Spectral-Temporal Trade-Off in Vocoded Sentence Recognition: Effects of Age, Hearing Thresholds, and Working Memory.

OBJECTIVES: Cochlear implant (CI) signal processing degrades the spectral components of speech. This requires CI users to rely primarily on temporal cues, specifically, amplitude modulations within the temporal envelope, to recognize speech. Auditory temporal processing ability for envelope modulations worsens with advancing age, which may put older CI users at a disadvantage compared with younger users. To evaluate how potential age-related limitations for processing temporal envelope modulations impact spectrally degraded sentence recognition, noise-vocoded sentences were presented to younger and older normal-hearing listeners in quiet. Envelope modulation rates were varied from 10 to 500 Hz by adjusting the low-pass filter cutoff frequency (LPF). The goal of this study was to evaluate if age impacts recognition of noise-vocoded speech and if this age-related limitation existed for a specific range of envelope modulation rates. DESIGN: Noise-vocoded sentence recognition in quiet was measured as a function of number of spectral channels (4, 6, 8, and 12 channels) and LPF (10, 20, 50, 75, 150, 375, and 500 Hz) in 15 younger normal-hearing listeners and 15 older near-normal-hearing listeners. Hearing thresholds and working memory were assessed to determine the extent to which these factors were related to recognition of noise-vocoded sentences. RESULTS: Younger listeners achieved significantly higher sentence recognition scores than older listeners overall. Performance improved in both groups as the number of spectral channels and LPF increased. As the number of spectral channels increased, the differences in sentence recognition scores between groups decreased. A spectral-temporal trade-off was observed in both groups in which performance in the 8- and 12-channel conditions plateaued with lower-frequency amplitude modulations compared with the 4- and 6-channel conditions. There was no interaction between age group and LPF, suggesting that both groups obtained similar improvements in performance with increasing LPF. The lack of an interaction between age and LPF may be due to the nature of the task of recognizing sentences in quiet. Audiometric thresholds were the only significant predictor of vocoded sentence recognition. Although performance on the working memory task declined with advancing age, working memory scores did not predict sentence recognition. CONCLUSIONS: Younger listeners outperformed older listeners for recognizing noise-vocoded sentences in quiet. The negative impact of age was reduced when ample spectral information was available. Age-related limitations for recognizing vocoded sentences were not affected by the temporal envelope modulation rate of the signal, but instead, appear to be related to a generalized task limitation or to reduced audibility of the signal.

Objective Assessment of Speech Intelligibility in Crowded Public Spaces.

The objective of this study was to obtain a normative database of speech intelligibility data for young normal-hearing listeners communicating in public spaces. A total of 174 listeners participated in an interactive speech intelligibility task that required four-person groups to conduct a live version of the Modified Rhyme Test in noisy public spaces. The public spaces tested included a college library, a college cafeteria, a casual dining restaurant during lunch hour, and a crowded bar during happy hour. At the start of each trial, one of the participants was randomly selected as the talker, and a tablet computer was used to prompt them to say a word aloud from the Modified Rhyme Test. Then, the other three participants were required to select this word from one of six rhyming alternatives displayed on three other tablet computers. The tablet computers were also used to record the SPL at each listener location during and after the interval where the target talker was speaking. These SPL measurements were used to estimate the signal-to-noise ratio (SNR) in each trial of the experiment. As expected, the results show that speech intelligibility decreases, response time increases, and perceived difficulty increases as the background noise level increases. There was also a systematic decrease in SNR with increasing background noise, with SNR decreasing 0.44 dB for every 1 dB increase in ambient noise level above 60 dB. Overall, the results of this study have demonstrated how low-cost tablet computer-based data collection systems can be used to collect live-talker speech intelligibility data in real-world environments. We believe these techniques could be adapted for use in future studies focused on obtaining ecologically valid assessments of the effects of age, hearing impairment, amplification, and other factors on speech intelligibility performance in real-world environments.

Macaque Monoclonal Antibodies Targeting Novel Conserved Epitopes within Filovirus Glycoprotein.

