Behind the Headset: Predictive Accuracy of Patient-Reported Outcome Measures for Voice Symptoms in Call Centers

Objective: This study examines factors predicting self-reported voice symptoms in call center workers. Methods: Multivariate analysis and predictive modeling assess personal, work-related, acoustic, and behavioral factors. Generalized Linear Models (GLMs) and Receiver Operating Characteristic (ROC) curves are employed. Results: Age and sleep patterns impacted voice quality and effort, while workplace factors influenced symptom perception. Unhealthy vocal behaviors related to tense voice and increased effort, while hydration was protective. Voice acoustics showed diagnostic potential, supported by ROC data. These findings emphasize voice symptom complexity in call center professionals, necessitating comprehensive assessment. Limitations: This study recognizes its limitations, including a moderate-sized convenience sample and reliance on PROM metrics. Future research should incorporate more objective measures in addition to self-reports and acoustic analysis. Value: This research provides novel insights into the interplay of personal, occupational, and voice-related factors in developing voice symptoms among call center workers. Predictive modeling enhances risk assessment and understanding of individual susceptibility to voice disorders. Conclusion: Results show associations between various factors and self-reported voice symptoms. Protective factors include sleeping more than six hours and consistent hydration, whereas risk factors include working conditions, such as location and behaviors like smoking. Diagnostic models indicate good accuracy for some voice symptom PROMs, emphasizing the need for comprehensive models considering work factors, vocal behaviors, and acoustic parameters to understand voice issues complexity.

Objetivo: Este estudio examina los factores que predicen los síntomas de voz en los trabajadores de call centers. Métodos: Se utilizan análisis multivariados y modelos predictivos para evaluar factores personales, laborales, acústicos y de comportamiento. Se emplean Modelos Lineales Generalizados (GLM) y curvas ROC. Resultados: La edad y los patrones de sueño afectaron la calidad vocal y el esfuerzo, mientras que los factores laborales influyeron en la percepción de síntomas. Los comportamientos vocales no saludables se relacionaron con voz tensa y mayor esfuerzo, mientras que la hidratación fue protectora. Los parámetros acústicos de voz mostraron potencial diagnóstico respaldado por datos de ROC. Los hallazgos subrayan complejidad de síntomas vocales en profesionales de centros de llamadas, requiriendo una evaluación integral. Limitaciones: Este estudio reconoce sus limitaciones, que incluyen una muestra de conveniencia de tamaño moderado y la dependencia de medidas PROMs. Futuras investigaciones deberían incorporar medidas objetivas, además de los autorreportes y análisis acústico. Importancia: Esta investigación aporta nuevos conocimientos sobre factores personales, laborales y síntomas de voz en trabajadores de call centers. El modelado predictivo mejora la evaluación de riesgos y la comprensión de la susceptibilidad individual a trastornos de la voz. Conclusión: Los resultados muestran asociaciones entre diversos factores y los síntomas vocales reportados. Los factores de protección incluyen dormir más de seis horas y una hidratación constante; los factores de riesgo incluyen las condiciones de trabajo, como la ubicación y comportamientos como fumar. Los modelos de diagnóstico indican una buena precisión para algunas PROMs de síntomas de la voz, lo que subraya la necesidad de modelos integrales que tengan en cuenta los factores laborales, los comportamientos vocales y los parámetros acústicos para comprender la complejidad de los problemas de la voz.

Exploring the Feasibility of a Comprehensive Screening for Voice and Swallowing Function in Post-Extubation Patients: A Pilot Study

Objectives: This pilot study aimed to identify and test a battery of time-efficient and cost-effective voice and swallowing screening tools for post-extubated patients in Chile. Methods: A panel of four experts selected and rated voice and swallowing screening tools. Seven measures were selected: smoothed cepstral peak prominence (CPPS) and maximum phonation time (MPT) for voice assessment, Volume-Viscosity Swallow Test (V-VST) for swallowing, voluntary and reflex peak cough flow for cough assessment, Eating Assessment Tool-10 (EAT-10), and Vocal Symptom Scale (VoiSS) for patient-reported outcomes. These tools were applied to four post-extubation patients within 48-72 hours post-hospital discharge, alongside the assessment of 17 matched controls. Results: Post-extubation patients showed significantly shorter MPT, lower CPPS values, increased V-VST dysphagia signs, reduced voluntary peak cough flow, and more pronounced symptoms on both the VoiSS and EAT-10 compared to controls. Limitations: The study had a modest sample size and relied solely on clinical screening tools. Value: This pilot study suggests a feasible and cost-effective approach to voice and swallowing screening for post-extubation patients, valuable in resource-constrained settings. Conclusion: While these accessible tools are not gold-standard assessments, they offer valuable insights and can guide future research. This study underscores the potential of selected tools in facilitating early detection of voice and swallowing disorders in post-extubation patients.

