Predicting effects of hearing-instrument signal processing on consonant perception.

This study investigated the influence of hearing-aid (HA) and cochlear-implant (CI) processing on consonant perception in normal-hearing (NH) listeners. Measured data were compared to predictions obtained with a speech perception model [Zaar and Dau (2017). J. Acoust. Soc. Am. 141, 1051-1064] that combines an auditory processing front end with a correlation-based template-matching back end. In terms of HA processing, effects of strong nonlinear frequency compression and impulse-noise suppression were measured in 10 NH listeners using consonant-vowel stimuli. Regarding CI processing, the consonant perception data from DiNino et al. [(2016). J. Acoust. Soc. Am. 140, 4404-4418] were considered, which were obtained with noise-vocoded vowel-consonant-vowel stimuli in 12 NH listeners. The inputs to the model were the same stimuli as were used in the corresponding experiments. The model predictions obtained for the two data sets showed a large agreement with the perceptual data both in terms of consonant recognition and confusions, demonstrating the model's sensitivity to supra-threshold effects of hearing-instrument signal processing on consonant perception. The results could be useful for the evaluation of hearing-instrument processing strategies, particularly when combined with simulations of individual hearing impairment.

Challenges and solutions for clinical development of new antibacterial agents: results of a survey among pharmaceutical industry professionals.

As the number of antibacterial medicines in the pipeline remains low, we anonymously surveyed pharmaceutical industry professionals on challenges and solutions for clinical development of these agents. Challenges were reported primarily as financial and regulatory. For multidrug-resistant organisms, there are needs for rapid diagnostic tests, new regulatory guidance, and adaptation of endpoints/trial designs. Regulators and public/private initiatives are addressing these challenges to help ensure that proposed solutions have the support of all involved stakeholders.

Metabolic Profiling of Alpine and Ecuadorian Lichens.

Non-targeted ¹H-NMR methods were used to determine metabolite profiles from crude extracts of Alpine and Ecuadorian lichens collected from their natural habitats. In control experiments, the robustness of metabolite detection and quantification was estimated using replicate measurements of Stereocaulon alpinum extracts. The deviations in the overall metabolite fingerprints were low when analyzing S. alpinum collections from different locations or during different annual and seasonal periods. In contrast, metabolite profiles observed from extracts of different Alpine and Ecuadorian lichens clearly revealed genus- and species-specific profiles. The discriminating functions determining cluster formation in principle component analysis (PCA) were due to differences in the amounts of genus-specific compounds such as sticticin from the Sticta species, but also in the amounts of ubiquitous metabolites, such as sugar alcohols or trehalose. However, varying concentrations of these metabolites from the same lichen species e.g., due to different environmental conditions appeared of minor relevance for the overall cluster formation in PCA. The metabolic clusters matched phylogenetic analyses using nuclear ribosomal DNA (nrDNA) internal transcribed spacer (ITS) sequences of lichen mycobionts, as exemplified for the genus Sticta. It can be concluded that NMR-based non-targeted metabolic profiling is a useful tool in the chemo-taxonomy of lichens. The same approach could also facilitate the discovery of novel lichen metabolites on a rapid and systematical basis.

Evaluating the efficacy and safety of two doses of the polyclonal anti-tumor necrosis factor-α fragment antibody AZD9773 in adult patients with severe sepsis and/or septic shock: randomized, double-blind, placebo-controlled phase IIb study*.

OBJECTIVE: This trial compared the efficacy/safety of two IV doses of AZD9773, a polyclonal antibody to tumor necrosis factor-α, in adult patients with severe sepsis/septic shock. DESIGN: Multicenter, randomized, double-blind, placebo-controlled phase IIb trial. SETTING: ICUs in seven countries (Australia, Belgium, Canada, Czech Republic, Finland, France, and Spain). PATIENTS: Patients 18 years old or older with severe sepsis and/or septic shock. Patients were required to have 1) objective clinical evidence of infection; 2) at least two of four systemic inflammatory response syndrome criteria; and 3) cardiovascular and/or respiratory sepsis-related failure. INTERVENTIONS: Patients were randomized 1:1:1 to a single loading infusion of AZD9773 250 U/kg followed by 50 U/kg every 12 hours (low dose, n = 100), a single loading infusion of AZD9773 500 U/kg followed by 100 U/kg every 12 hours (high dose, n = 100), or placebo (n = 100) for 5 days. Follow-up assessments were performed up to day 90. MEASUREMENTS AND MAIN RESULTS: Mean number of ventilator-free days (primary endpoint) did not differ between low-dose (19.7 d) or high-dose AZD9773 (17.3 d) and placebo (18.3 d) (one-sided p = 0.18 and 0.74, respectively). Mortality rates were comparable across treatment groups; relative risk of death versus placebo at day 29 was 0.80 for low-dose AZD9773 (one-sided p = 0.25) and 1.64 for high-dose AZD9773 (p = 0.97). Most patients experienced at least one treatment-emergent adverse event (87.8% in AZD9773-treated patients, 92.9% in placebo patients) although most were mild/moderate in nature. No differences in the incidence of adverse events or laboratory or vital sign abnormalities were observed between groups. CONCLUSIONS: AZD9773 rapidly and efficiently decreased plasma tumor necrosis factor-α concentration in patients with severe sepsis/septic shock, but this effect did not translate into clinical benefit.

Can a treatment be licenced on the basis of post-treatment predictive biomarkers?

