The relationship between social isolation, social support, and loneliness with cardiovascular disease and shared risk factors: A narrative review.

BACKGROUND: Cardiovascular disease (CVD) is the greatest contributor to global morbidity and mortality. Poor social health plays a critical role in CVD incidence. Additionally, the relationship between social health and CVD may be mediated through CVD risk factors. However, the underlying mechanisms between social health and CVD are poorly understood. Certain social health constructs (social isolation, low social support and loneliness) have complicated the characterisation of a causal relationship between social health and CVD. AIM: To provide an overview of the relationship between social health and CVD (and its shared risk factors). METHOD: In this narrative review, we examined published literature on the relationship between three social health constructs (social isolation, social support, and loneliness) and CVD. Evidence was synthesised in a narrative format, focusing on the potential ways in which social health affects CVD, including shared risk factors. RESULTS: The current literature highlights an established relationship between social health and CVD with a likelihood for bi-directionality. However, there is speculation and varied evidence regarding how these relationships may be mediated through CVD risk factors. CONCLUSIONS: Social health can be considered an established risk factor for CVD. However, the potential bi-directional pathways of social health with CVD risk factors are less established. Further research is needed to understand whether targeting certain constructs of social health may directly improve the management of CVD risk factors. Given the health and economic burdens of poor social health and CVD, improvements to addressing or preventing these interrelated health conditions would have societal benefits.

A controlled evaluation of the effect of social prescribing programs on loneliness for adults in Queensland, Australia (protocol).

BACKGROUND: In social prescribing, link workers support individuals whose persistent health problems are exacerbated by loneliness by connecting them to community-based social activities. This approach is well established in the UK and is gaining attention in Australia. However, a major limitation of research to date has been a lack of theoretically informed and rigorous evaluations of social prescribing. We will address these points in this study, applying a social identity framework to examine the effects of group-based social prescribing (SP) activity compared to primary care treatment as usual (TAU). METHODS: Ninety participants experiencing loneliness recruited from primary care services and community centres across five sites in Southeast Queensland will be assigned to one of two conditions (SP, TAU) and assessed at two timepoints (baseline, + 8 weeks). Individuals will be aged 18 years and over, have sufficient English language skills to provide consent, and at the time of recruitment they will not be experiencing acute symptoms or social issues that require urgent intervention. Primary outcomes are loneliness, mental well-being, and health service use (total number of GP, hospital, and allied health visits in the past 3 months). Secondary outcomes will assess social group processes, including number of important social groups, new group identification, multiple identity compatibility, and group-based support and emotion regulation. DISCUSSION: This study will provide comprehensive data about the extent to which, and how, social prescribing to community-based group activities may help people to feel less lonely, more socially integrated, and healthy over the first 8 weeks. If effective, this social identity-informed model of social prescribing can be disseminated in communities across Australia. TRIAL REGISTRATION: ANZCTR, Registered 8 June 2022 - Retrospectively registered, https://www.anzctr.org.au/ACTRN12622000801718.aspx.

In ineffective esophageal motility, failed swallows are more functionally relevant than weak swallows.

BACKGROUND: Esophageal pressure topography (EPT) diagnosis of ineffective esophageal motility (IEM) can be non-specific with unclear clinical significance. AIMS: To determine whether peristaltic vigor or lower esophageal sphincter (LES) integrity is associated with poor clearance and acid reflux in IEM. METHODS: Bolus clearance on high-resolution impedance manometry (HRIM) and available reflux studies in patients with IEM were retrospectively reviewed. Bolus clearance was assessed using both line tracing and colored contour methods on HRIM. EPT parameters, bolus clearance, and acid reflux variables were explored. KEY RESULTS: Eighty-eight patients with IEM were included. Bolus clearance occurred in 71% of all swallows, and 55.7% of patients had complete bolus transit (CBT, bolus clearance in ≥80% of swallows). Bolus clearance was impaired in swallows with distal contractile integral (DCI) <100 mmHg•cm•s compared to DCI 100-450 (0.43 vs 0.79, P < .0001). A cutoff at DCI 100 mmHg•cm•s was associated with clearance with an accuracy of 76% compared to 49% at DCI 450 (P = .0001 for both). A median DCI <100 was associated with a higher Eckardt score (9 vs 3, P = .03), and on reflux testing available in 47 patients, with abnormal acid exposure time (P = .002). Peristaltic reserve (PR) defined as (DCI of multiple rapid swallow/median DCI of wet swallows), integrated relaxation pressure, and resting lower esophageal sphincter pressure were not associated with clearance or acid exposure. CONCLUSIONS & INFERENCES: Failed peristalsis, as defined by DCI <100 mmHg•cm•s, is associated with impaired bolus clearance and more severe dysphagia in IEM, and likely abnormal acid exposure.