Objetivos: Este estudio piloto tuvo como objetivo identificar y probar una batería de herramientas de detección de problemas de voz y deglución que fueran eficientes en cuanto a tiempo y costo para pacientes chilenos postextubados. Métodos: Un panel de cuatro expertos seleccionó y evaluó herramientas de detección de voz y deglución. Se seleccionaron siete medidas: prominencia de pico cepstral suavizado (CPPS) y tiempo máximo de fonación (TMF) para la evaluación de la voz, prueba de volumen-viscosidad (V-VST) para la deglución, flujo máximo voluntario y reflejo de la tos para evaluar la tos, Eating Assessment Tool-10 (EAT-10) y la Escala de Sintomas Vocales (ESV) para los resultados informados por los pacientes. Estas herramientas se aplicaron a cuatro pacientes postextubados (48-72 horas), junto con la evaluación de 17 controles pareados. Resultados: Los pacientes postextubados mostraron un TMF y CPPS significativamente más bajos, aumento de los indicios de disfagia en la V-VST, reducción del flujo máximo de la tos y síntomas más pronunciados tanto en la ESV como en la EAT-10 en comparación con los controles. Limitaciones: El estudio tuvo un tamaño de muestra reducida y se basó únicamente en herramientas de detección clínica. Valor: Este estudio piloto sugiere un enfoque factible y rentable para la detección de problemas de voz y deglución en pacientes postextubados, valioso en entornos con recursos limitados. Conclusión: Aunque ese abordaje no sustituye a las evaluaciones de referencia, ofrece información valiosa y puede guiar futuras investigaciones que busquen facilitar la detección temprana de los trastornos de la voz-deglución en pacientes postextubados.

Intradermal but not intramuscular modified vaccinia Ankara immunizations protect against intravaginal tier2 simian-human immunodeficiency virus challenges in female macaques.

Route of immunization can markedly influence the quality of immune response. Here, we show that intradermal (ID) but not intramuscular (IM) modified vaccinia Ankara (MVA) vaccinations provide protection from acquisition of intravaginal tier2 simian-human immunodeficiency virus (SHIV) challenges in female macaques. Both routes of vaccination induce comparable levels of serum IgG with neutralizing and non-neutralizing activities. The protection in MVA-ID group correlates positively with serum neutralizing and antibody-dependent phagocytic activities, and envelope-specific vaginal IgA; while the limited protection in MVA-IM group correlates only with serum neutralizing activity. MVA-ID immunizations induce greater germinal center Tfh and B cell responses, reduced the ratio of Th1 to Tfh cells in blood and showed lower activation of intermediate monocytes and inflammasome compared to MVA-IM immunizations. This lower innate activation correlates negatively with induction of Tfh responses. These data demonstrate that the MVA-ID vaccinations protect against intravaginal SHIV challenges by modulating the innate and T helper responses.

Plasmacytoid dendritic cells have divergent effects on HIV infection of initial target cells and induce a pro-retention phenotype.

Although HIV infection inhibits interferon responses in its target cells in vitro, interferon signatures can be detected in vivo soon after sexual transmission, mainly attributed to plasmacytoid dendritic cells (pDCs). In this study, we examined the physiological contributions of pDCs to early HIV acquisition using coculture models of pDCs with myeloid DCs, macrophages and the resting central, transitional and effector memory CD4 T cell subsets. pDCs impacted infection in a cell-specific manner. In myeloid cells, HIV infection was decreased via antiviral effects, cell maturation and downregulation of CCR5 expression. In contrast, in resting memory CD4 T cells, pDCs induced a subset-specific increase in intracellular HIV p24 protein expression without any activation or increase in CCR5 expression, as measured by flow cytometry. This increase was due to reactivation rather than enhanced viral spread, as blocking HIV entry via CCR5 did not alter the increased intracellular p24 expression. Furthermore, the load and proportion of cells expressing HIV DNA were restricted in the presence of pDCs while reverse transcriptase and p24 ELISA assays showed no increase in particle associated reverse transcriptase or extracellular p24 production. In addition, pDCs also markedly induced the expression of CD69 on infected CD4 T cells and other markers of CD4 T cell tissue retention. These phenotypic changes showed marked parallels with resident memory CD4 T cells isolated from anogenital tissue using enzymatic digestion. Production of IFNα by pDCs was the main driving factor for all these results. Thus, pDCs may reduce HIV spread during initial mucosal acquisition by inhibiting replication in myeloid cells while reactivating latent virus in resting memory CD4 T cells and retaining them for immune clearance.