UNLABELLED: Filoviruses cause highly lethal viral hemorrhagic fever in humans and nonhuman primates. Current immunotherapeutic options for filoviruses are mostly specific to Ebola virus (EBOV), although other members of Filoviridae such as Sudan virus (SUDV), Bundibugyo virus (BDBV), and Marburg virus (MARV) have also caused sizeable human outbreaks. Here we report a set of pan-ebolavirus and pan-filovirus monoclonal antibodies (MAbs) derived from cynomolgus macaques immunized repeatedly with a mixture of engineered glycoproteins (GPs) and virus-like particles (VLPs) for three different filovirus species. The antibodies recognize novel neutralizing and nonneutralizing epitopes on the filovirus glycoprotein, including conserved conformational epitopes within the core regions of the GP1 subunit and a novel linear epitope within the glycan cap. We further report the first filovirus antibody binding to a highly conserved epitope within the fusion loop of ebolavirus and marburgvirus species. One of the antibodies binding to the core GP1 region of all ebolavirus species and with lower affinity to MARV GP cross neutralized both SUDV and EBOV, the most divergent ebolavirus species. In a mouse model of EBOV infection, this antibody provided 100% protection when administered in two doses and partial, but significant, protection when given once at the peak of viremia 3 days postinfection. Furthermore, we describe novel cocktails of antibodies with enhanced protective efficacy compared to individual MAbs. In summary, the present work describes multiple novel, cross-reactive filovirus epitopes and innovative combination concepts that challenge the current therapeutic models. IMPORTANCE: Filoviruses are among the most deadly human pathogens. The 2014-2015 outbreak of Ebola virus disease (EVD) led to more than 27,000 cases and 11,000 fatalities. While there are five species of Ebolavirus and several strains of marburgvirus, the current immunotherapeutics primarily target Ebola virus. Since the nature of future outbreaks cannot be predicted, there is an urgent need for therapeutics with broad protective efficacy against multiple filoviruses. Here we describe a set of monoclonal antibodies cross-reactive with multiple filovirus species. These antibodies target novel conserved epitopes within the envelope glycoprotein and exhibit protective efficacy in mice. We further present novel concepts for combination of cross-reactive antibodies against multiple epitopes that show enhanced efficacy compared to monotherapy and provide complete protection in mice. These findings set the stage for further evaluation of these antibodies in nonhuman primates and development of effective pan-filovirus immunotherapeutics for use in future outbreaks.

Pan-ebolavirus and Pan-filovirus Mouse Monoclonal Antibodies: Protection against Ebola and Sudan Viruses.

UNLABELLED: The unprecedented 2014-2015 Ebola virus disease (EVD) outbreak in West Africa has highlighted the need for effective therapeutics against filoviruses. Monoclonal antibody (MAb) cocktails have shown great potential as EVD therapeutics; however, the existing protective MAbs are virus species specific. Here we report the development of pan-ebolavirus and pan-filovirus antibodies generated by repeated immunization of mice with filovirus glycoproteins engineered to drive the B cell responses toward conserved epitopes. Multiple pan-ebolavirus antibodies were identified that react to the Ebola, Sudan, Bundibugyo, and Reston viruses. A pan-filovirus antibody that was reactive to the receptor binding regions of all filovirus glycoproteins was also identified. Significant postexposure efficacy of several MAbs, including a novel antibody cocktail, was demonstrated. For the first time, we report cross-neutralization and in vivo protection against two highly divergent filovirus species, i.e., Ebola virus and Sudan virus, with a single antibody. Competition studies indicate that this antibody targets a previously unrecognized conserved neutralizing epitope that involves the glycan cap. Mechanistic studies indicated that, besides neutralization, innate immune cell effector functions may play a role in the antiviral activity of the antibodies. Our findings further suggest critical novel epitopes that can be utilized to design effective cocktails for broad protection against multiple filovirus species. IMPORTANCE: Filoviruses represent a major public health threat in Africa and an emerging global concern. Largely driven by the U.S. biodefense funding programs and reinforced by the 2014 outbreaks, current immunotherapeutics are primarily focused on a single filovirus species called Ebola virus (EBOV) (formerly Zaire Ebola virus). However, other filoviruses including Sudan, Bundibugyo, and Marburg viruses have caused human outbreaks with mortality rates as high as 90%. Thus, cross-protective immunotherapeutics are urgently needed. Here, we describe monoclonal antibodies with cross-reactivity to several filoviruses, including the first report of a cross-neutralizing antibody that exhibits protection against Ebola virus and Sudan virus in mice. Our results further describe a novel combination of antibodies with enhanced protective efficacy. These results form a basis for further development of effective immunotherapeutics against filoviruses for human use. Understanding the cross-protective epitopes are also important for rational design of pan-ebolavirus and pan-filovirus vaccines.

