Public Health Nurse-delivered Group Cognitive Behavioural Therapy for Postpartum Depression: A Randomized Controlled Trial.

OBJECTIVES: To examine the effectiveness of group cognitive behavioural therapy (CBT) for postpartum depression (PPD) delivered by public health nurses with little to no previous psychiatric training at improving depression, worry, social support and the mother-infant relationship. METHODS: Mothers (n = 141) living in Ontario, Canada with Edinburgh Postnatal Depression Scale Scores ≥10 and an infant <12 months of age were randomized to receive nine weekly 2-h sessions of in-person group CBT for PPD delivered by two public health nurses plus treatment as usual (TAU; experimental group) or TAU alone (control group). Primary outcomes were change in EPDS score and current major depressive disorder (Mini International Neuropsychiatric Interview) assessed immediately post-treatment (T2). Secondary outcomes included maternal worry, social support, and quality of the mother-infant relationship. All outcomes were assessed again six months post-treatment (T3). RESULTS: Participants in the experimental group had statistically significantly greater reductions in PPD symptoms immediately post-treatment (T2) (B = -5.35, p < 0.01), were more likely to manifest a clinically significant improvement in EPDS scores (≥4 points; OR = 3.44, 95%CI: 1.49-7.94), and no longer have symptoms consistent with current MDD (OR = 5.31, 95% CI: 1.78-15.83). Six months post-treatment (T3), experimental group participants had higher odds of clinically significant PPD improvement (OR = 5.10, 95%CI: 1.89-13.78), while 25% of the experimental group and 70% of remaining control group participants reported current MDD (p < 0.01). Statistically significant improvements in worry and the mother-infant relationship were also observed, decreases maintained at six months post-treatment. CONCLUSIONS: Public health nurses with little to no previous psychiatric training can be trained to deliver effective group CBT for PPD to improve depression, worry, and the mother-infant relationship. Task shifting PPD treatment with group CBT to public health nurses could improve treatment uptake and lead to better outcomes for mothers, families, and the healthcare system.(Trial Registration NCT03039530).

The Use of Fluoride Varnish in Primary Care in Ontario: A Qualitative Study.

OBJECTIVES: Fluoride varnish (FV) has been shown to prevent dental caries. Physicians and nurses may be ideally situated to apply FV during well-child visits. Currently, public health units across Ontario have been successfully piloting this intervention. Yet, challenges remain at both the political and practice levels. The objectives of this research were to understand the perspectives of key stakeholders on making FV application a routine primary care practice in Ontario and to consider the potential enabling factors and barriers to implementation. METHODS: In this qualitative study, 16 key stakeholders representing medicine, nursing, dentistry, dental hygiene, public health and government were interviewed. Interview data were transcribed and coded, and a conceptual framework for implementing change to daily health care practice was used as a guide for thematic analysis. RESULTS: Our findings suggest that there is an opportunity for interdisciplinary care when considering children's oral health. There is also motivation and acceptance of this specific intervention across all fields. However, we found that concerns related to funding, knowledge and interprofessional relationships could impede implementation and limit any potential short- or mid-term window for meaningful policy and practice change. CONCLUSION: With respect to introducing FV into medical practice for children under 5 years of age, the many factors required to implement immediate change are arguably not in alignment. However, policymakers and practitioners are motivated and have identified opportunities for change that may form the foundation for this program in the future.

Public health nurse delivered group cognitive behavioral therapy (CBT) for postpartum depression: A pilot study.

OBJECTIVES: Although postpartum depression (PPD) affects 1 in 5 women, just 15% receive treatment. Cognitive Behavioural Therapy (CBT) is a first-line treatment for PPD. The objective of this pilot study was to determine the feasibility and acceptability of public health nurse (PHN)-delivered group CBT for PPD and to determine preliminary estimates of effect. DESIGN: A pre-posttest design was used. Participants provided data before and after the CBT groups. SAMPLE: Seven women who were over the age of 18 and had given birth in the past year participated. MEASUREMENTS: Feasibility and acceptability focused on PHN training, recruitment, retention, and adherence to the intervention. Participants provided data on depression, worry, health care utilization and mother-infant relations. Women and their partners reported on infant temperament. INTERVENTION: Participants attended a 9-week CBT group delivered by two PHNs. RESULTS: The PHN training, CBT intervention and our study protocol were found to be feasible and acceptable to participants. Reductions were seen in depression and worry. The number of health care visits decreased; mother-infant relations improved. CONCLUSIONS: These findings highlight the feasibility of PHN-delivered group CBT for PPD and suggest that it could reduce the burden of PPD on women and their children.