Utilizing Computational Machine Learning Tools to Understand Immunogenic Breadth in the Context of a CD8 T-Cell Mediated HIV Response.

Predictive models are becoming more and more commonplace as tools for candidate antigen discovery to meet the challenges of enabling epitope mapping of cohorts with diverse HLA properties. Here we build on the concept of using two key parameters, diversity metric of the HLA profile of individuals within a population and consideration of sequence diversity in the context of an individual's CD8 T-cell immune repertoire to assess the HIV proteome for defined regions of immunogenicity. Using this approach, analysis of HLA adaptation and functional immunogenicity data enabled the identification of regions within the proteome that offer significant conservation, HLA recognition within a population, low prevalence of HLA adaptation and demonstrated immunogenicity. We believe this unique and novel approach to vaccine design as a supplement to vitro functional assays, offers a bespoke pipeline for expedited and rational CD8 T-cell vaccine design for HIV and potentially other pathogens with the potential for both global and local coverage.

Impairment, disability, and handicap associated with hearing problems and voice disorders among Colombian teachers / Deficiencia, discapacidad y minusvalía asociadas a los problemas de voz y audición en profesores colombianos

Objectives: 1. define the occurrence of work-related hearing problems and voice disorders among teachers that have contacted the Colombian National Board of Disability Assessment (NBDA) for follow-up; 2. identify individual associated factors of hearing problems and voice disorders among teachers; 3. assess the limitations and restrictions due to hearing problems and voice disorders among these participants. Methods: Retrospective study. The National Database of the Colombian NBDA was reviewed. Information on distributions of occupation, individual characteristics, and diagnosis code (ICD-10) was analyzed. Results: Communication disorders among teachers that have contacted the Colom-bian NBDA for follow-up included voice disorders, with a prevalence of 51%, and hearing problems, with a prevalence of 7%. Female teachers who have contacted the Colombian NBDA for follow-up were 4 times more likely to be identified as having voice disorders compared with their male colleagues. Conclusions: While teachers that have contacted the Colombian NBDA for fol-low-up have a high occurrence of voice disorders, hearing problems are more likely to be stated as a debilitating condition. One possible explanation is that teachers who contacted the Colombian NBDA for follow-up continued working even when many voice symptoms were evident, while hearing problems would prevent a teacher from interacting with students, thereby affecting the teaching-learning process soon-er. Nevertheless, with both voice and hearing problems, work performance and social interaction is affected, and, therefore, quality of life is reduced.

Objetivos: 1. definir la ocurrencia de problemas de audición y de voz relacionados con el trabajo de docentes que contactaron la Junta Nacional de Evaluación de la Discapacidad de Colombia (NBDA) para su seguimiento; 2. identificar los factores individuales asociados a los problemas de audición y voz entre los profesores; 3. eva-luar las limitaciones y restricciones debidas a problemas de audición y voz asociados al trabajo entre los participantes.Métodos: estudio retrospectivo. Se revisó la Base de Datos Nacional de la NBDA colombiana. Se analizó información sobre distribuciones de ocupación, característi-cas individuales y código de diagnóstico (CIE-10).Resultados: Los trastornos de comunicación entre los docentes que han contacta-do a la NBDA colombiana para seguimiento incluyeron problemas de la voz, con una prevalencia del 51%, y problemas de audición, con una prevalencia del 7%. Las pro-fesoras que se han puesto en contacto con la NBDA colombiana para el seguimiento tenían 4 veces más probabilidades de ser identificadas con trastornos de la voz en comparación con sus colegas masculinos.Conclusiones: Si bien los maestros que contactaron a la NBDA colombiana para el seguimiento tienen una alta incidencia de trastornos de la voz, es más probable que los problemas de audición se consideren una condición debilitante. Una posible ex-plicación es que los maestros que se comunicaron con la NBDA colombiana para el seguimiento continuaron trabajando incluso cuando muchos síntomas vocales eran evidentes, mientras que los problemas de audición evitarían que un maestro inte-ractuara con los estudiantes, afectando así el proceso de enseñanza-aprendizaje. Sin embargo, tanto con los problemas de voz como de audición, el desempeño laboral y la interacción social se ven afectados y, por lo tanto, la calidad de vida se reduce.

T cell-inducing vaccine durably prevents mucosal SHIV infection even with lower neutralizing antibody titers.