Bolus clearance in esophagogastric junction outflow obstruction is associated with strength of peristalsis.

BACKGROUND: A manometric diagnosis of esophagogastric junction outflow obstruction (EGJOO) without a mechanical cause creates a therapeutic conundrum. The aim of this study was to assess esophageal bolus clearance in EGJOO and assess manometric factors associated with clearance in EGJOO. METHODS: Bolus clearance was assessed using line-tracing method and contour method to determine Complete Bolus Transit (CBT) and Functional Clearance (FC), respectively, on combined High-Resolution Impedance Manometry (HRIM). HRIM studies of EGJOO patients, as well as a sample of achalasia types I-III and asymptomatic controls, were retrospectively analyzed. In EGJOO, associations between Integrated Relaxation Pressure (IRP) or Distal Contractile Integral (DCI) and clearance were assessed using receiver-operating-characteristic (ROC) curves. KEY RESULTS: Seventy-five EGJOO, 28 achalasia, and 11 normal subjects were included. Agreement between CBT and FC was good (Kappa=0.75). CBT across swallows in each group was as follows: type I achalasia: 14%, type II achalasia: 8%, type III achalasia: 61%, EGJOO: 86%, and normal: 98% (p values .023, .006, and <.0001 for EGJOO vs normals, type III achalasia, and all achalasia, respectively). In idiopathic EGJOO, CBT ≥60% of swallows was seen in 96.4% of patients when mean DCI>610 mmHg-s-cm (accuracy 87.7%, P=.004). Complete Bolus Transit( CBT) across individual swallows was 97.8% when DCI>884 mmHg-s-cm (accuracy 81.9%, P<.0001). IRP was poorly associated with bolus clearance. CONCLUSIONS & INFERENCES: Bolus clearance in EGJOO is impaired compared to normal, but not as severely as in achalasia. In idiopathic EGJOO, weak peristalsis is associated with poor bolus clearance. Bolus transit appears to be unimpaired when DCI>900 mmHg-s-cm.

Pheochromocytoma: A Rare Presentation.

Pheochromocytoma is a very rare neuroendocrine tumor usually located in one or both adrenal glands with an incidence of about 4 per 1,000,000 and about 1000 diagnosed per year. Pheochromocytomas can be located in extra-adrenal locations with about 1% being located in the urinary bladder.(1) We describe the presentation, diagnosis and treatment of one of these extremely rare tumors in the bladder.

We think you can dance! A pilot randomised controlled trial of dance for nursing home residents with moderate to severe dementia.

OBJECTIVES: To evaluate the feasibility of a dance program for people with moderate to severe dementia living in nursing homeswith regards to recruitment and retention, assessment tools, intervention safety, attendance and engagement. DESIGN: Pilot randomised controlled trial with assessments at weeks 0, 16 and 32. SETTING: A nursing home in Sydney, Australia. INTERVENTIONS: Experienced dance teachers conducted dance groups (intervention) or music appreciation and socialisation groups (control) for 45min, three times a week for 16 weeks. MAIN OUTCOME MEASURES: Descriptive statistics for recruitment and retention, adverse events and attendance and engagement. RESULTS: Recruitment was smooth, attrition was17% over 32 weeks. Engagement during the sessions was high, and no serious falls or behavioural incidents occurred. Average attendance was poorer than anticipated for dance groups (67%) in comparison to music groups (89%). A ceiling effect on the Severe Impairment Battery and the logistical challenges of the Clinical Global Impression of Change meant they may not be optimal tools. CONCLUSIONS: It is feasible to conduct a study of group dance for people with moderate to severe dementia in residential care. Choice of attention control condition should be reconsidered.

Oxidative stress dependent microRNA-34a activation via PI3Kα reduces the expression of sirtuin-1 and sirtuin-6 in epithelial cells.

