Auditory-motor adaptation is reduced in adults who stutter but not in children who stutter

Previous studies have shown that adults who stutter produce smaller corrective motor responses to compensate for unexpected auditory perturbations in comparison to adults who do not stutter, suggesting that stuttering may be associated with deficits in integration of auditory feedback for online speech monitoring. In this study, we examined whether stuttering is also associated with deficiencies in integrating and using discrepancies between expect ed and received auditory feedback to adaptively update motor programs for accurate speech production. Using a sensorimotor adaptation paradigm, we measured adaptive speech responses to auditory formant frequency perturbations in adults and children who stutter and their matched nonstuttering controls. We found that the magnitude of the speech adaptive response for children who stutter did not differ from that of fluent children. However, the adaptation magnitude of adults who stutter in response to formant perturbation was significantly smaller than the adaptation magnitude of adults who do not stutter. Together these results indicate that stuttering is associated with deficits in integrating discrepancies between predicted and received auditory feedback to calibrate the speech production system in adults but not children. This auditory-motor integration deficit thus appears to be a compensatory effect that develops over years of stuttering

Intestinal Immunity to Poliovirus Following Sequential Trivalent Inactivated Polio Vaccine/Bivalent Oral Polio Vaccine and Trivalent Inactivated Polio Vaccine-only Immunization Schedules: Analysis of an Open-label, Randomized, Controlled Trial in Chilean Infants.

Background: Identifying polio vaccine regimens that can elicit robust intestinal mucosal immunity and interrupt viral transmission is a key priority of the polio endgame. Methods: In a 2013 Chilean clinical trial (NCT01841671) of trivalent inactivated polio vaccine (IPV) and bivalent oral polio vaccine (bOPV; targeting types 1 and 3), infants were randomized to receive IPV-bOPV-bOPV, IPV-IPV-bOPV, or IPV-IPV-IPV at 8, 16, and 24 weeks of age and challenged with monovalent oral polio vaccine type 2 (mOPV2) at 28 weeks. Using fecal samples collected from 152 participants, we investigated the extent to which IPV-bOPV and IPV-only immunization schedules induced intestinal neutralizing activity and immunoglobulin A against polio types 1 and 2. Results: Overall, 37% of infants in the IPV-bOPV groups and 26% in the IPV-only arm had detectable type 2-specific stool neutralization after the primary vaccine series. In contrast, 1 challenge dose of mOPV2 induced brisk intestinal immune responses in all vaccine groups, and significant rises in type 2-specific stool neutralization titers (P < .0001) and immunoglobulin A concentrations (P < 0.0001) were measured 2 weeks after the challenge. In subsidiary analyses, duration of breastfeeding also appeared to be associated with the magnitude of polio-specific mucosal immune parameters measured in infant fecal samples. Conclusions: Taken together, these results underscore the concept that mucosal and systemic immune responses to polio are separate in their induction, functionality, and potential impacts on transmission and, specifically, provide evidence that primary vaccine regimens lacking homologous live vaccine components are likely to induce only modest, type-specific intestinal immunity

Cryptococcus gattii in North American Pacific Northwest: whole-population genome analysis provides insights into species evolution and dispersal

The emergence of distinct populations of Cryptococcus gattii in the temperate North American Pacific Northwest (PNW) was surprising, as this species was previously thought to be confined to tropical and semitropical regions. Beyond a new habitat niche, the dominant emergent population displayed increased virulence and caused primary pulmonary disease, as opposed to the predominantly neurologic disease seen previously elsewhere. Whole-genome sequencing was performed on 118 C. gattii isolates, including the PNW subtypes and the global diversity of molecular type VGII, to better ascertain the natural source and genomic adaptations leading to the emergence of infection in the PNW. Overall, the VGII population was highly diverse, demonstrating large numbers of mutational and recombinational events; however, the three dominant subtypes from the PNW were of low diversity and were completely clonal. Although strains of VGII were found on at least five continents, all genetic subpopulations were represented or were most closely related to strains from South America. The phylogenetic data are consistent with multiple dispersal events from South America to North America and elsewhere. Numerous gene content differences were identified between the emergent clones and other VGII lineages, including genes potentially related to habitat adaptation, virulence, and pathology. Evidence was also found for possible gene introgression from Cryptococcus neoformans var. grubii that is rarely seen in global C. gattii but that was present in all PNW populations. These findings provide greater understanding of C. gattii evolution in North America and support extensive evolution in, and dispersal from, South America. Importance: Cryptococcus gattii emerged in the temperate North American Pacific Northwest (PNW) in the late 1990s. Beyond a new environmental niche, these emergent populations displayed increased virulence and resulted in a different pattern of clinical disease. In particular, severe pulmonary infections predominated in contrast to presentation with neurologic disease as seen previously elsewhere. We employed population-level whole-genome sequencing and analysis to explore the genetic relationships and gene content of the PNW C. gattii populations. We provide evidence that the PNW strains originated from South America and identified numerous genes potentially related to habitat adaptation, virulence expression, and clinical presentation. Characterization of these genetic features may lead to improved diagnostics and therapies for such fungal infections. The data indicate that there were multiple recent introductions of C. gattii into the PNW. Public health vigilance is warranted for emergence in regions where C. gattii is not thought to be endemic

