Refining epidemiological forecasts with simple scoring rules.

Estimates from infectious disease models have constituted a significant part of the scientific evidence used to inform the response to the COVID-19 pandemic in the UK. These estimates can vary strikingly in their bias and variability. Epidemiological forecasts should be consistent with the observations that eventually materialize. We use simple scoring rules to refine the forecasts of a novel statistical model for multisource COVID-19 surveillance data by tuning its smoothness hyperparameter. This article is part of the theme issue 'Technical challenges of modelling real-life epidemics and examples of overcoming these'.

Short-Term Memory Performance in 7- and 8-Year-Old Children: The Relationship Between Phonological and Pitch Processing.

Purpose: The relationship between short-term memory for phonology and pitch was explored by examining accuracy scores for typically developing children for 5 experimental tasks: immediate nonword repetition (NWR), nonword repetition with an 8-s silent interference (NWRS), pitch discrimination (PD), pitch discrimination with an 8-s silent interference (PDS), and pitch matching (PM). Method: Thirty-six 7- and 8-year-old children (21 girls, 15 boys) with normal hearing, language, and cognition were asked to listen to and repeat nonsense words (NWR, NWRS), make a same versus different decision between 2 tones (PD, PDS), and listen to and then vocally reproduce a tone (PM). Results: Results showed no significant correlations between tasks of phonological memory and tests of pitch memory, that participants scored significantly better on nonword repetition tasks than PD and PM tasks, and that participants performed significantly better on tasks with no silent interference. Discussion: These findings suggest that, for typically developing children, pitch may be stored and rehearsed in a separate location than phonological information. Because of fundamental task differences, further research is needed to corroborate these data and determine the presence of developmental effects and neuroanatomical locations where a potential language/music overlap is occurring in children.

The impact of listening condition on background noise acceptance for young adults with normal hearing.

PURPOSE: To evaluate the effect of different speech conditions on background noise acceptance. A total of 23 stimulus pairings, differing in primary talker gender (female, male, conventional), number of background talkers (1, 4, 12), and gender composition of the background noise (female, male, mixed) were used to evaluate background noise acceptance. METHOD: A repeated measures research design was used. Participants were 15 female and 15 male young adults with normal hearing. Background noise acceptance was evaluated with the acceptable noise level (ANL). RESULTS: The results revealed main effects of primary talker gender, number of background talkers, and listener gender. ANL was lower for conditions of a female primary talker and for conditions with multitalker backgrounds. Male listeners had significantly lower ANLs than female listeners. An interaction occurred between primary talker and background noise composition. For female primary talker conditions, the male talker backgrounds produced the lowest ANLs. For male primary talker conditions, the lowest ANLs were obtained with the female and male background talker conditions. CONCLUSIONS: Background noise acceptance depends on the listener and the stimulus condition. Stimulus selection can influence the measurement of ANL. The results support the use of the commercially available ANL materials.

Speech intelligibility differences across sound classes with in-the-ear and free-field microphones in quiet.

Speech intelligibility performance with an in-the-ear microphone embedded in a custom-molded deep-insertion earplug was compared with results obtained using a free-field microphone. Intelligibility differences between microphones were further analyzed to assess whether reduced intelligibility was specific to certain sound classes. 36 participants completed the Modified Rhyme Test using recordings made with each microphone. While speech intelligibility for both microphones was highly accurate, intelligibility with the free-field microphone was significantly better than with the in-the-ear microphone. There were significant effects of place and manner of sound production. Significant differences in recognition among specific phonemes were also revealed. Implications included modifying the in-the-ear microphone to transmit more high frequency energy. Use of the in-the-ear microphone was limited by significant loss of high-frequency energy of the speech signal which resulted in reduced intelligibility for some sounds; however, the in-the-ear microphone is a promising technology for effective communication in military environments.

Pitch-matching accuracy in trained singers and untrained individuals: the impact of musical interference and noise.