Recent efforts toward an HIV vaccine focus on inducing broadly neutralizing antibodies, but eliciting both neutralizing antibodies (nAbs) and cellular responses may be superior. Here, we immunized macaques with an HIV envelope trimer, either alone to induce nAbs, or together with a heterologous viral vector regimen to elicit nAbs and cellular immunity, including CD8+ tissue-resident memory T cells. After ten vaginal challenges with autologous virus, protection was observed in both vaccine groups at 53.3% and 66.7%, respectively. A nAb titer >300 was generally associated with protection but in the heterologous viral vector + nAb group, titers <300 were sufficient. In this group, protection was durable as the animals resisted six more challenges 5 months later. Antigen stimulation of T cells in ex vivo vaginal tissue cultures triggered antiviral responses in myeloid and CD4+ T cells. We propose that cellular immune responses reduce the threshold of nAbs required to confer superior and durable protection.

Better Viral Control despite Higher CD4+ T Cell Activation during Acute HIV-1 Infection in Zambian Women Is Linked to the Sex Hormone Estradiol.

The influence of biological sex on disease progression in HIV-1-infected individuals has been focused on the chronic stage of infection, but little is known about how sex differences influence acute HIV-1 infection. We observed profound differences in viral load and CD4+ T cell activation from the earliest time points in men and women in a Zambian heterosexual acute infection cohort. Women exhibited a >2-fold higher rate of CD4+ T cell loss despite significantly lower viral loads (VL) than men. The importance of studying acute infection was highlighted by the observation that very early in infection, women exhibited significantly higher levels of CD4+ T cell activation, a difference that was lost over the first 3 years of infection as activation in men increased. In women, activation of CD4+ T cells in the acute phase was significantly correlated with plasma levels of 17ß-estradiol (E2). However, unlike in men, higher CD4+ T cell activation in women was not associated with higher VL. In contrast, a higher E2 level in early infection was associated with lower early and set-point VL in women. We attribute this to an inhibitory effect of estradiol on virus replication, which we were able to observe with relevant transmitted/founder viruses in vitro Thus, estradiol plays a key role in defining major differences between men and women during early HIV-1 infection by contributing to both viral control and CD4+ T cell loss, an effect that extends into the chronic phase of the disease.IMPORTANCE Previous studies have identified sex-specific differences during chronic HIV-1 infection, but little is known about sex differences in the acute phase, or how disparities in the initial response to the virus may affect disease. We demonstrate that restriction of viral load in women begins during acute infection and is maintained into chronic infection. Despite this, women exhibit more rapid CD4+ T cell loss than men. These profound differences are influenced by 17ß-estradiol, which contributes both to T cell activation and to reduced viral replication. Thus, we conclude that estradiol plays a key role in shaping responses to early HIV-1 infection that influence the chronic phase of disease.

Translation and Adaptation of the Vocal Fatigue Index into Spanish / Traducción y adaptación del Índice de Fatiga Vocal al español

Aim: the purpose of this study was to translate and adapt the English version of the Vocal Fatigue Index (VFI) into the Spanish language. Methods: the English version of the Vocal Fatigue Index (VFI) was translated into Spanish by two bilingual speech-language pathologists, and then was back-translated into English. The Spanish VFI (o "Índice de Fatiga Vocal", IFV) was administrated to a pilot group of 10 individuals, which revealed some small typographical and grammati-cal adjustments to the index. The final updated version was then administrated to 34 subjects (21 with voice disorders, and 13 without voice disorders). Internal consistency and scale reliability were analyzed using Cronbach alpha coefficient. Results: a high Cronbach alpha coefficient for the three factors (0.87) was obtained. The results of the item role in reliability of the Spanish VFI demonstrated that all of them showed a positive role according to this criterion. The results of the ANOVA indicate a statistically significant difference between groups on the three scores of the Spanish translation of the VFI. In comparison to the healthy participants, those with voice disorders obtained statistically significant higher scores for the Spanish VFI subscales. Conclusion: the present study suggests that the Spanish translation of the Vocal Fatigue Index has a good internal consistency and high reliability on each of the three factors. The results suggest that the Spanish VFI can be used reliably to identify persons with vocal fatigue and has good clinical validity.

Objetivo: el propósito de este estudio fue traducir y adaptar la versión en inglés del Índice de Fatiga Vocal (VFI) al español. Métodos: la versión en Inglés del Índice de Fatiga Vocal (VFI) fue traducida al espa-ñol por dos fonoaudiólogos bilingües, y después traducida de vuelta al inglés. El VFI en español (o IFV) fue administrado a un grupo piloto de 10 sujetos, lo que reveló pequeños errores tipográficos y gramaticales, los cuales fueron corregidos. La versión final fue administrada a 34 sujetos (21 con desordenes de voz y 13 sin desordenes de voz). El análisis de datos incluyó evaluación de consistencia interna y fiabilidad usan-do el coeficiente Alpha de Cronbach. Resultados: se encontró un coeficiente Alpha de Cronbach alto para los tres fac-tores (0.87). Los resultados del rol de los elementos en la fiabilidad del IFV en espa-ñol sugieren que todos tienen roles positivos dentro de este criterio. Los resultados del análisis de ANOVA indican diferencias estadísticamente significativas entre los grupos en los tres componentes de la versión en español del VFI. En comparación con los participantes sanos, los participantes con problemas de voz tuvieron puntajes significativamente más altos en las subescalas del VFI en español. Conclusión: este estudio sugiere que la traducción al español del Índice de Fatiga Vocal tiene buena consistencia interna y alta fiabilidad en los tres factores. Los resul-tados sugieren que el IFV en español puede ser usado con fiabilidad para identificar personas con fatiga vocal con una buena validez clínica.

