Discrimination of gain increments in speech

During a hearing-aid fitting, the gain applied across frequencies is often adjusted from an initial prescription in order to meet individual needs and preferences. These gain adjustments in one or more frequency bands are commonly verified using speech in quiet (e.g., the clinician’s own voice). Such adjustments may be unreliable and inefficient if they are not discriminable. To examine what adjustments are discriminable when made to speech, the current study measured the just-noticeable differences (JNDs) for gain increments in male, single-talker sentences. Sentences were presented with prescribed gains to the better ears of 41 hearing-impaired listeners. JNDs were measured at d' of 1 for octave-band, dual-octave-band and broadband increments using a fixed-level, same-different task. The JNDs and interquartile ranges (IQRs) for 0.25, 1 and 4 kHz octave-band increments were 6.4 [4.0-7.8], 6.7 [4.6-9.1] and 9.6 [7.3-12.4] dB respectively. The JNDs and IQRs for low, mid and high-frequency dual-octave-band increments were 3.7 [2.5-4.6], 3.8 [2.9-4.7] and 6.8 [4.7-9.1] dB, respectively. The JND for broadband increments was 2.0 [1.5-2.7] dB. High-frequency dual-octave-band JNDs were positively correlated with high-frequency pure-tone thresholds and sensation levels, suggesting an effect of audibility for this condition. All other JNDs were independent of pure-tone threshold and sensation level. JNDs were independent of age and hearing-aid experience. These results suggest using large initial adjustments when using short sentences in a hearing-aid fitting to ensure patient focus, followed by smaller subsequent adjustments, if necessary, to ensure audibility, comfort and stability

The perceptual limitations of troubleshooting hearing-aids based on patients’ descriptions

ObjectivesHearing-aid frequency-gain responses are routinely adjusted by clinicians to patient preferences and descriptions. This study measured the minimum gain adjustments required to elicit preferences, and the assignment of descriptors to gain adjustments, to perceptually evaluate description-based troubleshooting.DesignParticipants judged whether short sentences with ±0-12 dB gain adjustments in one of three frequency bands were “better”, “worse” or “no different” from the same sentence at their individual real-ear or prescribed gain. If judged “better” or “worse”, participants were then asked to assign one of six common sound-quality descriptors to their preference.Study SampleThirty-two adults (aged 51-75 years) all with hearing-aid experience.ResultsMedian preference thresholds, the minimum gain adjustments to elicit “better” or “worse” judgments, ranged from 4-12 dB, increasing with frequency. There was some between-participant agreement in preferences: participants generally preferred greater low-frequency gain. Within-participant reliability for preferences was moderate. There was, however, little between-participant agreement in descriptor selection for gain adjustments. Furthermore, within-participant reliability for descriptor selection was weak.ConclusionsThe scale of gain adjustments necessary to elicit preferences, along with the low agreement and reliability in descriptors for these adjustments questions the efficiency and efficacy of current description-based troubleshooting, especially with short speech stimuli

Bridging the Mid-Infrared-to-Telecom Gap with Silicon Nanophotonic Spectral Translation

Expanding far beyond traditional applications in optical interconnects at telecommunications wavelengths, the silicon nanophotonic integrated circuit platform has recently proven its merits for working with mid-infrared (mid-IR) optical signals in the 2-8 {\mu}m range. Mid-IR integrated optical systems are capable of addressing applications including industrial process and environmental monitoring, threat detection, medical diagnostics, and free-space communication. Rapid progress has led to the demonstration of various silicon components designed for the on-chip processing of mid-IR signals, including waveguides, vertical grating couplers, microcavities, and electrooptic modulators. Even so, a notable obstacle to the continued advancement of chip-scale systems is imposed by the narrow-bandgap semiconductors, such as InSb and HgCdTe, traditionally used to convert mid-IR photons to electrical currents. The cryogenic or multi-stage thermo-electric cooling required to suppress dark current noise, exponentially dependent upon the ratio Eg/kT, can limit the development of small, low-power, and low-cost integrated optical systems for the mid-IR. However, if the mid-IR optical signal could be spectrally translated to shorter wavelengths, for example within the near-infrared telecom band, photodetectors using wider bandgap semiconductors such as InGaAs or Ge could be used to eliminate prohibitive cooling requirements. Moreover, telecom band detectors typically perform with higher detectivity and faster response times when compared with their mid-IR counterparts. Here we address these challenges with a silicon-integrated approach to spectral translation, by employing efficient four-wave mixing (FWM) and large optical parametric gain in silicon nanophotonic wires