The effects of musical interference and noise on pitch-matching accuracy were examined. Vocal training was explored as a factor influencing pitch-matching accuracy, and the relationship between pitch matching and pitch discrimination was examined. Twenty trained singers (TS) and 20 untrained individuals (UT) vocally matched tones in six conditions (immediate, four types of chords, noise). Fundamental frequencies were calculated, compared with the frequency of the target tone, and converted to semitone difference scores. A pitch discrimination task was also completed. TS showed significantly better pitch matching than UT across all conditions. Individual performances for UT were highly variable. Therefore, untrained participants were divided into two groups: 10 untrained accurate and 10 untrained inaccurate. Comparison of TS with untrained accurate individuals revealed significant differences between groups and across conditions. Compared with immediate vocal matching of target tones, pitch-matching accuracy was significantly reduced, given musical chord and noise interference unless the target tone was presented in the musical chord. A direct relationship between pitch matching and pitch discrimination was revealed. Across pitch-matching conditions, TS were consistently more accurate than UT. Pitch-matching accuracy diminished when auditory interference consisted of chords that did not contain the target tone and noise.

Effects of reverberation on acceptable noise level measurements in younger and older adults.

Acceptable noise level (ANL) test materials were digitally modified to create five reverberant conditions by applying different values of reverberation time (RT) to a non-reverberant condition (RT = 0, 0.4, 0.7, 1.2, and 2 s). Two groups of 12 subjects participated: younger individuals (22­29 years, M = 24.3) and older adults (50­69 years, M = 57.5). Mean hearing threshold levels (250 to 8000 Hz) for both groups were 30 dB HL or better. Most comfortable listening level (MCL) and background noise level (BNL) measurements were completed in each reverberant condition, and from these measurements, ANLs were calculated. Significant main effects for age and reverberation were not found for ANL or MCL. These results suggest that reverberation does not affect the amount of background noise individuals are willing to accept, or the level of speech individuals choose as the MCL. These results can be used by clinical audiologists to counsel patients regarding the use of communication strategies. Additionally, these results can be used to support previous findings that ANL is not related to the intelligibility of the speech signal.

Effects of speech rate, background noise, and simulated hearing loss on speech rate judgment and speech intelligibility in young listeners.

PURPOSE: To study the effect of noise on speech rate judgment and signal-to-noise ratio threshold (SNR50) at different speech rates (slow, preferred, and fast). RESEARCH DESIGN: Speech rate judgment and SNR50 tasks were completed in a normal-hearing condition and a simulated hearing-loss condition. STUDY SAMPLE: Twenty-four female and six male young, normal-hearing participants. RESULTS: Speech rate judgment was not affected by background noise regardless of hearing condition. Results of the SNR50 task indicated that, as speech rate increased, performance decreased for both hearing conditions. There was a moderate correlation between speech rate judgment and SNR50 with the various speech rates, such that as judgment of speech rate increased from too slow to too fast, performance deteriorated. CONCLUSIONS: These findings can be used to support the need for counseling patients and their families about the potential advantages to using average speech rates or rates that are slightly slowed while conversing in the presence of background noise.

Effects of increasing time delays on pitch-matching accuracy in trained singers and untrained individuals.

Trained singers (TS) generally demonstrate accurate pitch matching, but this ability varies within the general population. Pitch-matching accuracy, given increasing silence intervals of 5, 15, and 25 seconds between target tones and vocal matches, was investigated in TS and untrained individuals. A relationship between pitch discrimination and pitch matching was also examined. Thirty-two females (20-30 years) were grouped based on individual vocal training and performance in an immediate pitch-matching task. Participants matched target pitches following time delays, and completed a pitch discrimination task, which required the classification of two tones as same or different. TS and untrained accurate participants performed comparably on all pitch-matching tasks, while untrained inaccurate participants performed significantly less accurately than the other two groups. Performances declined across groups as intervals of silence increased, suggesting degradation of pitch matching as pitch memory was taxed. A significant relationship between pitch discrimination and pitch matching was revealed across participants.

Acceptance of noise with intelligible, reversed, and unfamiliar primary discourse.