A randomized, placebo-controlled trial of canakinumab in patients with peripheral artery disease.

Extensive atherosclerotic plaque burden in the lower extremities often leads to symptomatic peripheral artery disease (PAD) including impaired walking performance and claudication. Interleukin-1ß (IL-1ß) may play an important pro-inflammatory role in the pathogenesis of this disease. Interruption of IL-1ß signaling was hypothesized to decrease plaque progression in the leg macrovasculature and improve the mobility of patients with PAD with intermittent claudication. Thirty-eight patients (mean age 65 years; 71% male) with symptomatic PAD (confirmed by ankle-brachial index) were randomized 1:1 to receive canakinumab (150 mg subcutaneously) or placebo monthly for up to 12 months. The mean vessel wall area (by 3.0 T black-blood magnetic resonance imaging (MRI)) of the superficial femoral artery (SFA) was used to measure plaque volume. Mobility was assessed using the 6-minute walk test. Canakinumab was safe and well tolerated. Markers of systemic inflammation (interleukin-6 and high-sensitivity C-reactive protein) fell as early as 1 month after treatment. MRI (32 patients at 3 months; 21 patients at 12 months) showed no evidence of plaque progression in the SFA in either placebo-treated or canakinumab-treated patients. Although an exploratory endpoint, placebo-adjusted maximum and pain-free walking distance (58 m) improved as early as 3 months after treatment with canakinumab when compared with placebo. Although canakinumab did not alter plaque progression in the SFA, there is an early signal that it may improve maximum and pain-free walking distance in patients with symptomatic PAD. Larger studies aimed at this endpoint will be required to definitively demonstrate this. ClinicalTrials.gov Identifier: NCT01731990.

Siponimod pharmacokinetics, safety, and tolerability in combination with the potent CYP3A4 inhibitor itraconazole in healthy subjects with different CYP2C9 genotypes.

PURPOSE: To evaluate the PK and safety of siponimod, a substrate of CYP2C9/3A4, in the presence or absence of a CYP3A4 inhibitor, itraconazole. METHODS: This was an open-label study in healthy subjects (aged 18-50 years; genotype: CYP2C9 *1*2 [cohort 1; n = 17] or *1*3 [cohort 2; n = 13]). Subjects received siponimod 0.25-mg single dose in treatment period 1 (days 1-14), itraconazole 100 mg twice daily in treatment period 2 (days 15-18), and siponimod 0.25-mg single dose (day 19) with itraconazole until day 31 (cohort 1) or day 35 (cohort 2) in treatment period 3. PK of siponimod alone and with itraconazole and safety were assessed. RESULTS: Overall, 29/30 subjects completed the study. In treatment period 1, geometric mean AUCinf, T1/2, and median Tmax were higher while systemic clearance was lower in cohort 2 than cohort 1. In treatment period 3, siponimod AUC decreased by 10% (geo-mean ratio [90% confidence intervals]: 0.90 [0.84; 0.96]) and 24% (0.76 [0.69; 0.82]) in cohorts 1 and 2, respectively. Siponimod Cmax was similar between treatment periods 1 and 3. In both cohorts, the Cmax and AUC of the metabolites (M17, M3, and M5) decreased in the presence of itraconazole. All adverse events were mild. CONCLUSIONS: The minor albeit significant reduction in plasma exposure of siponimod and its metabolites by itraconazole was unexpected. While the reason is unclear, the results suggest that coadministration of the two drugs would not cause a considerable increase of siponimod exposure independent of CYP2C9 genotype.

Effectiveness of a live oral human rotavirus vaccine after programmatic introduction in Bangladesh: A cluster-randomized trial.