Genetic Variants Associated With Cancer Therapy-Induced Cardiomyopathy

BACKGROUND: Cancer therapy-induced cardiomyopathy (CCM) is associated with cumulative drug exposures and preexisting cardiovascular disorders. These parameters incompletely account for substantial interindividual susceptibility to CCM. We hypothesized that rare variants in cardiomyopathy genes contribute to CCM. METHODS: We studied 213 patients with CCM from 3 cohorts: retrospectively recruited adults with diverse cancers (n=99), prospectively phenotyped adults with breast cancer (n=73), and prospectively phenotyped children with acute myeloid leukemia (n=41). Cardiomyopathy genes, including 9 prespecified genes, were sequenced. The prevalence of rare variants was compared between CCM cohorts and The Cancer Genome Atlas participants (n=2053), healthy volunteers (n=445), and an ancestry-matched reference population. Clinical characteristics and outcomes were assessed and stratified by genotypes. A prevalent CCM genotype was modeled in anthracycline-treated mice. RESULTS: CCM was diagnosed 0.4 to 9 years after chemotherapy; 90% of these patients received anthracyclines. Adult patients with CCM had cardiovascular risk factors similar to the US population. Among 9 prioritized genes, patients with CCM had more rare protein-altering variants than comparative cohorts ( P≤1.98e-04). Titin-truncating variants (TTNtvs) predominated, occurring in 7.5% of patients with CCM versus 1.1% of The Cancer Genome Atlas participants ( P=7.36e-08), 0.7% of healthy volunteers ( P=3.42e-06), and 0.6% of the reference population ( P=5.87e-14). Adult patients who had CCM with TTNtvs experienced more heart failure and atrial fibrillation ( P=0.003) and impaired myocardial recovery ( P=0.03) than those without. Consistent with human data, anthracycline-treated TTNtv mice and isolated TTNtv cardiomyocytes showed sustained contractile dysfunction unlike wild-type ( P=0.0004 and P<0.002, respectively). CONCLUSIONS: Unrecognized rare variants in cardiomyopathy-associated genes, particularly TTNtvs, increased the risk for CCM in children and adults, and adverse cardiac events in adults. Genotype, along with cumulative chemotherapy dosage and traditional cardiovascular risk factors, improves the identification of patients who have cancer at highest risk for CCM. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov . Unique identifiers: NCT01173341; AAML1031; NCT01371981.This work was supported in part by grants from the Instituto de Salud Carlos III (ISCIII) (PI15/01551, PI17/01941 and CB16/11/00432 to P.G-P. and L.A-P.), the Spanish Ministry of Economy and Competitiveness (SAF2015-71863-REDT to P.G-P.), the John S. LaDue Memorial Fellowship at Harvard Medical School (Y.K.), Wellcome Trust (107469/Z/15/Z to J.S.W.), Medical Research Council (intramural awards to S.A.C. and J.S.W; MR/M003191/1 to U.T), National Institute for Health Research Biomedical Research Unit at the Royal Brompton and Harefield National Health Service Foundation Trust and Imperial College London (P.J.B., S.A.C., J.S.W.), National Institute for Health Research Biomedical Research Centre at Imperial College London Healthcare National Health Service Trust and Imperial College London (D.O.R., S.A.C., S.P., J.S.W.), Sir Henry Wellcome Postdoctoral Fellowship (C.N.T.), Rosetrees and Stoneygate Imperial College Research Fellowship (N.W.), Fondation Leducq (S.A.C., C.E.S., J.G.S.), Health Innovation Challenge Fund award from the Wellcome Trust and Department of Health (UK; HICF-R6-373; S.A.C., P.J.B., J.S. W.), the British Heart Foundation (NH/17/1/32725 to D.O.R.; SP/10/10/28431 to S.A.C), Alex’s Lemonade Stand Foundation (K.G.), National Institutes of Health (R.A.: U01CA097452, R01CA133881, and U01CA097452; Z.A.: R01 HL126797; B.K.: R01 HL118018 and K23-HL095661; J.G.S. and C.E.S.: 5R01HL080494, R01HL084553), and the Howard Hughes Medical Institute (C.E.S.). The Universitario Puerta de Hierro and Virgen de la Arrixaca Hospitals are members of the European Reference Network on Rare and Complex Diseases of the Heart (Guard-Heart; http://guard-heart.ern-net.eu). This publication includes independent research commissioned by the Health Innovation Challenge Fund (HICF), a parallel funding partnership between the Department of Health and Wellcome Trust. The Centro Nacional de Investigaciones Cardiovasculares (CNIC) is supported by the Ministry of Economy, Industry and Competitiveness and the Pro CNIC Foundation, and is a Severo Ochoa Center of Excellence (SEV-2015-0505). Grants from ISCIII and the Spanish Ministry of Economy and Competitiveness are supported by the Plan Estatal de I+D+I 2013-2016 – European Regional Development Fund (FEDER) “A way of making Europe”.S