Inhibition of Ebola and Marburg Virus Entry by G Protein-Coupled Receptor Antagonists.

UNLABELLED: Filoviruses, consisting of Ebola virus (EBOV) and Marburg virus (MARV), are among the most lethal infectious threats to mankind. Infections by these viruses can cause severe hemorrhagic fevers in humans and nonhuman primates with high mortality rates. Since there is currently no vaccine or antiviral therapy approved for humans, there is an urgent need to develop prophylactic and therapeutic options for use during filoviral outbreaks and bioterrorist attacks. One of the ideal targets against filoviral infection and diseases is at the entry step, which is mediated by the filoviral glycoprotein (GP). In this report, we screened a chemical library of small molecules and identified numerous inhibitors, which are known G protein-coupled receptor (GPCR) antagonists targeting different GPCRs, including histamine receptors, 5-HT (serotonin) receptors, muscarinic acetylcholine receptor, and adrenergic receptor. These inhibitors can effectively block replication of both infectious EBOV and MARV, indicating a broad antiviral activity of the GPCR antagonists. The time-of-addition experiment and microscopic studies suggest that GPCR antagonists block filoviral entry at a step following the initial attachment but prior to viral/cell membrane fusion. These results strongly suggest that GPCRs play a critical role in filoviral entry and GPCR antagonists can be developed as an effective anti-EBOV/MARV therapy. IMPORTANCE: Infection of Ebola virus and Marburg virus can cause severe illness in humans with a high mortality rate, and currently there is no FDA-approved vaccine or therapeutic treatment available. The 2013-2015 epidemic in West Africa underscores a lack of our understanding in the infection and pathogenesis of these viruses and the urgency of drug discovery and development. In this study, we have identified numerous inhibitors that are known G protein-coupled receptor (GPCR) antagonists targeting different GPCRs. These inhibitors can effectively block replication of both infectious EBOV and MARV, indicating a broad antiviral activity of the GPCR antagonists. Our results strongly suggest that GPCRs play a critical role in filoviral entry and GPCR antagonists can be developed as an effective anti-EBOV/MARV therapy.

Role of EXT1 and Glycosaminoglycans in the Early Stage of Filovirus Entry.

UNLABELLED: Filoviruses, including both Ebola virus (EBOV) and Marburg virus (MARV), can infect humans and other animals, causing hemorrhagic fever with a high mortality rate. Entry of these viruses into the host is mediated by a single filoviral glycoprotein (GP). GP is composed of two subunits: GP1, which is responsible for attachment and binding to receptor(s) on susceptible cells, and GP2, which mediates viral and cell membrane fusion. Although numerous host factors have been implicated in the entry process, the initial attachment receptor(s) has not been well defined. In this report, we demonstrate that exostosin 1 (EXT1), which is involved in biosynthesis of heparan sulfate (HS), plays a role in filovirus entry. Expression knockdown of EXT1 by small interfering RNAs (siRNAs) impairs GP-mediated pseudoviral entry and that of infectious EBOV and MARV in tissue cultured cells. Furthermore, HS, heparin, and other related glycosaminoglycans (GAGs), to different extents, can bind to and block GP-mediated viral entry and that of infectious filoviruses. These results strongly suggest that HS and other related GAGs are attachment receptors that are utilized by filoviruses for entry and infection. These GAGs may have therapeutic potential in treating EBOV- and MARV-infected patients. IMPORTANCE: Infection by Ebola virus and Marburg virus can cause severe illness in humans, with a high mortality rate, and currently there is no FDA-approved vaccine or therapeutic treatment available. The ongoing 2014 outbreak in West Africa underscores a lack of our understanding in the infection and pathogenesis of these viruses and the urgency of drug discovery and development. In this study, we provide several pieces of evidence that demonstrate that heparan sulfate and other closely related glycosaminoglycans are the molecules that are used by filoviruses for initial attachment. Furthermore, we demonstrate that these glycosaminoglycans can block entry of and infection by filoviruses. Thus, this work provides mechanistic insights on the early step of filoviral infection and suggests a possible therapeutic option for diseases caused by filovirus infection.