PURPOSE: The purpose of this study was to investigate the effects of intelligible and unintelligible primary discourse on acceptance of noise. Of particular interest was the effect of intelligibility on the most comfortable loudness (MCL) component of acceptable noise level (ANL). METHOD: ANLs were measured for 30 participants using an intelligible discourse, a reversed discourse, and an unfamiliar primary discourse. For each discourse, MCL and background noise level (BNL) were found. The ANL was then computed by subtracting the mean BNL from the MCL. RESULTS: The intelligibility of the primary discourse did not affect MCL. The ANL was significantly different for the intelligible versus reversed condition and the intelligible versus unfamiliar (Chinese) condition. CONCLUSION: Results indicate that ANL may change as speech intelligibility changes and/or speech recognition ability decreases in adults with normal hearing.

Pitch discrimination and pitch matching abilities with vocal and nonvocal stimuli.

Various stimulus types have been investigated in pitch discrimination and pitch matching tasks. However, previous studies have not explored the use of recorded samples of an individual's own voice in performing these two tasks. The purpose of this study was to investigate pitch discrimination and pitch matching abilities using three stimuli conditions (participant's own voice, a neutral female voice, and nonvocal complex tones) to determine if pitch discrimination and/or pitch matching abilities are influenced by the type of stimuli presented. Results of the pitch discrimination tasks yielded no significant difference in discrimination ability for the three stimuli. For the pitch matching tasks, a significant difference was found for the participants' voice versus neutral female voice and the participants' voice versus tonal stimuli. There was no significant difference in pitch matching ability between the neutral female voice and the tonal stimuli. There was no significant correlation between pitch discrimination and pitch matching abilities for any of the three stimuli types. These results suggest that it is easier to match the pitch of one's own voice than to match the pitch of a neutral female voice and nonvocal complex tones, although no difference was found for pitch discrimination abilities. One possible implication of this study is that differences in matching the pitch of one's own voice compared to matching other stimuli types may help to differentiate the source of singing inaccuracy (motor vs discrimination skills).

Relations of pitch matching, pitch discrimination, and otoacoustic emission suppression in individuals not formally trained as musicians.

Research has yielded a relationship between pitch matching and pitch discrimination. Good pitch matchers tend to be good pitch discriminators and are often judged to be vocally talented. Otoacoustic emission suppression measures the function of the efferent auditory system which may affect accuracy for pitch matching and pitch discrimination. Formally trained musicians show pitch matching and pitch discrimination superior to those of nonmusicians and have greater efferent otoacoustic emission suppression than nonmusicians. This study investigated the relationship among pitch matching, pitch discrimination, and otoacoustic emission suppression in individuals with no formal musical training and who showed varied pitch matching and pitch discrimination. Analysis suggested a significant relationship between pitch matching and pitch discrimination but not between otoacoustic emission suppression and pitch matching and pitch discrimination. Findings are presented in the context of previous research indicating a significant relationship between otoacoustic emission suppression and musical talent in trained musicians.

Influence of music and music preference on acceptable noise levels in listeners with normal hearing.

Acceptable noise level (ANL) is defined as the maximum level of background noise that an individual is willing to accept while listening to speech. The type of background noise does not affect ANL results with the possible exception of music. The purpose of this study was to determine if ANL for music was different from ANL for twelve-talker babble and investigate if there was a correlation between ANL for music samples and preference for those music samples. Results demonstrated that ANL for music tended to be better than ANL for twelve-talker babble, indicating listeners were more willing to accept music as a background noise than speech babble. The results further demonstrated that ANL for the music samples were not correlated with preference for the music samples, indicating that ANL for music was not related to music preference. Therefore, music appeared to be processed differently as a background noise than twelve-talker babble.

Effects of reverberation and filtering on speech rate judgment.

