Masking release due to linguistic and phonetic dissimilarity between the target and masker speech

Purpose: To investigate masking release for speech maskers for linguistically and phonetically close (English and Dutch) and distant (English and Mandarin) language pairs. Method: Thirty-two monolingual speakers of English with normal audiometric thresholds participated in the study. Data are reported for an English sentence recognition task in English and for Dutch and Mandarin competing speech maskers (Experiment 1) and noise maskers (Experiment 2) that were matched either to the long-term average speech spectra or to the temporal modulations of the speech maskers from Experiment 1. Results: Listener performance increased as the target-tomasker linguistic distance increased (English-in-English < English-in-Dutch < English-in-Mandarin). Conclusion: Spectral differences between maskers can account for some, but not all, of the variation in performance between maskers; however, temporal differences did not seem to play a significant role

Topical Flunixin Meglumine Effects on Pain Associated Biomarkers after Dehorning

Twenty-four calves were dehorned and treated with either topical flunixin meglumine formulated for systemic absorption or a placebo. Biomarkers associated with pain were evaluated for up to 72 hour after the dehorning procedure. Plasma cortisol concentrations, 90 minutes post-dehorning, and mechanical nociception threshold at the control site were the only tested biomarkers where a significant difference was demonstrated. No other differences of biomarkers between the two dehorned groups were observed for any time points. Although this product is easy to dose and dispense, its effects on pain biomarkers appears to be negligible

Cost-effectiveness analysis of fidaxomicin versus vancomycin in <i>Clostridium difficile</i> infection

Fidaxomicin was non-inferior to vancomycin with respect to clinical cure rates in the treatment of Clostridium difficile infections (CDIs) in two Phase III trials, but was associated with significantly fewer recurrences than vancomycin. This economic analysis investigated the cost-effectiveness of fidaxomicin compared with vancomycin in patients with severe CDI and in patients with their first CDI recurrence. A 1 year time horizon Markov model with seven health states was developed from the perspective of Scottish public healthcare providers. Model inputs for effectiveness, resource use, direct costs and utilities were obtained from published sources and a Scottish expert panel. The main model outcome was the incremental cost-effectiveness ratio (ICER), expressed as cost per quality-adjusted life year (QALY), for fidaxomicin versus vancomycin; ICERs were interpreted using willingness-to-pay thresholds of A 20aEuroS000 pound/QALY and A 30aEuroS000 pound/QALY. One-way and probabilistic sensitivity analyses were performed. Total costs were similar with fidaxomicin and vancomycin in patients with severe CDI (A 14aEuroS515 pound and A 14aEuroS344 pound, respectively) and in patients with a first recurrence (A 16aEuroS535 pound and A 16aEuroS926 pound, respectively). Improvements in clinical outcomes with fidaxomicin resulted in small QALY gains versus vancomycin (severe CDI, +0.010; patients with first recurrence, +0.019). Fidaxomicin was cost-effective in severe CDI (ICER A 16aEuroS529 pound/QALY) and dominant (i.e. more effective and less costly) in patients with a first recurrence. The probability that fidaxomicin was cost-effective at a willingness-to-pay threshold of A 30aEuroS000 pound/QALY was 60% for severe CDI and 68% in a first recurrence. Fidaxomicin is cost-effective in patients with severe CDI and in patients with a first CDI recurrence versus vancomycin

[F-18]FDG-PET/CT to prevent futile surgery in indeterminate thyroid nodules:a blinded, randomised controlled multicentre trial

Purpose To assess the impact of an [F-18]FDG-PET/CT-driven diagnostic workup to rule out malignancy, avoid futile diagnostic surgeries, and improve patient outcomes in thyroid nodules with indeterminate cytology. Methods In this double-blinded, randomised controlled multicentre trial, 132 adult euthyroid patients with scheduled diagnostic surgery for a Bethesda III or IV thyroid nodule underwent [F-18]FDG-PET/CT and were randomised to an [F-18] FDG-PET/CT-driven or diagnostic surgery group. In the [F-18]FDG-PET/CT-driven group, management was based on the [F-18]FDG-PET/CT result: when the index nodule was visually [F-18]FDG-positive, diagnostic surgery was advised; when [F-18]FDG-negative, active surveillance was recommended. The nodule was presumed benign when it remained unchanged on ultrasound surveillance. In the diagnostic surgery group, all patients were advised to proceed to the scheduled surgery, according to current guidelines. The primary outcome was the fraction of unbeneficial patient management in one year, i.e., diagnostic surgery for benign nodules and active surveillance for malignant/borderline nodules. Intention-to-treat analysis was performed. Subgroup analyses were performed for non-Hurthle cell and Hurthle cell nodules. Results Patient management was unbeneficial in 42% (38/91 [95% confidence interval [CI], 32-53%]) of patients in the [F-18] FDG-PET/CT-driven group, as compared to 83% (34/41 [95% CI, 68-93%]) in the diagnostic surgery group (p < 0.001). [F-18]FDG-PET/CT-driven management avoided 40% (25/63 [95% CI, 28-53%]) diagnostic surgeries for benign nodules: 48% (23/48 [95% CI, 33-63%]) in non-Hurthle cell and 13% (2/15 [95% CI, 2-40%]) in I-Liable cell nodules (p = 0.02). No malignant or borderline tumours were observed in patients under surveillance. Sensitivity, specificity, negative and positive predictive value, and benign call rate (95% CI) of [F-18]FDG-PET/CT were 94.1% (80.3-99.3%), 39.8% (30.0-50.2%), 95.1% (83.5-99.4%), 35.2% (25.4-45.9%), and 31.1% (23.3-39.7%), respectively. Conclusion An [F-18]FDG-PET/CT-driven diagnostic workup of indeterminate thyroid nodules leads to practice changing management, accurately and oncologically safely reducing futile surgeries by 40%. For optimal therapeutic yield, application should be limited to non-Hurthle cell nodules