BACKGROUND: Rotavirus vaccines are now globally recommended by the World Health Organization (WHO), but in early 2009 WHO's Strategic Advisory Group of Experts on Immunization reviewed available data and concluded that there was no evidence for the efficacy or effectiveness of a two-dose schedule of the human rotavirus vaccine (HRV; Rotarix) given early at 6 and 10 wk of age. Additionally, the effectiveness of programmatic rotavirus vaccination, including possible indirect effects, has not been assessed in low-resource populations in Asia. METHODS AND FINDINGS: In Bangladesh, we cluster-randomized (1:1) 142 villages of the Matlab Health and Demographic Surveillance System to include two doses of HRV with the standard infant vaccines at 6 and 10 wk of age or to provide standard infant vaccines without HRV. The study was initiated November 1, 2008, and surveillance was conducted concurrently at Matlab Diarrhoea Hospital and two community treatment centers to identify children less than 2 y of age presenting with acute rotavirus diarrhea (ARD) through March 31, 2011. Laboratory confirmation was made by enzyme immunoassay detection of rotavirus antigen in stool specimens. Overall effectiveness of the HRV vaccination program (primary objective) was measured by comparing the incidence rate of ARD among all children age-eligible for vaccination in villages where HRV was introduced to that among such children in villages where HRV was not introduced. Total effectiveness among vaccinees and indirect effectiveness were also evaluated. In all, 6,527 infants were age-eligible for vaccination in 71 HRV villages, and 5,791 in 71 non-HRV villages. In HRV villages, 4,808 (73.7%) infants received at least one dose of HRV. The incidence rate of ARD was 4.10 cases per 100 person-years in non-HRV villages compared to 2.8 per 100 person-years in HRV villages, indicating an overall effectiveness of 29.0% (95% CI, 11.3% to 43.1%). The total effectiveness of HRV against ARD among vaccinees was 41.4% (95% CI, 23.2% to 55.2%). The point estimate for total effectiveness was higher against ARD during the first year of life than during the second (45.2% versus 28.9%), but estimates for the second year of life lacked precision and did not reach statistical significance. Indirect effects were not detected. To check for bias in presentation to treatment facilities, we evaluated the effectiveness of HRV against acute diarrhea associated with enterotoxigenic Escherichia coli; it was 4.0% (95% CI, -46.5% to 37.1%), indicating that bias likely was not introduced. Thirteen serious adverse events were identified among recipients of HRV, but none were considered related to receipt of study vaccine. The main limitation of this study is that it was an open-label study with an observed-only control group (no placebo). CONCLUSIONS: The two-dose HRV rotavirus vaccination program significantly reduced medically attended ARD in this low-resource population in Asia. Protection among vaccinees was similar to that in other low-resource settings. In low-resource populations with high rotavirus incidence, large-scale vaccination across a wide population may be required to obtain the full benefit of rotavirus vaccination, including indirect effects. TRIAL REGISTRATION: ClinicalTrials.gov NCT00737503.

The paediatrician and middle childhood parenting.

The 'forgotten years' of middle childhood, from age 6 to 12, represent a critical period in child development. Emotional, social and physical development during this time have a lifelong impact on health and adult contributions to society. Mental health conditions have displaced physical illness as the leading childhood disability. Positive parenting can improve child behaviour, prevent early-onset conduct problems and provide a buffer from adverse childhood events resulting in decreased toxic stress and improved health. Medical homes can play a key role in supporting parents with positive parenting skills that are practical, evidence-based and useful in everyday life. Paediatricians need to explore the domains that promote healthy development, including caring environments, fundamental needs and nurturing relationships. Our objective is to promote high-quality positive parenting through middle childhood by identifying opportunities for paediatricians to frame parenting discussions in the context of development, behaviour and safety and to provide access to valuable parenting resources.

Les « années oubliées ¼ de la phase intermédiaire de l'enfance, entre l'âge de six et 12 ans, sont une période critique du développement de l'enfant. Pendant cette période, le développement émotionnel, social et physique a des conséquences permanentes sur la santé et l'apport de l'adulte à la société. Les troubles de santé mentale ont remplacé les maladies physiques comme principale affection de l'enfance. Des pratiques parentales positives peuvent améliorer le comportement de l'enfant, prévenir les troubles des conduites d'apparition précoce et limiter les événements indésirables de l'enfance, réduisant ainsi le stress toxique et améliorant la santé. Les milieux médicaux peuvent beaucoup contribuer à soutenir les parents afin qu'ils acquièrent des compétences parentales positives pratiques, fondées sur des données probantes et utiles dans la vie quoti- dienne. Les pédiatres doivent explorer les sphères qui favorisent un développement sain, y compris les environnements attentionnés, les besoins fondamentaux et les relations aimantes. Afin de promouvoir des pratiques parentales positives de qualité tout au long de la phase intermédiaire de l'enfance, les auteurs visent à cerner les occasions que peuvent saisir les pédiatres pour structurer les discussions avec les parents sur le développement, le comportement et la sécurité et les orienter vers des ressources intéressantes sur ce type de pratiques.

A comparative analysis of early child health and development services and outcomes in countries with different redistributive policies.