This study investigated the effects of listening condition on speech rate judgment. Four listening conditions, in which a single sentence was presented at 21 speech rates ranging from 90 WPM to 250 WPM, were incorporated. These conditions included non-degraded, reverberation, band-pass filtered, and low-pass filtered conditions, each of which was selected to simulate listening conditions one might encounter in daily life. The participants were 20 young adults (20 to 40 years) with normal hearing. They were asked to make judgments of the rates of speech randomly presented in the four listening conditions using an equal-interval 5-step scale from too slow through too fast. Overall, speech rate was judged to be faster in the reverberant condition than in the other three conditions. These findings may have implications for auditory rehabilitation and counseling.

The role of pitch memory in pitch discrimination and pitch matching.

Accurate control of vocal pitch (fundamental frequency) requires coordination of sensory and motor systems. Previous research has supported the relationship between perceptual accuracy and vocal pitch matching accuracy. The purpose of this study was to investigate the role of memory for pitch in pitch matching and pitch discrimination ability. Three experimental tasks were used. First, a pitch matching task was completed, in which the participants listened to target tones and vocally matched the pitch of the tones. The second task was a pitch discrimination task that required the participants to judge the pitch (same or different) of complex tone pairs. The third task was pitch discrimination with memory interference task that was similar to the pitch discrimination task except interference tones were added. Results of the pitch matching and pitch discrimination tasks yielded a significant correlation between these values. When there was memory interference, pitch discrimination ability was poorer, and there was no significant correlation between pitch discrimination and pitch matching. These results support earlier findings of a relationship between pitch discrimination and pitch matching abilities. The results also suggest a possible role of pitch memory in both tasks. These findings may have implications for abilities related to accurate pitch control.

Speech rate effects upon intelligibility and acceptability of dysarthric speech.

Sentences recorded by four speakers with dysarthria and two control speakers were presented to listeners at three different rates: habitual, a 30% slower rate and a 30% higher rate. Rate changes were made by digitally manipulating the habitual sentences. Thirty young normal adult listeners rated the sentences for intelligibility (per cent correct words) and acceptability (via 9-point equal interval scale ranging from "terrible" through "excellent"). Intelligibility for each speaker remained unchanged across rate changes. Acceptability improved as rates increased for the two more intelligible impaired speakers. For the less intelligible impaired speakers, ratings were better and similar for the habitual and fast speaking rate conditions. Results are discussed in terms of the objective nature of intelligibility ratings vs. the subjective ratings of acceptability.

Human splicing factor SPF45 (RBM17) confers broad multidrug resistance to anticancer drugs when overexpressed--a phenotype partially reversed by selective estrogen receptor modulators.

The splicing factor SPF45 (RBM17) is frequently overexpressed in many solid tumors, and stable expression in HeLa cells confers resistance to doxorubicin and vincristine. In this study, we characterized stable transfectants of A2780 ovarian carcinoma cells. In a 3-day cytotoxicity assay, human SPF45 overexpression conferred 3- to 21-fold resistance to carboplatin, vinorelbine, doxorubicin, etoposide, mitoxantrone, and vincristine. In addition, resistance to gemcitabine and pemetrexed was observed at the highest drug concentrations tested. Knockdown of SPF45 in parental A2780 cells using a hammerhead ribozyme sensitized A2780 cells to etoposide by approximately 5-fold relative to a catalytically inactive ribozyme control and untransfected cells, suggesting a role for SPF45 in intrinsic resistance to some drugs. A2780-SPF45 cells accumulated similar levels of doxorubicin as vector-transfected and parental A2780 cells, indicating that drug resistance is not due to differences in drug accumulation. Efforts to identify small molecules that could block SPF45-mediated drug resistance revealed that the selective estrogen receptor (ER) modulators tamoxifen and LY117018 (a raloxifene analogue) partially reversed SPF45-mediated drug resistance to mitoxantrone in A2780-SPF45 cells from 21-fold to 8- and 5-fold, respectively, but did not significantly affect the mitoxantrone sensitivity of vector control cells. Quantitative PCR showed that ERbeta but not ERalpha was expressed in A2780 transfectants. Coimmunoprecipitation experiments suggest that SPF45 and ERbeta physically interact in vivo. Thus, SPF45-mediated drug resistance in A2780 cells may result in part from effects of SPF45 on the transcription or alternate splicing of ERbeta-regulated genes.