Female Sex Offenders: Public Awareness and Attributions.

Traditional gender roles, sex scripts, and the way female sex offenders are portrayed in the media may lead to misconceptions about who can commit sexual offenses. Sexual crimes by women may go unnoticed or unreported if there is a general lack of awareness that females commit these crimes. Data from the 2012 Nebraska Annual Social Indicators Survey were used to determine whether the public perceives women as capable sex offenders and the perceived causes of female sex offending. The traditional focus on male sex offenders by researchers, media, and politicians, in addition to gender stereotypes, introduces the possibility of group differences (e.g., between men and women) in perceptions of female sex offenders. Consequently, two secondary analyses were conducted that tested for group differences in both the public's perception of whether females can commit sex offenses and the explanations selected for why females sexually offend. The findings suggest that the public does perceive women as capable sex offenders, although there were group differences in the causal attributions for female sex offending.

Delayed treatment of Ebola virus infection with plant-derived monoclonal antibodies provides protection in rhesus macaques.

Filovirus infections can cause a severe and often fatal disease in humans and nonhuman primates, including great apes. Here, three anti-Ebola virus mouse/human chimeric mAbs (c13C6, h-13F6, and c6D8) were produced in Chinese hamster ovary and in whole plant (Nicotiana benthamiana) cells. In pilot experiments testing a mixture of the three mAbs (MB-003), we found that MB-003 produced in both manufacturing systems protected rhesus macaques from lethal challenge when administered 1 h postinfection. In a pivotal follow-up experiment, we found significant protection (P < 0.05) when MB-003 treatment began 24 or 48 h postinfection (four of six survived vs. zero of two controls). In all experiments, surviving animals that received MB-003 experienced little to no viremia and had few, if any, of the clinical symptoms observed in the controls. The results represent successful postexposure in vivo efficacy by a mAb mixture and suggest that this immunoprotectant should be further pursued as a postexposure and potential therapeutic for Ebola virus exposure.

Repurposing of clinically developed drugs for treatment of Middle East respiratory syndrome coronavirus infection.

Outbreaks of emerging infections present health professionals with the unique challenge of trying to select appropriate pharmacologic treatments in the clinic with little time available for drug testing and development. Typically, clinicians are left with general supportive care and often untested convalescent-phase plasma as available treatment options. Repurposing of approved pharmaceutical drugs for new indications presents an attractive alternative to clinicians, researchers, public health agencies, drug developers, and funding agencies. Given the development times and manufacturing requirements for new products, repurposing of existing drugs is likely the only solution for outbreaks due to emerging viruses. In the studies described here, a library of 290 compounds was screened for antiviral activity against Middle East respiratory syndrome coronavirus (MERS-CoV) and severe acute respiratory syndrome coronavirus (SARS-CoV). Selection of compounds for inclusion in the library was dependent on current or previous FDA approval or advanced clinical development. Some drugs that had a well-defined cellular pathway as target were included. In total, 27 compounds with activity against both MERS-CoV and SARS-CoV were identified. The compounds belong to 13 different classes of pharmaceuticals, including inhibitors of estrogen receptors used for cancer treatment and inhibitors of dopamine receptor used as antipsychotics. The drugs identified in these screens provide new targets for in vivo studies as well as incorporation into ongoing clinical studies.