BACKGROUND: The social environment is a fundamental determinant of early child development and, in turn, early child development is a determinant of health, well-being, and learning skills across the life course. Redistributive policies aimed at reducing social inequalities, such as a welfare state and labour market policies, have shown a positive association with selected health indicators. In this study, we investigated the influence of redistributive policies specifically on the social environment of early child development in five countries with different political traditions. The objective of this analysis was to highlight similarities and differences in social and health services between the countries and their associations with other health outcomes that can inform better global early child development policies and improve early child health and development. METHODS: Four social determinants of early child development were selected to provide a cross-section of key time periods in a child's life from prenatal to kindergarten. They included: 1) prenatal care, 2) maternal leave, 3) child health care, and 4) child care and early childhood education. We searched international databases and reports (e.g. Organization for Economic Cooperation and Development, World Bank, and UNICEF) to obtain information about early child development policies, services and outcomes. RESULTS: Although a comparative analysis cannot claim causation, our analysis suggests that redistributive policies aimed at reducing social inequalities are associated with a positive influence on the social determinants of early child development. Generous redistributive policies are associated with a higher maternal leave allowance and pay and more preventive child healthcare visits. A decreasing trend in infant mortality, low birth weight rate, and under five mortality rate were observed with an increase in redistributive policies. No clear influence of redistributive policies was observed on breastfeeding and immunization rates. In the analysis of child care and early education, the lack of uniform measures of early child development outcomes was apparent. CONCLUSIONS: This paper provides further support for an association between redistributive policies and early child health and development outcomes, along with the organization of early child health and development services.

Spontaneous control of HCV is associated with expression of HLA-B 57 and preservation of targeted epitopes.

BACKGROUND & AIMS: HLA class I alleles are linked to spontaneous control of hepatitis C virus (HCV) and human immunodeficiency virus-1, but for HCV the roles of particular alleles and corresponding CD8(+) T-cell responses remain incompletely defined. We aimed to determine the correlations between these alleles and natural outcomes of HCV and determine associated key T-cell responses. METHODS: In a cohort of HCV individuals, we determined HLA class I alleles, HCV outcomes, T-cell responses, and examined sequence data for mutational changes within key epitopes. RESULTS: Carriage of HLA-B 57 was associated with a higher rate of viral clearance (risk ratio = 2.0; 95% confidence interval: 1.2-3.4), while HLA-B 08 was associated with a lower rate (risk ratio = 0.34; 95% confidence interval: 0.1-0.9]. Two HLA-B 57-restricted T-cell epitopes were targeted in spontaneous clearance; subjects with chronic viremia expressing HLA-B 57 harbored HCV strains with a high frequency of mutations in key residues. HLA-B 57-mediated escape was supported by diminished immune recognition of these variants and acute HCV infection revealing viral evolution toward less recognized variants. Analysis of a genotype 1b strain from a single-source HCV outbreak in which HLA-B 57 was not protective revealed sequence variations that interfere with immunogenicity, thereby preventing HLA-B 57-mediated immune pressure. CONCLUSIONS: Our data indicate a role of HLA-B 57-restricted CD8(+) T-cell responses in mediating spontaneous clearance and evolution in HCV infection, and viral strains containing epitope variants that are less recognized abrogate the protective effects of HLA-B 57. The finding that HLA-B 57-mediated antiviral immunity is associated with control of both human immunodeficiency virus-1 and HCV suggests a common shared mechanism of a successful immune response against persistent viruses.

Effect of Online 1-Day Cognitive Behavioral Therapy-Based Workshops Plus Usual Care vs Usual Care Alone for Postpartum Depression: A Randomized Clinical Trial.