Sirtuin-1 (SIRT1) and SIRT6, NAD+-dependent Class III protein deacetylases, are putative anti-aging enzymes, down-regulated in patients with chronic obstructive pulmonary disease (COPD), which is characterized by the accelerated ageing of the lung and associated with increased oxidative stress. Here, we show that oxidative stress (hydrogen peroxide) selectively elevates microRNA-34a (miR-34a) but not the related miR-34b/c, with concomitant reduction of SIRT1/-6 in bronchial epithelial cells (BEAS2B), which was also observed in peripheral lung samples from patients with COPD. Over-expression of a miR-34a mimic caused a significant reduction in both mRNA and protein of SIRT1/-6, whereas inhibition of miR-34a (antagomir) increased these sirtuins. Induction of miR-34a expression with H2O2 was phosphoinositide-3-kinase (PI3K) dependent as it was associated with PI3Kα activation as well as phosphatase and tensin homolog (PTEN) reduction. Importantly, miR-34a antagomirs increased SIRT1/-6 mRNA levels, whilst decreasing markers of cellular senescence in airway epithelial cells from COPD patients, suggesting that this process is reversible. Other sirtuin isoforms were not affected by miR-34a. Our data indicate that miR-34a is induced by oxidative stress via PI3K signaling, and orchestrates ageing responses under oxidative stress, therefore highlighting miR-34a as a new therapeutic target and biomarker in COPD and other oxidative stress-driven aging diseases.

A HER2 selective theranostic agent for surgical resection guidance and photodynamic therapy.

In many cancers early intervention involves surgical resection of small localised tumour masses. Inadequate resection leads to recurrence whereas overzealous treatment can lead to organ damage. This work describes production of a HER2 targeting antibody Fab fragment dual conjugated to achieve both real time near-infrared fluorescent imaging and photodynamic therapy. The use of fluorescence emission from a NIR-dye could be used to guide resection of tumour bulk, for example during endoscopic diagnosis for oesophago-gastric adenocarcinoma, this would then be followed by activation of the photodynamic therapeutic agent to destroy untreated localised areas of cancer infiltration and tumour infiltrated lymph nodes. This theranostic agent was prepared from the Fab fragment of trastuzumab initially by functional disulfide re-bridging and site-specific click reaction of a NIR-dye. This was followed by further reaction with a novel pre-activated form of the photosensitiser chlorin e6 with the exposed fragments' lysine residues. Specific binding of the theranostic agent was observed in vitro with a HER2 positive cell line and cellular near-infrared fluorescence was observed with flow cytometry. Specific photo-activity of the conjugates when exposed to laser light was observed with HER2 positive but not HER2 negative cell lines in vitro, this selectivity was not seen with the unconjugated drug. This theranostic agent demonstrates that two different photo-active functions can be coupled to the same antibody fragment with little interference to their independent activities.

Children with social phobia have lower quality friendships than children with other anxiety disorders.

BACKGROUND AND OBJECTIVE: Whilst shy, socially anxious or socially withdrawn children in nonclinical community samples report lower friendship quality (FQ) than nonanxious children, no study has examined the FQ of clinically anxious children. The aim of the study was to examine the FQ of children with anxiety disorders; and whether it differs for clinical children with or without a diagnosis of social phobia (SP). DESIGN: The study design was cross-sectional self-report. METHODS: Clinical children - 39 anxiety-disordered children with SP and 28 anxiety-disordered children without SP (No-SP) - presented for psychological treatment, and 29 nonclinical children were recruited from the community. Same-sex close friends were invited to participate using an unrestricted nomination procedure. All children were aged between 7 and 13 years. Both target child and friend completed the Friendship Quality Questionnaire and the Spence Children's Anxiety Scale. RESULTS: Using multilevel modeling within the framework of the Actor-Partner Interdependence Model, SP dyads were found to report lower overall FQ than No-SP dyads. SP dyads did not report lower overall FQ than nonclinical dyads. CONCLUSION: Children with SP in their diagnostic profile may be unique in their friendship experiences relative to children with other anxiety disorders.

An investigation into the lower peer liking of anxious than nonanxious children.