Withdrawal of pharmacological treatment for heart failure in patients with recovered dilated cardiomyopathy (TRED-HF): an open-label, pilot, randomised trial.

BACKGROUND: Patients with dilated cardiomyopathy whose symptoms and cardiac function have recovered often ask whether their medications can be stopped. The safety of withdrawing treatment in this situation is unknown. METHODS: We did an open-label, pilot, randomised trial to examine the effect of phased withdrawal of heart failure medications in patients with previous dilated cardiomyopathy who were now asymptomatic, whose left ventricular ejection fraction (LVEF) had improved from less than 40% to 50% or greater, whose left ventricular end-diastolic volume (LVEDV) had normalised, and who had an N-terminal pro-B-type natriuretic peptide (NT-pro-BNP) concentration less than 250 ng/L. Patients were recruited from a network of hospitals in the UK, assessed at one centre (Royal Brompton and Harefield NHS Foundation Trust, London, UK), and randomly assigned (1:1) to phased withdrawal or continuation of treatment. After 6 months, patients in the continued treatment group had treatment withdrawn by the same method. The primary endpoint was a relapse of dilated cardiomyopathy within 6 months, defined by a reduction in LVEF of more than 10% and to less than 50%, an increase in LVEDV by more than 10% and to higher than the normal range, a two-fold rise in NT-pro-BNP concentration and to more than 400 ng/L, or clinical evidence of heart failure, at which point treatments were re-established. The primary analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT02859311. FINDINGS: Between April 21, 2016, and Aug 22, 2017, 51 patients were enrolled. 25 were randomly assigned to the treatment withdrawal group and 26 to continue treatment. Over the first 6 months, 11 (44%) patients randomly assigned to treatment withdrawal met the primary endpoint of relapse compared with none of those assigned to continue treatment (Kaplan-Meier estimate of event rate 45·7% [95% CI 28·5-67·2]; p=0·0001). After 6 months, 25 (96%) of 26 patients assigned initially to continue treatment attempted its withdrawal. During the following 6 months, nine patients met the primary endpoint of relapse (Kaplan-Meier estimate of event rate 36·0% [95% CI 20·6-57·8]). No deaths were reported in either group and three serious adverse events were reported in the treatment withdrawal group: hospital admissions for non-cardiac chest pain, sepsis, and an elective procedure. INTERPRETATION: Many patients deemed to have recovered from dilated cardiomyopathy will relapse following treatment withdrawal. Until robust predictors of relapse are defined, treatment should continue indefinitely. FUNDING: British Heart Foundation, Alexander Jansons Foundation, Royal Brompton Hospital and Imperial College London, Imperial College Biomedical Research Centre, Wellcome Trust, and Rosetrees Trust