Vaccine induction of antibodies and tissue-resident CD8+ T cells enhances protection against mucosal SHIV-infection in young macaques.

Antibodies and cytotoxic T cells represent 2 arms of host defense against pathogens. We hypothesized that vaccines that induce both high-magnitude CD8+ T cell responses and antibody responses might confer enhanced protection against HIV. To test this hypothesis, we immunized 3 groups of nonhuman primates: (a) Group 1, which includes sequential immunization regimen involving heterologous viral vectors (HVVs) comprising vesicular stomatitis virus, vaccinia virus, and adenovirus serotype 5-expressing SIVmac239 Gag; (b) Group 2, which includes immunization with a clade C HIV-1 envelope (Env) gp140 protein adjuvanted with nanoparticles containing a TLR7/8 agonist (3M-052); and (c) Group 3, which includes a combination of both regimens. Immunization with HVVs induced very high-magnitude Gag-specific CD8+ T cell responses in blood and tissue-resident CD8+ memory T cells in vaginal mucosa. Immunization with 3M-052 adjuvanted Env protein induced robust and persistent antibody responses and long-lasting innate responses. Despite similar antibody titers in Groups 2 and 3, there was enhanced protection in the younger animals in Group 3, against intravaginal infection with a heterologous SHIV strain. This protection correlated with the magnitude of the serum and vaginal Env-specific antibody titers on the day of challenge. Thus, vaccination strategies that induce both CD8+ T cell and antibody responses can confer enhanced protection against infection.

Comparison of Pitch Strength With Perceptual and Other Acoustic Metric Outcome Measures Following Medialization Laryngoplasty.

INTRODUCTION: The diagnoses of voice disorders, as well as treatment outcomes, are often tracked using visual (eg, stroboscopic images), auditory (eg, perceptual ratings), objective (eg, from acoustic or aerodynamic signals), and patient report (eg, Voice Handicap Index and Voice-Related Quality of Life) measures. However, many of these measures are known to have low to moderate sensitivity and specificity for detecting changes in vocal characteristics, including vocal quality. OBJECTIVE: The objective of this study was to compare changes in estimated pitch strength (PS) with other conventionally used acoustic measures based on the cepstral peak prominence (smoothed cepstral peak prominence, cepstral spectral index of dysphonia, and acoustic voice quality index), and clinical judgments of voice quality (GRBAS [grade, roughness, breathiness, asthenia, strain] scale) following laryngeal framework surgery. METHODS: This study involved post hoc analysis of recordings from 22 patients pretreatment and post treatment (thyroplasty and behavioral therapy). Sustained vowels and connected speech were analyzed using objective measures (PS, smoothed cepstral peak prominence, cepstral spectral index of dysphonia, and acoustic voice quality index), and these results were compared with mean auditory-perceptual ratings by expert clinicians using the GRBAS scale. RESULTS: All four acoustic measures changed significantly in the direction that usually indicates improved voice quality following treatment (P < 0.005). Grade and breathiness correlated the strongest with the acoustic measures (|r| ~ 0.7) with strain being the least correlated. CONCLUSIONS: Acoustic analysis on running speech highly correlates with judged ratings. PS is a robust, easily obtained acoustic measure of voice quality that could be useful in the clinical environment to follow treatment of voice disorders.

Work-related communicative profile of radio broadcasters: a case study.

Purpose: To explore the short-term effect of work-related voice use on voice function, and noise exposure on hearing function among radio broadcasters. Method: A 1-week follow-up study with the participation of two radio broadcasters was conducted. Participants were monitored at the beginning and at the end of the working week. Premonitoring assessment on Monday (baseline measure) and postmonitoring assessment on Friday (follow-up measure) were performed to identify short-term effects of work-related conditions on voice and hearing function among radio broadcasters. Result: Changes in fundamental frequency postmonitoring at the end of the work week may be an indication of work-related vocal fatigue. Changes in the distribution and standard deviation of SPL during the monitoring from Monday to Friday may indicate control of the vocal loudness as a strategy to reduce vocal effort during broadcasting. During a 1-week follow-up, noise conditions during radio broadcasting were below occupational exposure limits and without noticeable consequences on hearing function. Conclusion: The work-related communicative profile of radio broadcasting, from this pilot study, suggests that although vocal demands in terms of vocal load may differ among broadcasters, the work-related conditions of broadcasting may play a role on vocal function among these occupational voice users. Concerning hearing function, our results indicate that occupational noise exposure represented minimal risk for hearing problems but the consequences of long-term noise exposure on hearing mechanisms may yet occur. Future studies with bigger sample sizes are warranted to confirm our results.