Human SPF45, a splicing factor, has limited expression in normal tissues, is overexpressed in many tumors, and can confer a multidrug-resistant phenotype to cells.

Our effort to identify novel drug-resistant genes in cyclophosphamide-resistant EMT6 mouse mammary tumors led us to the identification of SPF45. Simultaneously, other groups identified SPF45 as a component of the spliceosome that is involved in alternative splicing. We isolated the human homologue and examined the normal human tissue expression, tumor expression, and the phenotype caused by overexpression of human SPF45. Our analyses revealed that SPF45 is expressed in many, but not all, normal tissues tested with predominant expression in normal ductal epithelial cells of the breast, liver, pancreas, and prostate. Our analyses using tissue microarrays and sausages of tumors indicated that SPF45 is highly expressed in numerous carcinomas including bladder, breast, colon, lung, ovarian, pancreatic, and prostate. Interestingly, this study revealed that overexpression of SPF45 in HeLa, a cervical carcinoma cell line, resulted in drug resistance to doxorubicin and vincristine, two chemotherapeutic drugs commonly used in cancer. To our knowledge, this is the first study showing tumor overexpression of an alternate splicing factor resulting in drug resistance.

The mechanism of ferrichrome transport through Arn1p and its metabolism in Saccharomyces cerevisiae.

Siderophores are low molecular weight compounds, synthesized and secreted by microorganisms, that specifically bind ferric iron with exceptionally high affinity. Microbes capture these compounds and take up the bound iron through specific, high-affinity systems. Saccharomyces cerevisiae can take up iron bound to siderophores through the transporters of the ARN family; however, the mechanism by which the siderophore-bound iron enters the cell via these transporters is not known. Here we describe how ferrichrome, a siderophore of the hydroxamate class, is taken up by Arn1p. Arn1p exhibits two surface binding sites for ferrichrome, one that is similar in affinity to the K(T) for uptake and one of a much higher affinity that is specific for the metallated form of ferrichrome. Ferrichrome may gain access to the higher-affinity site through endocytosis. Tracer studies using (14)C-labeled ferrichrome bound to either iron(III) or aluminum(III), a nonreducible ligand for ferrichrome, indicate that ferrichrome enters the cell as the intact metallosiderophore and accumulates in the cytosol. Both ferrichrome chelates were relatively stable within the cell, and metal-free ferrichrome did not accumulate, indicating a role for ferrichrome in intracellular iron storage. Iron stored as ferrichrome was readily mobilized to meet the metabolic needs of the cell.

A very early induction of major vault protein accompanied by increased drug resistance in U-937 cells.

U-937 human leukemia cells were selected for resistance to doxorubicin in the presence or absence of a specific drug modulator that inhibits the activity of P-glycoprotein (Pgp), encoded by the multidrug-resistance gene (MDR1). Parental cells expressed low basal levels of the multidrug-resistance-associated gene (MRP1) and major vault protein (MVP) mRNAs and no MDR1 mRNA. Two doxorubicin-resistant cell lines were selected. Both drug-resistant cell lines upregulated the MVP mRNA level 1.5-fold within 1 cell passage. The MVP mRNA level continued to increase over time as the doxorubicin selection pressure was increased. MVP protein levels generally paralleled the mRNA levels. The 2 high molecular weight vault protein mRNAs were always expressed at constitutive levels. Fully formed vault particles consisting of the MVP, the 2 high molecular weight proteins and the vault RNA assembled and accumulated to increased levels in drug-selected cells. MVP induction is therefore the rate-limiting step for vault particle formation in U-937 cells. By passage 25 and thereafter, the selected cells were resistant to doxorubicin, etoposide, mitoxantrone and 5-fluorouracil by a pathway that was independent of MDR1, MRP1, MRP2 and breast cancer resistance protein. In summary, U-937 doxorubicin-selected cells are programmed to rapidly upregulate MVP mRNA levels, to accumulate vault particles and to become multidrug resistant.