Disease-specific variant pathogenicity prediction significantly improves variant interpretation in inherited cardiac conditions

Funder: Science and Technology Development Fund; doi: https://doi.org/10.13039/Funder: Al-Alfi FoundationFunder: Magdi Yacoub Heart FoundationFunder: Rosetrees and Stoneygate Imperial College Research FellowshipFunder: National Health and Medical Research Council (Australia)Abstract: Purpose: Accurate discrimination of benign and pathogenic rare variation remains a priority for clinical genome interpretation. State-of-the-art machine learning variant prioritization tools are imprecise and ignore important parameters defining gene–disease relationships, e.g., distinct consequences of gain-of-function versus loss-of-function variants. We hypothesized that incorporating disease-specific information would improve tool performance. Methods: We developed a disease-specific variant classifier, CardioBoost, that estimates the probability of pathogenicity for rare missense variants in inherited cardiomyopathies and arrhythmias. We assessed CardioBoost’s ability to discriminate known pathogenic from benign variants, prioritize disease-associated variants, and stratify patient outcomes. Results: CardioBoost has high global discrimination accuracy (precision recall area under the curve [AUC] 0.91 for cardiomyopathies; 0.96 for arrhythmias), outperforming existing tools (4–24% improvement). CardioBoost obtains excellent accuracy (cardiomyopathies 90.2%; arrhythmias 91.9%) for variants classified with >90% confidence, and increases the proportion of variants classified with high confidence more than twofold compared with existing tools. Variants classified as disease-causing are associated with both disease status and clinical severity, including a 21% increased risk (95% confidence interval [CI] 11–29%) of severe adverse outcomes by age 60 in patients with hypertrophic cardiomyopathy. Conclusions: A disease-specific variant classifier outperforms state-of-the-art genome-wide tools for rare missense variants in inherited cardiac conditions (https://www.cardiodb.org/cardioboost/), highlighting broad opportunities for improved pathogenicity prediction through disease specificity

Disease-specific variant pathogenicity prediction significantly improves variant interpretation in inherited cardiac conditions

Funder: Science and Technology Development Fund; doi: https://doi.org/10.13039/Funder: Al-Alfi FoundationFunder: Magdi Yacoub Heart FoundationFunder: Rosetrees and Stoneygate Imperial College Research FellowshipFunder: National Health and Medical Research Council (Australia)Abstract: Purpose: Accurate discrimination of benign and pathogenic rare variation remains a priority for clinical genome interpretation. State-of-the-art machine learning variant prioritization tools are imprecise and ignore important parameters defining gene–disease relationships, e.g., distinct consequences of gain-of-function versus loss-of-function variants. We hypothesized that incorporating disease-specific information would improve tool performance. Methods: We developed a disease-specific variant classifier, CardioBoost, that estimates the probability of pathogenicity for rare missense variants in inherited cardiomyopathies and arrhythmias. We assessed CardioBoost’s ability to discriminate known pathogenic from benign variants, prioritize disease-associated variants, and stratify patient outcomes. Results: CardioBoost has high global discrimination accuracy (precision recall area under the curve [AUC] 0.91 for cardiomyopathies; 0.96 for arrhythmias), outperforming existing tools (4–24% improvement). CardioBoost obtains excellent accuracy (cardiomyopathies 90.2%; arrhythmias 91.9%) for variants classified with >90% confidence, and increases the proportion of variants classified with high confidence more than twofold compared with existing tools. Variants classified as disease-causing are associated with both disease status and clinical severity, including a 21% increased risk (95% confidence interval [CI] 11–29%) of severe adverse outcomes by age 60 in patients with hypertrophic cardiomyopathy. Conclusions: A disease-specific variant classifier outperforms state-of-the-art genome-wide tools for rare missense variants in inherited cardiac conditions (https://www.cardiodb.org/cardioboost/), highlighting broad opportunities for improved pathogenicity prediction through disease specificity