The Dangers of Short-Term Confinement: Indicators of Safety Risks Among Individuals in Jail.

Guided by the premise that an individual's safety may be more at risk when their routines, personal attributes, or lack of guardianship influence their opportunity for exposure to violence, we examined the factors that influenced victimization risks and safety perceptions among a representative sample of respondents incarcerated at a large Midwestern jail. Results showed that vulnerable individuals such as those who were victimized prior to their incarceration, and those who antagonized others such as those who perpetrated assault, were threatened more often, were more at risk of assault victimization, and perceived more dangerous conditions. Conversely, females and individuals with greater self-control were less likely to have experienced victimization and generally felt safer in jail. Our results illustrate the importance of identifying and protecting individuals who might experience greater safety risks during jail incarceration and should be interpreted alongside research and policy aimed at improving safety and welfare within correctional institutions.

Independent Evaluation of Two Prototype Immunochromatographic Tests for Dengue Fever Developed by InBios.

INTRODUCTION: Dengue fever, caused by any of the four dengue viruses (DENV1-4), is endemic in more than 100 countries around the world. Each year, up to 400 million people get infected with dengue virus. It is one of the most important arthropod-borne viral diseases. Dengue's global presence poses a medical threat to deploying military personnel and their dependents. An accurate diagnosis followed by attentive supportive care can improve outcomes in patients with severe dengue disease. Dengue diagnostic tests based on PCR and ELISA platforms have been developed and cleared by the U.S. FDA. However, these diagnostic assays are laborious and usually require highly trained personnel and specialized equipment, which presents a significant challenge when conducting operations in austere and resource-constrained areas. InBios International, Inc. (Seattle, WA) has developed two rapid and instrument-free immunochromatographic test prototype devices (multiplex and traditional formats) for dengue diagnosis. MATERIALS AND METHODS: To determine the performance of the InBios immunochromatographic tests, 183 clinical samples were tested on both prototype devices. Both assays were performed without any instruments and the results were read in 20 minutes. RESULTS: The traditional format had better overall performance (sensitivity: 97.4%; specificity: 90%) than the multiplex format (sensitivity: 86.9%; specificity: 63.3%). The traditional format was superior in serotype-specific detection with 100% overall sensitivity for DENV1, DENV3, and DENV4 and 93.3% sensitivity for DENV2 compared to the multiplex format (91.7%, 78.3%, 83.3%, and 96.3% for DENV1, 2, 3, and 4, respectively). The traditional format was easier to read than the multiplex format. The multiplex format was simpler and faster to set up than the traditional format. CONCLUSIONS: The InBios traditional format had a better overall performance and readability profile than the multiplex format, while the multiplex format was easier to set up. Both formats were highly sensitive and specific, were easy to perform, and did not require sophisticated equipment. They are ideal for use in resource-limited settings where dengue is endemic. Based on our overall assessment, the traditional format should be considered for further development and used in the upcoming multicenter clinical trial toward FDA clearance.

Binaural advantages in a real-world environment on speech intelligibility, response time, and subjective listening difficulty.

This study examined the speech-related advantages of binaural listening for individuals conversing in a noisy restaurant. Young, normal-hearing adults were tested in groups of four during monaural and binaural listening conditions. Monosyllabic word stimuli were presented in a closed-set format. Speech intelligibility, response time (RT), and self-reported difficulty were measured. Results showed a speech intelligibility advantage of 17%, a 0.26 s decrease in RT, and a reduction in reported difficulty in binaural compared to monaural listening. These data suggest the binaural advantage obtained in real-world settings compares favorably with that observed in the laboratory, indicating that speech testing in laboratories approximates real-world performance.

Ultrasound Guided Transversus Thoracic Plane block, Parasternal block and fascial planes hydrodissection for internal mammary post thoracotomy pain syndrome.