Peer dislike of anxious behaviour was investigated in 7-12 year olds. Child actors delivered an identical verbal presentation: once in an anxious manner and once confidently. The videos were rated for liking and seven potential mediators by three groups of children: 32 anxiety-disordered peers with social phobia; 16 anxiety-disordered peers without social phobia; and 48 nonclinical peers. A mediation model with moderation effects was tested within a within-subjects framework. "Anxious" actors were liked significantly less than "confident" actors. This effect differed by group rater, in that relative dislike of the anxious actor was significantly greater for the nonclinical than socially phobic raters. Physical attractiveness and friend acceptance mediated the effect for all group raters. Other identified mediators differed depending upon the group rater. The findings direct future efforts to help anxiety-disordered children circumvent an increased risk of negative peer relations, and testify to consideration of the rater in sociometric studies.

Friendship quality and social information processing in clinically anxious children.

The association between perceived friendship quality (FQ) and social information processing (SIP) was examined in three groups of children and their close friends aged 7-12 years: 16 anxiety disordered children with social phobia (SP); 12 anxiety disordered children without SP (No-SP); and 32 nonclinical children. Positive and negative FQ positively associated with target children's positive and negative responding on a vignette measure of SIP. SP children reported lower positive SIP than No-SP but not nonclinical children; and this was the only group difference in SIP. Target children and their friends were similar in negative but not positive SIP. Following discussion about the vignette with a close friend, all target children increased in positive SIP; negative SIP did not change. Lower FQ and a more socially anxious friend predicted higher negative target child SIP postdiscussion. Close friendships play an important role in the SIP of both clinical and nonclinical children.

US Hemophilia Treatment Center population trends 1990-2010: patient diagnoses, demographics, health services utilization.

For several decades, US government agencies have partially supported regional networks of Hemophilia Treatment Centers (HTC). HTC multidisciplinary teams provide comprehensive and coordinated diagnosis, treatment, prevention, education, outreach and surveillance services to improve the health of people with genetic bleeding disorders. However, national data are scarce on HTC-patient population trends and services. The aim of the study was to examine national trends over the past 20 years in patient diagnoses, demographics and health services utilization among the Health Resources and Services Administration (HRSA) and Centers for Disease Control and Prevention (CDC)-supported HTC network. Diagnoses, demographics and health services utilization data from 1990 to 2010 were aggregated from all HTCs using the Hemophilia Data Set (HDS). From 1990 to 2010, the HTC population grew 90% from 17 177 to 32 612. HTC patients with von Willebrand's disease increased by 148%, females by 346%, Hispanic patients by 236% and African Americans by 104%. Four thousand and seventy-five deaths were reported. From 2002 to 2010, annual comprehensive evaluations grew 38%, and persons with severe haemophilia on a home intravenous therapy programme rose 37%. In 2010, 46% of patients were less than 18 years vs. 24% for the general US population. The Hemophilia Data Set documents the growth and diversity of the US Hemophilia Treatment Center Network's patient population and services. Despite disproportionate deaths due to HIV, the HTC patient base grew faster than the general US population. The HDS is a vital national public health registry for this rare-disorder population.

Friendship quality predicts treatment outcome in children with anxiety disorders.

It was examined whether friendship quality (FQ) and friends' anxiety predicted treatment outcome in 116 children with anxiety disorders (72.3% Australian) receiving cognitive behavioural therapy (CBT). Target children and an identified close friend aged between 7 and 13 years (50% female) completed the Friendship Quality Questionnaire (Parker & Asher, 1993) before treatment, and child diagnoses were based on the Anxiety Disorders Interview Schedule for DSM-IV-Child/Parent Version (Silverman & Albano, 1996). Children who reported higher FQ were significantly more likely to be free of their initial primary anxiety disorder and of any anxiety disorder at posttreatment and 6-month follow-up; friend report of FQ and friend's anxiety as measured by the Spence Child Anxiety Scale (Spence, 1998) did not predict treatment outcome. Children with anxiety disorders reporting higher FQ responded better to CBT than children with anxiety disorders reporting lower FQ. FQ measures could help identify anxious children at heightened risk of poor treatment response. Further, good quality friendships may be an important aid in anxious children's treatment response.

Safety and immunogenicity of a novel nanoemulsion mucosal adjuvant W805EC combined with approved seasonal influenza antigens.