Importance: Postpartum depression (PPD) affects as many as 20% of mothers, yet just 1 in 10 of these women receives evidence-based treatment. The COVID-19 pandemic has increased PPD risk, reduced treatment access, and shifted preferences toward virtual care. Objective: To determine whether an online 1-day cognitive behavioral therapy (CBT)-based workshop added to treatment as usual improves PPD, anxiety, social support, mother-infant relationship quality, and infant temperament more than treatment as usual alone. Design, Setting, and Participants: This randomized clinical trial included 403 women with PPD who were recruited across Ontario, Canada, during the COVID-19 pandemic (April 20 to October 4, 2020). Women with Edinburgh Postnatal Depression Scale (EPDS) scores of at least 10 who were 18 years or older and had an infant younger than 12 months were eligible. Interventions: Women were randomly assigned to receive a live, interactive online 1-day CBT-based workshop delivered by a registered psychotherapist, psychiatrist, or clinical psychology graduate student in addition to treatment as usual (n = 202) or to receive treatment as usual and wait-listed to receive the workshop 12 weeks later (n = 201). Main Outcomes and Measures: The primary outcome was change in PPD (EPDS scores) in experimental and wait list control groups 12 weeks after baseline. Secondary outcomes included maternal anxiety (7-item Generalized Anxiety Disorder Questionnaire [GAD-7]), social support (Social Provisions Scale), quality of the mother-infant relationship (Postpartum Bonding Questionnaire), and infant temperament (Infant Behavior Questionnaire-Revised Very Short Form). Results: Participants all identified as women with a mean (SD) age of 31.8 (4.4) years. The workshop led to significant mean (SD) reductions in EPDS scores (from 16.47 [4.41] to 11.65 [4.83]; B = -4.82; P < .001) and was associated with a higher odds of exhibiting a clinically significant decrease in EPDS scores (odds ratio, 4.15; 95% CI, 2.66-6.46). The mean (SD) GAD-7 scores decreased from 12.41 (5.12) to 7.97 (5.54) after the workshop (B = -4.44; 95% CI, -5.47 to -3.38; P < .001) and participants were more likely to experience a clinically significant change (odds ratio, 3.09; 95% CI, 1.99-4.81). Mothers also reported improvements in bonding (B = -3.22; 95% CI, -4.72 to -1.71; P < .001), infant-focused anxiety (B = -1.64; 95% CI, -2.25 to 1.00; P < .001), social support (B = 3.31; 95% CI, 1.04 to 5.57; P < .001), and positive affectivity/surgency in infants (B = 0.31; 95% CI, 0.05 to 0.56; P < .001). Conclusions and Relevance: In this randomized clinical trial, an online 1-day CBT-based workshop for PPD provides an effective, brief option for mothers, reducing PPD and anxiety as well as improving social support, the mother-infant relationship, and positive affectivity/surgency in offspring. Trial Registration: ClinicalTrials.gov Identifier: NCT04485000.

Protocol for a randomised trial evaluating a preconception-early childhood telephone-based intervention with tailored e-health resources for women and their partners to optimise growth and development among children in Canada: a Healthy Life Trajectory Initiative (HeLTI Canada).

INTRODUCTION: The 'Developmental Origins of Health and Disease' hypothesis suggests that a healthy trajectory of growth and development in pregnancy and early childhood is necessary for optimal health, development and lifetime well-being. The purpose of this paper is to present the protocol for a randomised controlled trial evaluating a preconception-early childhood telephone-based intervention with tailored e-health resources for women and their partners to optimise growth and development among children in Canada: a Healthy Life Trajectory Initiative (HeLTI Canada). The primary objective of HeLTI Canada is to determine whether a 4-phase 'preconception to early childhood' lifecourse intervention can reduce the rate of child overweight and obesity. Secondary objectives include improved child: (1) growth trajectories; (2) cardiometabolic risk factors; (3) health behaviours, including nutrition, physical activity, sedentary behaviour and sleep; and (4) development and school readiness at age 5 years. METHOD AND ANALYSIS: A randomised controlled multicentre trial will be conducted in two of Canada's highly populous provinces-Alberta and Ontario-with 786 nulliparous (15%) and 4444 primiparous (85%) women, their partners and, when possible, the first 'sibling child.' The intervention is telephone-based collaborative care delivered by experienced public health nurses trained in healthy conversation skills that includes detailed risk assessments, individualised structured management plans, scheduled follow-up calls, and access to a web-based app with individualised, evidence-based resources. An 'index child' conceived after randomisation will be followed until age 5 years and assessed for the primary and secondary outcomes. Pregnancy, infancy (age 2 years) and parental outcomes across time will also be assessed. ETHICS AND DISSEMINATION: The study has received approval from Clinical Trials Ontario (CTO 1776). The findings will be published in peer-reviewed journals and disseminated to policymakers at local, national and international agencies. Findings will also be shared with study participants and their communities. TRIAL REGISTRATION NUMBER: ISRCTN13308752; Pre-results.

It takes a village: a realist synthesis of social pediatrics program.

OBJECTIVES: To better understand how social pediatric initiatives (SPIs) enact equitable, integrated, embedded approaches with high-needs children and families while facilitating proportionate distribution of health resources. METHODS: The realist review method incorporated the following steps: (1) identifying the review question, (2) formulating the initial theory, (3) searching for primary studies, (4) selecting and appraising study quality, (5) synthesizing relevant data and (6) refining the theory. RESULTS: Our analysis identified four consistent patterns of care that may be effective in social pediatrics: (1) horizontal partnerships based on willingness to share status and power; (2) bridged trust initiated through previously established third party relationships; (3) knowledge support increasing providers' confidence and skills for engaging community; and (4) increasing vulnerable families' self-reliance through empowerment strategies. CONCLUSIONS: This research is unique because it focused on "how" outcomes are achieved and offers insight into the knowledge, skills and philosophical orientation clinicians need to effectively deliver care in SPIs. Research insights offer guidance for organizational leaders with a mandate to address child and youth health inequities and may be applicable to other health initiatives.

