otoacoustic-emission (OAE) probe inserted at the entrance of long tubes of various diameters show a decline in the evanescent wave with distance from the source when advancing a probe tube through the OAE probe and into the long tube. The amplitude of the evanescent pressure increases with frequency and depends strongly on the diameter of the long tube. Modifying the shape of the aperture of the probe's sound source, thus effectively enlarging its diameter and redirecting acoustic flow, greatly reduced evanescent waves. The reduction in evanescent-wave pressure was observed in calibration cavities used to determine the Thévenin-equivalent source pressure and impedance of the probe. Errors in source calibrations were considerably larger in the unmodified configuration. An alternative method is proposed for calculation of acoustic source parameters that models the evanescent-wave pressure and reduces its influence on the calculation. This reduction greatly improves the quality of source calibrations, which should improve the accuracy of ear-canal impedance measurements and related quantities.

The Relation Between White Matter Microstructure and Network Complexity: Implications for Processing Efficiency.

Brain structure has been proposed to facilitate as well as constrain functional interactions within brain networks. Simulation models suggest that integrity of white matter (WM) microstructure should be positively related to the complexity of BOLD signal - a measure of network interactions. Using 121 young adults from the Human Connectome Project, we empirically tested whether greater WM integrity would be associated with greater complexity of the BOLD signal during rest via multiscale entropy. Multiscale entropy measures the lack of predictability within a given time series across varying time scales, thus being able to estimate fluctuating signal dynamics within brain networks. Using multivariate analysis techniques (Partial Least Squares), we found that greater WM integrity was associated with greater network complexity at fast time scales, but less network complexity at slower time scales. These findings implicate two separate pathways through which WM integrity affects brain function in the prefrontal cortex - an executive-prefrontal pathway and a perceptuo-occipital pathway. In two additional samples, the main patterns of WM and network complexity were replicated. These findings support simulation models of WM integrity and network complexity and provide new insights into brain structure-function relationships.

Spectral Ripples in Round-Window Cochlear Microphonics: Evidence for Multiple Generation Mechanisms.

The cochlear microphonic (CM) results from the vector sum of outer hair cell transduction currents excited by a stimulus. The classical theory of CM generation-that the response measured at the round window is dominated by cellular sources located within the tail region of the basilar membrane (BM) excitation pattern-predicts that CM amplitude and phase vary little with stimulus frequency. Contrary to expectations, CM amplitude and phase-gradient delay measured in response to low-level tones in chinchillas demonstrate a striking, quasiperiodic pattern of spectral ripples, even at frequencies > 5 kHz, where interference with neurophonic potentials is unlikely. The spectral ripples were reduced in the presence of a moderate-level saturating tone at a nearby frequency. When converted to the time domain, only the delayed CM energy was diminished in the presence of the saturator. We hypothesize that the ripples represent an interference pattern produced by CM components with different phase gradients: an early-latency component originating within the tail region of the BM excitation and two delayed components that depend on active cochlear processing near the peak region of the traveling wave. Using time windowing, we show that the early, middle, and late components have delays corresponding to estimated middle-ear transmission, cochlear forward delays, and cochlear round-trip delays, respectively. By extending the classical model of CM generation to include mechanical and electrical irregularities, we propose that middle components are generated through a mechanism of "coherent summation" analogous to the production of reflection-source otoacoustic emissions (OAEs), while the late components arise through a process of internal cochlear reflection related to the generation of stimulus-frequency OAEs. Although early-latency components from the passive tail region typically dominate the round-window CM, at low stimulus levels, substantial contributions from components shaped by active cochlear processing provide a new avenue for improving CM measurements as assays of cochlear health.

Differentiating Middle Ear and Medial Olivocochlear Effects on Transient-Evoked Otoacoustic Emissions.

The response of the inner ear is modulated by the middle ear muscle (MEM) and olivocochlear (OC) efferent systems. Both systems can be activated reflexively by acoustic stimuli delivered to one or both ears. The acoustic middle ear muscle reflex (MEMR) controls the transmission of acoustic signals through the middle ear, while reflex activation of the medial component of the olivocochlear system (the MOCR) modulates cochlear mechanics. The relative prominence of the two efferent systems varies widely between species. Measuring the effect of either of these systems can be confounded by simultaneously activating the other. We describe a simple, sensitive online method that can identify the effects both systems have on otoacoustic emissions (OAEs) evoked by transient stimuli such as clicks or tone pips (TEOAEs). The method detects directly in the time domain the changes in the stimulus and/or emission pressures caused by contralateral noise. Measurements in human participants are consistent with other reports that the threshold for MOCR activation is consistently lower than for MEMR. The method appears to control for drift and subject-generated noise well enough to avoid the need for post hoc processing, making it promising for application in animal experiments (even if awake) and in the hearing clinic.