BACKGROUND: Improving the systemic and mucosal immune response following intranasal vaccination could enhance disease protection against respiratory pathogens. We assessed the safety and immunogenicity of a novel nanoemulsion mucosal adjuvant W(80)5EC combined with approved seasonal influenza antigens. METHODS: This was a first-in-human Phase I study in 199 healthy adult volunteers randomized to receive a single intranasal administration of 5%, 10%, 15% or 20% W(80)5EC, combined with 4 or 10 µg strain-specific Fluzone(®) HA, compared with intranasal PBS, intranasal Fluzone(®), or 15 ug strain-specific intramuscular Fluzone(®). Safety was evaluated by physical examination, laboratory parameters, symptom diaries, and adverse event reports. Serum HAI titers and nasal wash IgA were assessed at baseline as well as 28 and 60 days after vaccination. RESULTS: W(80)5EC adjuvant combined with seasonal influenza antigens was well tolerated without safety concerns or significant adverse events. The highest dose of 20% W(80)5EC combined with 10 µg strain-specific HA elicited clinically meaningful systemic immunity based on increases in serum HAI GMT and ≥ 70% seroprotection for all 3 influenza strains, as well as a rise in antigen-specific IgA in nasal wash specimens. CONCLUSIONS: W(80)5EC adjuvant was safe and well tolerated in healthy adult volunteers and elicited both systemic and mucosal immunity following a single intranasal vaccination.

Distinct roles for S100a8 in early embryo development and in the maternal deciduum.

S100a8 is a cytosolic protein expressed in myeloid cells where it forms a stable heterodimer with another S100 protein family member, S100a9. The S100a9(-/-) mouse is viable and phenotypically normal, whereas the S100a8(-/-) condition is embryonic lethal. We present evidence that S100a8, without S100a9, has a previously unrecognized role in embryo development between fertilization and the 8-cell stage at embryonic day (E) 2.5. S100a8 also has a second role in the maternal deciduum, where expression is associated with the vasculature from the E8.5 stage to the formation of mature placenta. Uterine natural killer cells that have a role in vascular remodelling colocalise with the S100a8 vascular expression in the metrial triangle. In inflammatory responses in peripheral tissues, S100a8 is a potent chemoattractant and also an anti-oxidant. Both roles may be important in the developing placenta. Thus we highlight two new S100a9-independent roles for S100a8 in early embryo development.

In vitro antibacterial activity of NB-003 against Propionibacterium acnes.

NB-003 and NB-003 gel formulations are oil-in-water nanoemulsions designed for use in bacterial infections. In vitro susceptibility of Propionibacterium acnes to NB-003 formulations and comparator drugs was evaluated. Both NB-003 formulations were bactericidal against all P. acnes isolates, including those that were erythromycin, clindamycin, and/or tetracycline resistant. In the absence of sebum, the MIC(90)s/minimum bactericidal concentrations (MBC(90)s) for NB-003, NB-003 gel, salicylic acid (SA), and benzoyl peroxide (BPO) were 0.5/2.0, 1.0/2.0, 1,000/2,000, and 50/200 µg/ml, respectively. In the presence of 50% sebum, the MIC(90)s/MBC(90)s of NB003 and BPOs increased to 128/1,024 and 400/1,600 µg/ml, respectively. The MIC(90)s/MBC(90)s of SA were not significantly impacted by the presence of sebum. A reduction in the MBC(90)s for NB-003 and BPO was observed when 2% SA or 0.5% BPO was integrated into the formulation, resulting in MIC(90)s/MBC(90)s of 128/256 µg/ml for NB003 and 214/428 µg/ml for BPO. The addition of EDTA enhanced the in vitro efficacy of 0.5% NB-003 in the presence or absence of 25% sebum. The addition of 5 mM EDTA to each well of the microtiter plate resulted in a >16- and >256-fold decrease in MIC(90) and MBC(90), yielding a more potent MIC(90)/MBC(90) of ≤1/<1 µg/ml. The kinetics of bactericidal activity of NB-003 against P. acnes were compared to those of a commercially available product of BPO. Electron micrographs of P. acnes treated with NB-003 showed complete disruption of bacteria. Assessment of spontaneous resistance of P. acnes revealed no stably resistant mutant strains.

Surveillance of female patients with inherited bleeding disorders in United States Haemophilia Treatment Centres.