HIV testing and counselling couples together for affordable HIV prevention in Africa.

BACKGROUND: The impact and cost-effectiveness of couples' voluntary HIV counselling and testing (CVCT) has not been quantified in real-world settings. We quantify cost-per-HIV-infection averted by CVCT in Zambia from the donor's perspective. METHODS: From 2010 to 2016, CVCT was established in 73 Zambian government clinics. The cost-per-HIV-infection averted (CHIA) of CVCT was calculated using observed expenditures and effectiveness over longitudinal follow-up. These observed measures parameterized hypothetical 5-year nationwide implementations of: 'CVCT'; 'treatment-as-prevention (TasP) for discordant couples' identified by CVCT; and 'population TasP' for all HIV+ cohabiting persons identified by individual testing. RESULTS: In all, 207 428 couples were tested (US $52/couple). Among discordant couples in which HIV+ partners self-reported antiretroviral therapy (ART), HIV incidence was 8.5/100 person-years before and 1.8/100 person-years after CVCT (79% reduction). Corresponding reductions for non-ART-using discordant and concordant negative couples were 63% and 47%, respectively. CVCT averted an estimated 58% of new infections at US $659 CHIA. In nationwide implementation models, CVCT would prevent 17 times the number of infections vs 'TasP for discordant couples' at 86% of the cost, and nine times the infections vs 'population TasP' at 28% of the cost. CONCLUSIONS: CVCT is a cost-effective, feasible prevention strategy in Zambia. We demonstrate the novel, added effectiveness of providing CVCT to ART users, for whom ART use alone only partially mitigated transmission risk. Our results indicate a major policy shift (supporting development of CVCT indicators, budgets and targets) and have clinical implications (suggesting promotion of CVCT in ART clinics as a high-impact prevention strategy).

Mason-Pfizer Monkey Virus Envelope Glycoprotein Cycling and Its Vesicular Co-Transport with Immature Particles.

The envelope glycoprotein (Env) plays a crucial role in the retroviral life cycle by mediating primary interactions with the host cell. As described previously and expanded on in this paper, Env mediates the trafficking of immature Mason-Pfizer monkey virus (M-PMV) particles to the plasma membrane (PM). Using a panel of labeled RabGTPases as endosomal markers, we identified Env mostly in Rab7a- and Rab9a-positive endosomes. Based on an analysis of the transport of recombinant fluorescently labeled M-PMV Gag and Env proteins, we propose a putative mechanism of the intracellular trafficking of M-PMV Env and immature particles. According to this model, a portion of Env is targeted from the trans-Golgi network (TGN) to Rab7a-positive endosomes. It is then transported to Rab9a-positive endosomes and back to the TGN. It is at the Rab9a vesicles where the immature particles may anchor to the membranes of the Env-containing vesicles, preventing Env recycling to the TGN. These Gag-associated vesicles are then transported to the plasma membrane.

Characterization of the Plasmacytoid Dendritic Cell Response to Transmitted/Founder and Nontransmitted Variants of HIV-1.