Does the Maryland graduated driver licensing law affect both 16-year-old drivers and those who share the road with them?

PROBLEM: To assess effects of the 1999 Maryland graduated driver licensing (GDL) law on both 16-year-old drivers and other road users. METHOD: Calculation and comparison of crash involvement rates and non-fatal injury rates pre-GDL (1996-1998) and post-GDL (2001-2003) by type of road user, per population, and per licensed driver, with adjustment for trends among 30-59-year-old drivers. RESULTS: Post-GDL, prevalence of licensure decreased 24% among 16-year-olds, and rates of 16-year-old drivers involved in crashes significantly decreased per 16-year-old population (corrected rate ratio (RRc) 0.82; 95% CI (0.71, 0.96)). A significant decrease also was observed for non-fatal injuries per 16-year-old population among 16-year-old drivers involved in crashes (RRc 0.63; 95% CI (0.41, 0.98)). Similarly, decreases, albeit not statistically significant, were observed among their passengers and other vehicle occupants. Per 16-year-old licensed driver, a slight non-significant increase was observed in crash involvement rates; non-fatal injury rates per 16-year-old licensed driver suggest decreased risk (non-significant) among 16-year-old drivers, their passengers, and other vehicle occupants. SUMMARY: Maryland's GDL delayed licensure and reduced crashes and non-fatal injuries among 16-year-old drivers per population. Trends in injuries among other road users involved in crashes with 16-year-old drivers were suggestive of a benefit from GDL, although observed decreases were not significant. Per licensed driver, findings were not significant, but suggested little change in crash involvement and decreased non-fatal injuries. Because one-third fewer 16-year-olds were licensed post-GDL, these results may suggest a selection effect in licensure. IMPACT ON INDUSTRY: Because Maryland had nighttime restrictions for new drivers before 1999, this study suggests other components of GDL are beneficial for drivers and possibly for other road users. States with weak GDL laws should strongly consider revising them.

Knowledge, attitude, willingness and readiness of primary health care providers to provide oral health services to children in Niagara, Ontario: a cross-sectional survey.

BACKGROUND: Most children are exposed to medical, but not dental, care at an early age, making primary health care providers an important player in the reduction of tooth decay. The goal of this research was to understand the feasibility of using primary health care providers in promoting oral health by assessing their knowledge, attitude, willingness and readiness in this regard. METHODS: Using the Dillman method, a mail-in cross-sectional survey was conducted among all family physicians and pediatricians in the Niagara region of Ontario who have primary contact with children. A descriptive analysis was performed. RESULTS: Close to 70% (181/265) of providers responded. More than 90% know that untreated tooth decay could affect the general health of a child. More than 80% examine the oral cavity for more than 50% of their child patients. However, more than 50% are not aware that white spots or lines on the tooth surface are the first signs of tooth decay. Lack of clinical time was the top reason for not performing oral disease prevention measures. INTERPRETATION: Overall, survey responses show a positive attitude and willingness to engage in the oral health of children. To capitalize on this, there is a need to identify mechanisms of providing preventive oral health care services by primary health care providers; including improving their knowledge of oral health and addressing other potential barriers.

Characterization of Mucosal Immune Responses to Enterotoxigenic Escherichia coli Vaccine Antigens in a Human Challenge Model: Response Profiles after Primary Infection and Homologous Rechallenge with Strain H10407.