INTRODUCTION: Pectoral Nerves Block (PECS) and Serratus Plane Block (SPB) have been used to treat persistent post-surgical pain after breast and thoracic surgery; however, they cannot block the internal mammary region, so a residual pain may occur in that region. Parasternal block (PSB) and Thoracic Transversus Plane Block (TTP) anaesthetize the anterior branches of T2-6 intercostal nerves thus they can provide analgesia to the internal mammary region. METHODS: We describe a 60-year-old man suffering from right post-thoracotomy pain syndrome with residual pain located in the internal mammary region after a successful treatment with PECS and SPB. We performed a PSB and TTP and hydrodissection of fascial planes with triamcinolone and Ropivacaine. RESULTS: Pain disappeared and the result was maintained 3 months later. DISCUSSION: This report suggests that PSB and TTP with local anaesthetic and corticosteroid with hydrodissection of fascial planes might be useful to treat a post thoracotomy pain syndrome located in the internal mammary region. SIGNIFICANCE: The use of Transversus Thoracic Plane and Parasternal Blocks and fascial planes hydrodissection as a novel therapeutic approach to treat a residual post thoracotomy pain syndrome even when already treated with Pectoral Nerves Block and Serratus Plane Block.

The Impact of Inmate and Prison Characteristics on Prisoner Victimization.

A considerable amount of research has been directed at understanding the sources of inmate misconduct (offending within prison), whereas few studies have focused on identifying the causes and correlates of prisoner victimization. The sources of inmate victimization should be distinguished from those of offending, however, because the policy implications of each focus differ to some extent. In order to determine the predictors of inmate victimization and stimulate further research on the topic, we systematically reviewed studies of the causes/correlates of prisoner victimization published between 1980 and 2014. Our findings revealed that predictor variables reflecting inmates' background characteristics (e.g., history of victimization), their institutional routines and experiences (e.g., history of misconduct), and prison characteristics (e.g., population size) all influence victimization.

A screen of approved drugs and molecular probes identifies therapeutics with anti-Ebola virus activity.

Currently, no approved therapeutics exist to treat or prevent infections induced by Ebola viruses, and recent events have demonstrated an urgent need for rapid discovery of new treatments. Repurposing approved drugs for emerging infections remains a critical resource for potential antiviral therapies. We tested ~2600 approved drugs and molecular probes in an in vitro infection assay using the type species, Zaire ebolavirus. Selective antiviral activity was found for 80 U.S. Food and Drug Administration-approved drugs spanning multiple mechanistic classes, including selective estrogen receptor modulators, antihistamines, calcium channel blockers, and antidepressants. Results using an in vivo murine Ebola virus infection model confirmed the protective ability of several drugs, such as bepridil and sertraline. Viral entry assays indicated that most of these antiviral drugs block a late stage of viral entry. By nature of their approved status, these drugs have the potential to be rapidly advanced to clinical settings and used as therapeutic countermeasures for Ebola virus infections.

The cyanobacterial lectin scytovirin displays potent in vitro and in vivo activity against Zaire Ebola virus.

The cyanobacterial lectin scytovirin (SVN) binds with high affinity to mannose-rich oligosaccharides on the envelope glycoprotein (GP) of a number of viruses, blocking entry into target cells. In this study, we assessed the ability of SVN to bind to the envelope GP of Zaire Ebola virus (ZEBOV) and inhibit its replication. SVN interacted specifically with the protein's mucin-rich domain. In cell culture, it inhibited ZEBOV replication with a 50% virus-inhibitory concentration (EC50) of 50 nM, and was also active against the Angola strain of the related Marburg virus (MARV), with a similar EC50. Injected subcutaneously in mice, SVN reached a peak plasma level of 100 nm in 45 min, but was cleared within 4h. When ZEBOV-infected mice were given 30 mg/kg/day of SVN by subcutaneous injection every 6h, beginning the day before virus challenge, 9 of 10 animals survived the infection, while all infected, untreated mice died. When treatment was begun one hour or one day after challenge, 70-90% of mice survived. Quantitation of infectious virus and viral RNA in samples of serum, liver and spleen collected on days 2 and 5 postinfection showed a trend toward lower titers in treated than control mice, with a significant decrease in liver titers on day 2. Our findings provide further evidence of the potential of natural lectins as therapeutic agents for viral infections.