Vaccine-induced mucosal immunity to poliovirus: analysis of cohorts from an open-label, randomised controlled trial in Latin American infants.

BACKGROUND: Identification of mechanisms that limit poliovirus replication is crucial for informing decisions aimed at global polio eradication. Studies of mucosal immunity induced by oral poliovirus (OPV) or inactivated poliovirus (IPV) vaccines and mixed schedules thereof will determine the effectiveness of different vaccine strategies to block virus shedding. We used samples from a clinical trial of different vaccination schedules to measure intestinal immunity as judged by neutralisation of virus and virus-specific IgA in stools. METHODS: In the FIDEC trial, Latin American infants were randomly assigned to nine groups to assess the efficacy of two schedules of bivalent OPV (bOPV) and IPV and challenge with monovalent type 2 OPV, and stools samples were collected. We selected three groups of particular interest-the bOPV control group (serotypes 1 and 3 at 6, 10, and 14 weeks), the trivalent attenuated OPV (tOPV) control group (tOPV at 6, 10, and 14 weeks), and the bOPV-IPV group (bOPV at 6, 10, and 14 weeks plus IPV at 14 weeks). Neutralising activity and poliovirus type-specific IgA were measured in stool after a monovalent OPV type 2 challenge at 18 weeks of age. Mucosal immunity was measured by in-vitro neutralisation of a type 2 polio pseudovirus (PV2). Neutralisation titres and total and poliovirus-type-specific IgG and IgA concentrations in stools were assessed in samples collected before challenge and 2 weeks after challenge from all participants. FINDINGS: 210 infants from Guatemala and Dominican Republic were included in this analysis. Of 38 infants tested for mucosal antibody in the tOPV group, two were shedding virus 1 week after challenge, compared with 59 of 85 infants receiving bOPV (p<0·0001) and 53 of 87 infants receiving bOPV-IPV (p<0·0001). Mucosal type 2 neutralisation and type-specific IgA were noted primarily in response to tOPV. An inverse correlation was noted between virus shedding and both serum type 2 neutralisation at challenge (p<0·0001) and mucosal type 2 neutralisation at challenge (p<0·0001). INTERPRETATION: Mucosal type-2-specific antibodies can be measured in stool and develop in response to receipt of OPV type 2 either in the primary vaccine series or at challenge. These mucosal antibodies influence the amount of virus that is shed in an established infection. FUNDING: Bill & Melinda Gates Foundation

Mucosal immunity to poliovirus.

A cornerstone of the global initiative to eradicate polio is the widespread use of live and inactivated poliovirus vaccines in extensive public health campaigns designed to prevent the development of paralytic disease and interrupt transmission of the virus. Central to these efforts is the goal of inducing mucosal immunity able to limit virus replication in the intestine. Recent clinical trials have evaluated new combined regimens of poliovirus vaccines, and demonstrated clear differences in their ability to restrict virus shedding in stool after oral challenge with live virus. Analyses of mucosal immunity accompanying these trials support a critical role for enteric neutralizing IgA in limiting the magnitude and duration of virus shedding. This review summarizes key findings in vaccine-induced intestinal immunity to poliovirus in infants, older children, and adults. The impact of immunization on development and maintenance of protective immunity to poliovirus and the implications for global eradication are discussed

A Randomized Phase 4 Study of Immunogenicity and Safety After Monovalent Oral Type 2 Sabin Poliovirus Vaccine Challenge in Children Vaccinated with Inactivated Poliovirus Vaccine in Lithuania.