Enterotoxigenic Escherichia coli (ETEC) bacteria are the most common bacterial cause of diarrhea in children in resource-poor settings as well as in travelers. Although there are several approaches to develop an effective vaccine for ETEC, no licensed vaccines are currently available. A significant challenge to successful vaccine development is our poor understanding of the immune responses that correlate best with protection against ETEC illness. In this study, ETEC-specific mucosal immune responses were characterized and compared in subjects challenged with ETEC strain H10407 and in subjects rechallenged with the homologous organism. IgA responses to lipopolysaccharide (LPS), heat-labile toxin B subunit (LTB), and colonization factor antigen I (CFA/I) in antibody in lymphocyte supernatant (ALS), feces, lavage fluid, and saliva samples were evaluated. In all assay comparisons, ALS was the most sensitive indicator of a local immune response, but serum IgA was also a useful indirect marker of immune response to oral antigens. Volunteers challenged and then rechallenged with strain H10407 were protected from illness following rechallenge. Comparing mucosal antibody responses after primary and homologous rechallenge, protection against disease was reflected in reduced antibody responses to key ETEC antigens and in reduced fecal shedding of the H10407 challenge strain. Subjects challenged with strain H10407 mounted stronger antibody responses to LPS and LTB than subjects in the rechallenge group, while responses to CFA/I in the rechallenge group were higher than in the challenge group. We anticipate that this study will help provide an immunological benchmark for the evaluation of ETEC vaccines and immunization regimens in the future.

The oral, live attenuated enterotoxigenic Escherichia coli vaccine ACE527 reduces the incidence and severity of diarrhea in a human challenge model of diarrheal disease.

An oral, live attenuated, three-strain recombinant bacterial vaccine, ACE527, was demonstrated to generate strong immune responses to colonization factor and toxin antigens of enterotoxigenic Escherichia coli (ETEC) in human volunteers. The vaccine was safe and well tolerated at doses of up to 10(11) CFU, administered in each of two doses given 21 days apart. These observations have now been extended in a phase 2b study with a total of 70 subjects. Fifty-six of these subjects were challenged 28 days after the second dose of vaccine with the highly virulent ETEC strain H10407 to obtain preliminary indicators of efficacy against disease and to support further development of the vaccine for both travelers and infants in countries where ETEC is endemic. The vaccine had a significant impact on intestinal colonization by the challenge strain, as measured by quantitative fecal culture 2 days after challenge, demonstrating the induction of a functional immune response to the CFA/I antigen. The incidence and severity of diarrhea were also reduced in vaccinees as measured by a number of secondary and ad hoc endpoints, although the 27% reduction seen in the primary endpoint, moderate to severe diarrhea, was not statistically significant. Together, these observations support the hypothesis that the ACE527 vaccine has a dual mode of action, targeting both colonization factors and the heat-labile enterotoxin (LT), and suggest that it should be further developed for more advanced trials to evaluate its impact on the burden of ETEC disease in field settings.

Malnutrition levels among vaccinated and unvaccinated children between 2 and 3 years of age following enrollment in a randomized clinical trial with the pentavalent rotavirus vaccine (PRV) in Bangladesh.

A double-masked, individually randomized Phase 3 clinical trial to assess the efficacy, safety and immunogenicity of the pentavalent rotavirus vaccine (PRV), RotaTeq™, was conducted in rural Matlab, Bangladesh (NCT00362648). A total of 1136 infants were enrolled and randomized to receive either vaccine or placebo in a 1:1 ratio administered with the standard EPI vaccines at a mean age of approximately 8, 12, and 16 weeks. Weight was collected at four time points (study vaccine doses 1, 2, and 3, and a close-out visit in March 2009 at 15-26 months of age), and birth weight was retrospectively collected from information contained on the mother's health card when available. Approximately one year following trial completion a separate study was conducted to collect anthropometry measurements, including weight and height. These measurements were linked with Phase 3 trial data and a post hoc analysis was conducted to assess the effects of rotavirus vaccination on malnutrition among enrolled children who could be located when they were between 27 and 38 months old. Among the 1033 (91%) children located, and measured, for this analysis height-for-age and weight-for-height Z scores were calculated and compared between vaccine and placebo recipients at the anthropometry follow-up 1-year post-trial, and weight-for-age Z scores were calculated at four trial time points in addition to the anthropometry follow-up. The data indicated that there was no effect of rotavirus vaccination on malnutrition in this population at any of the measured time points. PRV, estimated to have about 43% efficacy against severe rotavirus gastroenteritis in this population, may not reduce the overall burden of diarrheal illness sufficiently among all vaccinees to appreciably measure impact on growth compared with non-vaccinees. Regardless of the impact on malnutrition indicators, rotavirus vaccines are an important intervention for reducing morbidity and mortality in children in developing countries.

A combination vaccine consisting of three live attenuated enterotoxigenic Escherichia coli strains expressing a range of colonization factors and heat-labile toxin subunit B is well tolerated and immunogenic in a placebo-controlled double-blind phase I trial in healthy adults.