Inherited bleeding disorders are especially problematic for affected girls and women due to the monthly occurrence of menstrual periods and the effects on reproductive health. Although heavy menstrual bleeding (HMB) is the most common manifestation, females with inherited bleeding disorders (FBD) experience other bleeding symptoms throughout the lifespan that can lead to increased morbidity and impairment of daily activities. The purpose of this article is to describe the utility of a female-focused surveillance effort [female Universal Data Collection (UDC) project] in the United States Haemophilia Treatment Centres (HTCs) and to describe the baseline frequency and spectrum of diagnoses and outcomes. All FBD aged 2 years and older receiving care at selected HTCs were eligible for enrollment. Demographic data, diagnoses and historical data regarding bleeding symptoms, treatments, gynaecological abnormalities and obstetrical outcomes were analysed. Analyses represent data collected from 2009 to 2010. The most frequent diagnoses were type 1 von Willebrand's disease (VWD) (195/319; 61.1%), VWD type unknown (49/319; 15.4%) and factor VIII deficiency (40/319; 12.5%). HMB was the most common bleeding symptom (198/253; 78.3%); however, 157 (49.2%) participants reported greater than four symptoms. Oral contraceptives were used most frequently to treat HMB (90/165; 54.5%), followed by desmopressin [1-8 deamino-D-arginine vasopressin (DDAVP)] (56/165; 33.9%). Various pregnancy and childbirth complications were reported, including bleeding during miscarriage (33/43; 76.7%) and postpartum haemorrhage (PPH) (41/109; 37.6%). FBD experience multiple bleeding symptoms and obstetrical-gynaecological morbidity. The female UDC is the first prospective, longitudinal surveillance in the US focusing on FBD and has the potential to further identify complications and reduce adverse outcomes in this population.

Differentiating dental pulp cells via RGD-dendrimer conjugates.

Traumatic dental injuries are often irreversible, underscoring the need for therapies that protect dental pulp cells and enhance their regeneration. We hypothesized that generation 5 poly amido amine (PAMAM) dendrimers (G5), functionalized with fluorescein isothiocyanate (FL) and αVß3-specific, cyclic arginine-glycine-aspartic acid (RGD) peptides, will bind to dental pulp cells (DPCs) and modulate their differentiation. Dental pulp cells and mouse odontoblast-like cells (MDPC-23) (±) treated with G5-FL-RGD were analyzed via Western blot, RT-PCR, and quantitative PCR. Transcription of dental differentiation markers was as follows: Dentin matrix protein (DMP-1), dentin sialoprotein (DSPP), and matrix extracellular phosphoglycoprotein (MEPE) as well as vascular endothelial growth factor (VEGF) all increased via the JNK pathway. Long-term G5-RGD treatment of dental pulp cells resulted in enhanced mineralization as examined via Von Kossa assay, suggesting that PAMAM dendrimers conjugated to cyclic RGD peptides can increase the odontogenic potential of these cells.

Induction of immune response to the 17 kDa OMPA Burkholderia cenocepacia polypeptide and protection against pulmonary infection in mice after nasal vaccination with an OMP nanoemulsion-based vaccine.

Burkholderia cepacia complex (Bcc) are opportunistic bacteria associated with life-threatening illness in persons with cystic fibrosis. Once Bcc colonization is established, these antimicrobial-resistant and biofilm-forming bacteria are difficult to eradicate and are associated with increased rates of morbidity and mortality. At present, no vaccines are available to prevent the Bcc infection. There is currently a paucity of published information regarding the development of vaccines designed to prevent Burkholderia colonization. This work expands on the recent studies published by Bertot et al. [Infect Immun 75(6):2740-2752, 2007], where successful protective immune responses were generated in mice using a B. multivorans OMP-based vaccine. Here, we evaluate an experimental mucosal vaccine against Bcc using a novel mucosal adjuvant (nanoemulsion) and a novel B. cenocepacia-based OMP antigen. The OMP antigen derived from B. cenocepacia was mixed with either nanoemulsion or with PBS and delivered intranasally to CD-1 mice. Serum analysis showed robust IgG and mucosal secretory IgA immune responses in vaccinated versus control mice. The antibodies had cross-neutralizing activity against both B. cenocepacia and B. multivorans species. We found that immunized mice were protected against pulmonary colonization with B. cenocepacia. We have also identified that a 17 kDa OmpA-like protein highly conserved between Burkholderia and Ralstonia species as a new immunodominant epitope in mucosal immunization.