Human immunodeficiency virus type 1 (HIV-1) infection often arises from a single transmitted/founder (TF) viral variant among a large pool of viruses in the quasispecies in the transmitting partner. TF variants are typically nondominant in blood and genital secretions, indicating that they have unique traits. The plasmacytoid dendritic cell (pDC) is the primary alpha interferon (IFN-α)-producing cell in response to viral infections and is rapidly recruited to the female genital tract upon exposure to HIV-1. The impact of pDCs on transmission is unknown. We investigated whether evasion of pDC responses is a trait of TF viruses. pDCs from healthy donors were stimulated in vitro with a panel of 20 HIV-1 variants, consisting of one TF variant and three nontransmitted (NT) variants each from five transmission-linked donor pairs, and secretion of IFN-α and tumor necrosis factor alpha (TNF-α) was measured by enzyme-linked immunosorbent assay (ELISA). No significant differences in cytokine secretion in response to TF and NT viruses were observed, despite a trend toward enhanced IFN-α and TNF-α production in response to TF viruses. NT viruses demonstrated polarization toward production of either IFN-α or TNF-α, indicating possible dysregulation. Also, for NT viruses, IFN-α secretion was associated with increased resistance of the virus to inactivation by IFN-α in vitro, suggesting in vivo evolution. Thus, TF viruses do not appear to preferentially subvert pDC activation compared to that with nontransmitted HIV-1 variants. pDCs may, however, contribute to the in vivo evolution of HIV-1.IMPORTANCE The plasmacytoid dendritic cell (pDC) is the first cell type recruited to the site of HIV-1 exposure; however, its contribution to the viral bottleneck in HIV-1 transmission has not been explored previously. We hypothesized that transmitted/founder viruses are able to avoid the pDC response. In this study, we used previously established donor pair-linked transmitted/founder and nontransmitted (or chronic) variants of HIV-1 to stimulate pDCs. Transmitted/founder HIV-1, instead of suppressing pDC responses, induced IFN-α and TNF-α secretion to levels comparable to those induced by viruses from the transmitting partner. We noted several unique traits of chronic viruses, including polarization between IFN-α and TNF-α production as well as a strong relationship between IFN-α secretion and the resistance of the virus to neutralization. These data rule out the possibility that TF viruses preferentially suppress pDCs in comparison to the pDC response to nontransmitted HIV variants. pDCs may, however, be important drivers of viral evolution in vivo.

Risk of heterosexual HIV transmission attributable to sexually transmitted infections and non-specific genital inflammation in Zambian discordant couples, 1994-2012.

Background: Studies have demonstrated the role of ulcerative and non-ulcerative sexually transmitted infections (STI) in HIV transmission/acquisition risk; less is understood about the role of non-specific inflammatory genital abnormalities. Methods: HIV-discordant heterosexual Zambian couples were enrolled into longitudinal follow-up (1994-2012). Multivariable models estimated the effect of genital ulcers and inflammation in both partners on time-to-HIV transmission within the couple. Population-attributable fractions (PAFs) were calculated. Results: A total of 207 linked infections in women occurred over 2756 couple-years (7.5/100 CY) and 171 in men over 3216 CY (5.3/100 CY). Incident HIV among women was associated with a woman's non-STI genital inflammation (adjusted hazard ratio (aHR) = 1.55; PAF = 8%), bilateral inguinal adenopathy (BIA; aHR = 2.33; PAF = 8%), genital ulceration (aHR = 2.08; PAF = 7%) and the man's STI genital inflammation (aHR = 3.33; PAF = 5%), BIA (aHR = 3.35; PAF = 33%) and genital ulceration (aHR = 1.49; PAF = 9%). Infection among men was associated with a man's BIA (aHR = 4.11; PAF = 22%) and genital ulceration (aHR = 3.44; PAF = 15%) as well as with the woman's non-STI genital inflammation (aHR = 1.92; PAF = 13%) and BIA (aHR = 2.76; PAF = 14%). In HIV-M+F- couples, the man being uncircumcised. with foreskin smegma. was associated with the woman's seroconversion (aHR = 3.16) relative to being circumcised. In F+M- couples, uncircumcised men with BIA had an increased hazard of seroconversion (aHR = 13.03 with smegma and 4.95 without) relative to being circumcised. Self-reporting of symptoms was low for ulcerative and non-ulcerative STIs. Conclusions: Our findings confirm the role of STIs and highlight the contribution of non-specific genital inflammation to both male-to-female and female-to-male HIV transmission/acquisition risk. Studies are needed to characterize pathogenesis of non-specific inflammation including inguinal adenopathy. A better understanding of genital practices could inform interventions.

Adjuvanting a Simian Immunodeficiency Virus Vaccine with Toll-Like Receptor Ligands Encapsulated in Nanoparticles Induces Persistent Antibody Responses and Enhanced Protection in TRIM5α Restrictive Macaques.