In recent years, there has been a great deal of literature published concerning the identification of predictive biomarkers and indeed, an increasing number of therapies have been licenced on this basis. However, this progress has been made almost exclusively on the basis of biomarkers measured prior to exposure to treatment. There are quite different challenges when the responding population can only be identified on the basis of outcomes observed following exposure to treatment, especially if it represents only a small proportion of patients. The purpose of this paper is to explore whether or when a treatment could be licenced on the basis of post-treatment predictive biomarkers (PTPB), the focus is on oncology but the concepts should apply to all therapeutic areas. We review the potential pitfalls in hypothesising the presence of a PTPB. We also present challenges in trial design required to confirm and licence on the basis of a PTPB: what's the control population?, could there be a detriment to non-responders by exposure to the new treatment?, can responders be identified rapidly?, could prior exposure to the new treatment adversely affect performance of the control in responders? Nevertheless, if the patients to be treated could be rapidly identified after prior exposure to treatment, and without harm to non-responders, in appropriately designed and analysed trials, may be more targeted therapies could be made available to patients.

Stage I of a phase 2 study assessing the efficacy, safety, and tolerability of barasertib (AZD1152) versus low-dose cytosine arabinoside in elderly patients with acute myeloid leukemia.

BACKGROUND: In this phase 2 study, the authors evaluated the efficacy, safety, and tolerability of the Aurora B kinase inhibitor barasertib compared with low-dose cytosine arabinoside (LDAC) in patients aged ≥ 60 years with acute myeloid leukemia (AML). METHODS: Patients were randomized 2:1 to receive either open-label barasertib 1200 mg (as a 7-day intravenous infusion) or LDAC 20 mg (subcutaneously twice daily for 10 days) in 28-day cycles. The primary endpoint was the objective complete response rate (OCRR) (complete responses [CR] plus confirmed CRs with incomplete recovery of neutrophils or platelets [CRi] according to Cheson criteria [also requiring reconfirmation of CRi ≥21 days after the first appearance and associated with partial recovery of platelets and neutrophils]). Secondary endpoints included overall survival (OS) and safety. RESULTS: In total, 74 patients (barasertib, n = 48; LDAC, n = 26) completed ≥1 cycle of treatment. A significant improvement in the OCRR was observed with barasertib (35.4% vs 11.5%; difference, 23.9%; 95% confidence interval, 2.7%-39.9%; P < .05). Although the study was not formally sized to compare OS data, the median OS with barasertib was 8.2 months versus 4.5 months with LDAC (hazard ratio, 0.88; 95% confidence interval, 0.49-1.58; P = .663). Stomatitis and febrile neutropenia were the most common adverse events with barasertib versus LDAC (71% vs 15% and 67% vs 19%, respectively). CONCLUSIONS: Barasertib produced a significant improvement in the OCRR versus LDAC and had a more toxic but manageable safety profile, consistent with previous studies.

A Phoneme Perception Test Method for High-Frequency Hearing Aid Fitting.

BACKGROUND: Outcomes with hearing aids (HAs) can be assessed using various speech tests, but many tests are not sensitive to changes in high-frequency audibility. PURPOSE: A Phoneme Perception Test (PPT), designed for the phonemes /s/ and /ʃ/, has been developed to investigate whether detection and recognition tasks are able to measure individual differences in phoneme audibility and recognition for various hearing instrument settings. These capabilities were studied using two different fricative stimulus materials. The first set of materials preserves natural low-level sound components in the low- and mid-frequency ranges (LF set); the second set of materials attempts to limit the audibility to high-frequency fricative noise (nLF set). To study the effect on phoneme detection and recognition when auditory representations of /s/ and /ʃ/ are modified, a too strong nonlinear frequency compression (NLFC) setting was applied. RESEARCH DESIGN: Repeated measure design was used under several different conditions. STUDY SAMPLE: A total of 31 hearing-impaired individuals participated in this study. Of the 31 participants, 10 individuals did not own HAs but were provided with them during the study and 21 individuals owned HAs and were experienced users. All participants had a symmetrical sensorineural hearing loss. DATA COLLECTION AND ANALYSIS: The present study applied a phoneme detection test and a recognition test with two different stimulus sets under different amplification conditions. The statistical analysis focused on the capability of the PPT to measure the effect on audibility and perception of high-frequency information with and without HAs, and between HAs with two different NLFC settings ("default" and "too strong"). RESULTS: Detection thresholds (DTs) and recognition thresholds (RTs) were compared with respective audiometric thresholds in the free field for all available conditions. Significant differences in thresholds between LF and nLF stimuli were observed. The thresholds for nLF stimuli showed higher correlation to the corresponding audiometric thresholds than the thresholds for LF stimuli. The difference in thresholds for unaided and aided conditions was larger for the stimulus set nLF than for the stimulus set LF. Also, thresholds were similar in both aided conditions for stimulus set LF, whereas a large difference between amplifications was observed for the stimulus set nLF. When NLFC was set "too strong," DTs and RTs differed significantly for /s/. CONCLUSIONS: The findings from this study strongly suggest that measuring DTs and RTs with the stimulus set nLF is beneficial and useful to quantify the effects of HAs and NLFC on high-frequency speech cues for detection and recognition tasks. The findings also suggest that both tests are necessary because they assess audibility as well as recognition abilities, particularly as they relate to speech modification algorithms. The experiments conducted in this study did not allow for any acclimatization of the participants to increased high-frequency gain or NLFC. Further investigations should therefore examine the impact on DTs and RTs in the PPT as well as the contrasting effects of strong setting of NLFC to DTs and RTs because of (re)learning of modified auditory representations of /s/ and /ʃ/ as caused by NLFC.