Cross-accent intelligibility of speech in noise: Long-term familiarity and short-term familiarization

Listeners must cope with a great deal of variability in the speech signal, and thus theories of speech perception must also account for variability, which comes from a number of sources, including variation between accents. It is well-known that there is a processing cost when listening to speech in an accent other than one’s own, but recent work has suggested that this cost is reduced when listening to a familiar accent widely represented in the media, and/or when short amounts of exposure to an accent are provided. Little is known, however, about how these factors (long-term familiarity and short-term familiarization with an accent) interact. The current study tested this interaction by playing listeners difficult-to-segment sentences in noise, before and after a familiarization period where the same sentences were heard in the clear, allowing us to manipulate short-term familiarization. Listeners were speakers of either Glasgow English or Standard Southern British English, and they listened to speech in either their own or the other accent, thereby allowing us to manipulate long-term familiarity. Results suggest that both long-term familiarity and short-term familiarization mitigate the perceptual processing costs of listening to an accent that is not one’s own, but seem not to compensate for them entirely, even when the accent is widely heard in the media

IGF2 is a potential factor in RAI-refractory differentiated thyroid cancer

Differentiated thyroid cancer (DTC) is the most frequent endocrine tumor with a good prognosis after primary treatment in most cases. By contrast, 30-40% of patients with metastatic DTC are unresponsive to I-131 radioactive iodide (RAI) treatment due to tumor dedifferentiation. Currently, underlying molecular mechanisms of dedifferentiation remain elusive and predictive biomarkers are lacking. Therefore, the present study aimed to identify molecular biomarkers in primary tumors associated with RAI refractoriness. A retrospective cohort was gathered consisting of RAI-sensitive patients with DTC and RAI-refractory patients with poorly DTC. In all patients, extensive intratumoral mutation profiling, gene fusions analysis, telomerase reverse transcriptase (TERT) promoter mutation analysis and formalin-fixed paraffin-embedded-compatible RNA sequencing were performed. Genetic analyses revealed an increased mutational load in RAI-refractory DTC, including mutations in AKT1, PTEN, TP53 and TERT promoter. Transcriptomic analyses revealed profound differential expression of insulin-like growth factor 2 (IGF2), with up to 100-fold higher expression in RAI-refractory DTC compared with in RAI-sensitive DTC cases. ELISA revealed significant lower IGF2 plasma concentrations after surgery and subsequent I-131 RAI therapy in patients with DTC compared with pretreatment baseline. Overall, the current findings suggested that the tumor-promoting growth factor IGF2 may have a potential role in acquiring RAI refractoriness.Diabetes mellitus: pathophysiological changes and therap

Allosteric control of Ubp6 and the proteasome via a bidirectional switch

The interplay of the proteasome and deubiquitinase Ubp6 is crucial for the degradation of ubiquitylated substrates. Here, the authors provide structural insights into the allosteric mechanism by which the activities of both Ubp6 and the proteasome are regulated. The proteasome recognizes ubiquitinated proteins and can also edit ubiquitin marks, allowing substrates to be rejected based on ubiquitin chain topology. In yeast, editing is mediated by deubiquitinating enzyme Ubp6. The proteasome activates Ubp6, whereas Ubp6 inhibits the proteasome through deubiquitination and a noncatalytic effect. Here, we report cryo-EM structures of the proteasome bound to Ubp6, based on which we identify mutants in Ubp6 and proteasome subunit Rpt1 that abrogate Ubp6 activation. The Ubp6 mutations define a conserved region that we term the ILR element. The ILR is found within the BL1 loop, which obstructs the catalytic groove in free Ubp6. Rpt1-ILR interaction opens the groove by rearranging not only BL1 but also a previously undescribed network of three interconnected active-site-blocking loops. Ubp6 activation and noncatalytic proteasome inhibition are linked in that they are eliminated by the same mutations. Ubp6 and ubiquitin together drive proteasomes into a unique conformation associated with proteasome inhibition. Thus, a multicomponent allosteric switch exerts simultaneous control over both Ubp6 and the proteasome

Half-metallic ferromagnets and their magneto-optical properties

We have calculated the electronic structure of PtMnSb in order to explain the very high magneto-optical Kerr effect (over 2.5° at 720 nm at room-temperature) of this compound. It is shown that this behavior is related to the unusual electronic properties of PtMnSb: it is a half-metallic ferromagnet like NiMnSb. The extreme asymmetry in the electronic structure of these compounds—metallic behavior for one spin direction and at the same time semiconducting behavior for the other spin direction—is responsible for the unusual magneto-optical properties