Our previous work has shown that antigens adjuvanted with ligands specific for Toll-like receptor 4 (TLR4) and TLR7/8 encapsulated in poly(lactic-co-glycolic) acid (PLGA)-based nanoparticles (NPs) induce robust and durable immune responses in mice and macaques. We investigated the efficacy of these NP adjuvants in inducing protective immunity against simian immunodeficiency virus (SIV). Rhesus macaques (RMs) were immunized with NPs containing TLR4 and TLR7/8 agonists mixed with soluble recombinant SIVmac239-derived envelope (Env) gp140 and Gag p55 (protein) or with virus-like particles (VLPs) containing SIVmac239 Env and Gag. NP-adjuvanted vaccines induced robust innate responses, antigen-specific antibody responses of a greater magnitude and persistence, and enhanced plasmablast responses compared to those achieved with alum-adjuvanted vaccines. NP-adjuvanted vaccines induced antigen-specific, long-lived plasma cells (LLPCs), which persisted in the bone marrow for several months after vaccination. NP-adjuvanted vaccines induced immune responses that were associated with enhanced protection against repeated low-dose, intravaginal challenges with heterologous SIVsmE660 in animals that carried TRIM5α restrictive alleles. The protection induced by immunization with protein-NP correlated with the prechallenge titers of Env-specific IgG antibodies in serum and vaginal secretions. However, no such correlate was apparent for immunization with VLP-NP or alum as the adjuvant. Transcriptional profiling of peripheral blood mononuclear cells isolated within the first few hours to days after primary vaccination revealed that NP-adjuvanted vaccines induced a molecular signature similar to that induced by the live attenuated yellow fever viral vaccine. This systems approach identified early blood transcriptional signatures that correlate with Env-specific antibody responses in vaginal secretions and protection against infection. These results demonstrate the adjuvanticity of the NP adjuvant in inducing persistent and protective antibody responses against SIV in RMs with implications for the design of vaccines against human immunodeficiency virus (HIV). IMPORTANCE: The results of the RV144 HIV vaccine trial, which demonstrated a rapid waning of protective immunity with time, have underscored the need to develop strategies to enhance the durability of protective immune responses. Our recent work in mice has highlighted the capacity of nanoparticle-encapsulated TLR ligands (NP) to induce potent and durable antibody responses that last a lifetime in mice. In the present study, we evaluated the ability of these NP adjuvants to promote robust and durable protective immune responses against SIV in nonhuman primates. Our results demonstrate that immunization of rhesus macaques with NP adjuvants mixed with soluble SIV Env or a virus-like particle form of Env (VLP) induces potent and durable Env-specific antibody responses in the serum and in vaginal secretions. These responses were superior to those induced by alum adjuvant, and they resulted in enhanced protection against a low-dose intravaginal challenge with a heterologous strain of SIV in animals with TRIM5a restrictive alleles. These results highlight the potential for such NP TLR L adjuvants in promoting robust and durable antibody responses against HIV in the next generation of HIV immunogens currently being developed.

Effects of voice-sparing cricotracheal resection on phonation in women.

INTRODUCTION: Individuals with idiopathic subglottic stenosis (SGS) are at risk for voice disorders prior to and following surgical management. This study examined the nature and severity of voice disorders in patients with SGS before and after a revised cricotracheal resection (CTR) procedure designed to minimize adverse effects on voice function. METHOD: Eleven women with idiopathic SGS provided presurgical and postsurgical audio recordings. Voice Handicap Index (VHI) scores were also collected. Cepstral, signal-to-noise, periodicity, and fundamental frequency (F0 ) analyses were undertaken for connected speech and sustained vowel samples. Listeners made auditory-perceptual ratings of overall quality and monotonicity. RESULTS: Paired samples statistical analyses revealed that mean F0 decreased from 215 Hz (standard deviation [SD] = 40 Hz) to 201 Hz (SD = 65 Hz) following surgery. In general, VHI scores decreased after surgery. Voice disorder severity based on the Cepstral Spectral Index of Dysphonia (KayPentax, Montvale, NJ) for sustained vowels decreased (improved) from 41 (SD = 41) to 25 (SD = 21) points; no change was observed for connected speech. Semitone SD (2.2 semitones) did not change from pre- to posttreatment. Auditory-perceptual ratings demonstrated similar results. CONCLUSION: These preliminary results indicate that this revised CTR procedure is promising in minimizing adverse voice effects while offering a longer-term surgical outcome for SGS. Further research is needed to determine causal factors for pretreatment voice disorders, as well as to optimize treatments in this population. LEVEL OF EVIDENCE: 4. Laryngoscope, 127:2085-2092, 2017.

Effects of speech style, room acoustics, and vocal fatigue on vocal effort.

Vocal effort is a physiological measure that accounts for changes in voice production as vocal loading increases. It has been quantified in terms of sound pressure level (SPL). This study investigates how vocal effort is affected by speaking style, room acoustics, and short-term vocal fatigue. Twenty subjects were recorded while reading a text at normal and loud volumes in anechoic, semi-reverberant, and reverberant rooms in the presence of classroom babble noise. The acoustics in each environment were modified by creating a strong first reflection in the talker position. After each task, the subjects answered questions addressing their perception of the vocal effort, comfort, control, and clarity of their own voice. Variation in SPL for each subject was measured per task. It was found that SPL and self-reported effort increased in the loud style and decreased when the reflective panels were present and when reverberation time increased. Self-reported comfort and control decreased in the loud style, while self-reported clarity increased when panels were present. The lowest magnitude of vocal fatigue was experienced in the semi-reverberant room. The results indicate that early reflections may be used to reduce vocal effort without modifying reverberation time.