BACKGROUND: Understanding immunogenicity and safety of monovalent type 2 oral poliovirus vaccine (mOPV2) in inactivated poliovirus vaccine (IPV)-immunized children is of major importance in informing global policy to control circulating vaccine-derived poliovirus outbreaks. METHODS: In this open-label, phase 4 study (NCT02582255) in 100 IPV-vaccinated Lithuanian 1-5-year-olds, we measured humoral and intestinal type 2 polio neutralizing antibodies before and 28 days after 1 or 2 mOPV2 doses given 28 days apart and measured stool viral shedding after each dose. Parents recorded solicited adverse events (AEs) for 7 days after each dose and unsolicited AEs for 6 weeks after vaccination. RESULTS: After 1 mOPV2 challenge, the type 2 seroprotection rate increased from 98% to 100%. Approximately 28 days after mOPV2 challenge 34 of 68 children (50%; 95% confidence interval, 38%-62%) were shedding virus; 9 of 37 (24%; 12%-41%) were shedding 28 days after a second challenge. Before challenge, type 2 intestinal immunity was undetectable in IPV-primed children, but 28 of 87 (32%) had intestinal neutralizing titers ≥32 after 1 mOPV2 dose. No vaccine-related serious or severe AEs were reported. CONCLUSIONS: High viral excretion after mOPV2 among exclusively IPV-vaccinated children was substantially lower after a subsequent dose, indicating induction of intestinal immunity against type 2 poliovirus

Community engagement education in academic health centers, colleges, and universities

Community engagement (CE) is critical for advancing health equity and a key approach for promoting inclusive clinical and translational science. However, it requires a workforce trained to effectively design, implement, and evaluate health promotion and improvement strategies through meaningful collaboration with community members. This paper presents an approach for designing CE curricula for research, education, clinical care, and public health learners. A general pedagogical framework is presented to support curriculum development with the inclusion of community members as facilitators or faculty. The overall goal of the curriculum is envisioned as enabling learners to effectively demonstrate the principles of CE in working with community members on issues of concern to communities to promote health and well-being. We highlight transformations needed for the commonly used critical service-learn- ing model and the importance of faculty well-versed in CE. Courses may include didactics and practicums with well-defined objectives and evaluation components. Because of the importance of building and maintaining relationships in CE, a preparatory phase is recommended prior to experiential learning, which should be guided and designed to include debriefing and reflec- tive learning. Depending on the scope of the course, evaluation should include community perspectives on the experience

Intestinal Immune Responses to Type 2 Oral Polio Vaccine (OPV) Challenge in Infants Previously Immunized With Bivalent OPV and Either High-Dose or Standard Inactivated Polio Vaccine.

Background: The impact of inactivated polio vaccines (IPVs) on intestinal mucosal immune responses to live poliovirus is poorly understood. Methods: In a 2014 phase 2 clinical trial, Panamanian infants were immunized at 6, 10, and 14 weeks of age with bivalent oral polio vaccine (bOPV) and randomized to receive either a novel monovalent high-dose type 2-specific IPV (mIPV2HD) or a standard trivalent IPV at 14 weeks. Infants were challenged at 18 weeks with a monovalent type 2 oral polio vaccine (mOPV2). Infants' intestinal immune responses during the 3 weeks following challenge were investigated by measuring poliovirus type-specific neutralization and immunoglobulin (Ig) A, IgA1, IgA2, IgD, IgG, and IgM antibodies in stool samples. Results: Despite mIPV2HD's 4-fold higher type 2 polio D-antigen content and heightened serum neutralization profile, mIPV2HD-immunized infants' intestinal immune responses to mOPV2 challenge were largely indistinguishable from those receiving standard IPV. Mucosal responses were tightly linked to evidence of active infection and, in the 79% of participants who shed virus, robust type 2-specific IgA responses and stool neutralization were observed by 2 weeks after challenge. Conclusions: Enhancing IPV-induced serum neutralization does not substantively improve intestinal mucosal immune responses or limit viral shedding on mOPV2 challenge. Clinical Trials Registration: NCT02111135