The James Webb Space Telescope Mission

Twenty-six years ago a small committee report, building on earlier studies, expounded a compelling and poetic vision for the future of astronomy, calling for an infrared-optimized space telescope with an aperture of at least $4m$. With the support of their governments in the US, Europe, and Canada, 20,000 people realized that vision as the $6.5m$ James Webb Space Telescope. A generation of astronomers will celebrate their accomplishments for the life of the mission, potentially as long as 20 years, and beyond. This report and the scientific discoveries that follow are extended thank-you notes to the 20,000 team members. The telescope is working perfectly, with much better image quality than expected. In this and accompanying papers, we give a brief history, describe the observatory, outline its objectives and current observing program, and discuss the inventions and people who made it possible. We cite detailed reports on the design and the measured performance on orbit.Comment: Accepted by PASP for the special issue on The James Webb Space Telescope Overview, 29 pages, 4 figure

Discrimination of Gain Increments in Speech-Shaped Noises

Frequency-dependent gain adjustments are routine in hearing-aid fittings, whether in matching to real-ear targets or fine-tuning to patient feedback. Patient feedback may be unreliable and fittings inefficient if adjustments are not discriminable. To examine what gain adjustments are discriminable, we measured the just-noticeable differences (JNDs) for level increments in speech-shaped noises processed with prescription gains. JNDs were measured in the better ears of 38 participants with hearing impairment using a fixed-level, same-different task. JNDs were measured for increments at six individual frequency-bands: a 0.25-kHz low-pass band; octave-wide bands at 0.5, 1, 2, and 4 kHz; and a 6-kHz high-pass band. JNDs for broadband increments were also measured. JNDs were estimated at d’ of 1 for a minimally discriminable increment in optimal laboratory conditions. The JND for frequency-band increments was 2.8 dB excluding the 0.25-kHz low-pass band, for which the JND was 4.5 dB. The JND for broadband increments was 1.5 dB. Participants’ median frequency-band and broadband JNDs were positively correlated. JNDs were mostly independent of age, pure-tone thresholds, and cognitive score. In consideration of self-fitting adjustments in noisier conditions, JNDs were additionally estimated at a more sensitive d’ of 2. These JNDs were 6 dB for bands below 1 kHz, and 5 dB for bands at and above 1 kHz. Overall, the results suggest noticeable fine-tuning adjustments of 3 dB and self-fitting adjustments of 5 dB

The effect of stimulus duration on preferences for gain adjustments when listening to speech

Objectives: In the personalisation of hearing-aid fittings, gain is often adjusted to suit patient preferences using live speech. When using brief sentences as stimuli, the minimum gain adjustments necessary to elicit consistent preferences (“preference thresholds”) were previously found to be much greater than typical adjustments in current practice. The current study examined the role of duration on preference thresholds. Design: Participants heard 2, 4 and 6-s segments of a continuous monologue presented successively in pairs. The first segment of each pair was presented at each individual’s real-ear or prescribed gain. The second segment was presented with a ±0–12 dB gain adjustment in one of three frequency bands. Participants judged whether the second was “better”, “worse” or “no different” from the first. Study sample: Twenty-nine adults, all with hearing-aid experience. Results: The minimum gain adjustments needed to elicit “better” or “worse” judgments decreased with increasing duration for most adjustments. Inter-participant agreement and intra-participant reliability increased with increasing duration up to 4 s, then remained stable. Conclusions: Providing longer stimuli improves the likelihood of patients providing reliable judgments of hearing-aid gain adjustments, but the effect is limited, and alternative fitting methods may be more viable for effective hearing-aid personalisation