Immune responses against colonization factors (CFs) and the nontoxic B component of the enterotoxigenic Escherichia coli (ETEC) heat-labile toxin (LTB) are considered to be important for immunity against diarrhea caused by ETEC. Individual live attenuated ETEC derivatives that have had their toxin genes removed and whose aroC, ompC, and ompF genes are deleted have shown promise as vaccines against ETEC. The development of such strains has culminated in the testing of a three-strain-combination live attenuated vaccine known as ACE527, comprised of strains ACAM2025 expressing colonization factor antigen I (CFA/I) and LTB; ACAM2022, expressing CS5, CS6, and LTB; and ACAM2027, expressing CS1, CS2, CS3, and LTB. The recombinant CF and LTB genes expressed in the three strains were inserted into the bacterial chromosome to ensure their stable inheritance and expression without the requirement for any selection. ACE527 has been tested in a randomized placebo-controlled, double-blind, phase I safety and immunogenicity study in healthy adult volunteers and proved to be well tolerated and immunogenic at dose levels of 10(10) and 10(11) total CFU. There was no indication of strain interference on the basis of fecal shedding patterns, with all three being detected in the feces of 50% and 83% of low- and high-dose vaccine recipients, respectively. Similarly, strong immune responses to LTB and to CFs expressed on all three constituent strains were induced, with at least 50% of subjects in the high-dose group responding to LTB, CFA/I, CS3, and CS6.

Refinement of a human challenge model for evaluation of enterotoxigenic Escherichia coli vaccines.

Enterotoxigenic Escherichia coli (ETEC) strain H10407 (serotype O78:H11 producing heat-labile toxin [LT], heat-stable toxin [ST], and colonization factor I [CFA/I]) induces reliably high diarrheal attack rates (ARs) in a human challenge model at doses of ≥10(9) CFU. A descending-dose challenge study was conducted with changes to the standard fasting time and buffer formulation, seeking conditions that permit lower inocula while maintaining reproducibly high ARs. In cohort 1, 20 subjects were fasted overnight and randomized 1:1:1:1 to receive H10407 at doses of 10(8) CFU with bicarbonate, 10(8) CFU with CeraVacx, 10(7) CFU with bicarbonate, or 10(7) CFU with CeraVacx. Subsequent cohorts received H10407 (10(7) CFU with bicarbonate) with similar fasting conditions. Cohort 2 included 15 ETEC-naïve volunteers. Cohort 3 included 10 ETEC-naïve volunteers and 10 rechallenged volunteers. In all, 25/35 (71%) ETEC-naïve recipients of 10(7) CFU of H10407 developed moderate or severe diarrhea (average maximum stool output/24 h = 1,042 g), and most (97%) shed H10407 (maximum geometric mean titer = 7.5 × 10(7) CFU/gram of stool). Only one of 10 rechallenged volunteers developed diarrhea. These rechallenged subjects had reduced intestinal colonization, reflected by quantitative microbiology of fecal samples. Among the 35 ETEC-naïve subjects, anti-lipopolysaccharide (LPS) O78 serum antibody responses were striking, with positive IgA and IgG antibody responses in 33/35 (94%) and 25/35 (71%), respectively. Anti-heat-labile enterotoxin (LTB) serum IgA and IgG responses developed in 19/35 (54%) and 14/35 (40%) subjects, respectively. Anti-CFA/I serum IgA and IgG responses were detected in 15/35 (43%) and 8/35 (23%) subjects. After the second challenge, participants exhibited blunted anti-LPS and -LTB responses but a booster response to CFA/I. This ETEC model should prove useful in the future evaluation of ETEC vaccine candidates.

Comparative evaluation of the antibody in lymphocyte supernatant (ALS) and enzyme-linked immunospot (ELISPOT) assays for measuring mucosal immune responses to Shigella antigens.

Accurately assessing mucosal immune responses to candidate vaccines remains a technical challenge. ELISPOT is widely used as a surrogate of mucosal immune response by directly enumerating circulating antibody secreting cells (ASCs), while antibody in lymphocyte supernatant (ALS) titers the total amount of antibody secreted by ASC ex vivo using ELISA. ALS is more practical than ELISPOT because the ASC supernatant is frozen for ELISA that can be conducted at any time, with any antigen, and in any laboratory. We compared IgA and IgG responses to serotype-specific Shigella LPS using ELISPOT and ALS in subjects following vaccination or infection with Shigella. ALS results correlated well with ELISPOT results, and the ALS method was both sensitive and specific for the detection of antibody responses against Shigella LPS. Based on these observations, the ALS assay is a practical and flexible alternative to ELISPOT for measuring mucosal IgA responses to Shigella LPS antigen.