Prioritizing the needs of children in a changing climate.

In a Perspective, Lawrence Stanberry and colleagues discuss impacts of climate change on children.

Current thinking on genital herpes.

PURPOSE OF REVIEW: Genital herpes has a high global prevalence and burden of disease. This manuscript highlights recent advances in our understanding of genital herpes simplex virus (HSV) infections. RECENT FINDINGS: Studies demonstrate a changing epidemiological landscape with an increasing proportion of genital herpes cases associated with HSV type 1. There is also growing evidence that the majority of infected individuals exhibit frequent, brief shedding episodes that are most often asymptomatic, which likely contribute to high HSV transmission rates. Given this finding as well as readily available serological assays, some have proposed that routine HSV screening be performed; however, this remains controversial and is not currently recommended. Host immune responses, particularly local CD4 and CD8 T cell activity, are crucial for HSV control and clearance following initial infection, during latency and after reactivation. Prior HSV immunity may also afford partial protection against HSV reinfection and disease. Although HSV vaccine trials have been disappointing to date and existing antiviral medications are limited, novel prophylactic and therapeutic modalities are currently in development. SUMMARY: Although much remains unknown about genital herpes, improved knowledge of HSV epidemiology, pathogenesis and host immunity may help guide new strategies for disease prevention and control.

Infection prevention and control and related practices in African neonatal units: The Pan-African neonatal care assessment study (PANCAS).

BACKGROUND: The burden of neonatal mortality is primarily borne by low- and middle-income countries (LMICs), including deaths due to healthcare-associated infections (HAIs). Few studies have assessed infection prevention and control (IP&C) practices in African units caring for small and/or sick newborns aimed to reduce HAIs. METHODS: We performed a mixed-methods study composed of a survey and virtual tour to assess IP&C and related practices. We created a survey composed of multiple-choice and open-ended questions delivered to site respondents via Zoom or video equivalent. Respondents provided a virtual tour of their unit via video and the study team used a checklist to evaluate specific practices. RESULTS: We recruited 45 units caring for small and sick newborns in 20 African countries. Opportunities to optimize hand hygiene, Water, Sanitation and Hygiene (WASH) practices, Kangaroo Mother Care, and IP&C training were noted. The virtual tour offered further understanding of IP&C challenges unique to individual sites. All respondents expressed the need for additional space, equipment, supplies, education, and IP&C staff and emphasized that attention to maternal comfort was important to IP&C success. DISCUSSION: This study identified opportunities to improve IP&C practices using low-cost measures including further education and peer support through learning collaboratives. Virtual tours can be used to provide site-specific assessment and feedback from peers, IP&C specialists and environmental engineering experts.

Diagnosis, Treatment, and Prevention Resources for Infectious Diseases in Sub-Saharan African Hospitals Caring for Children.

Objective. The Children's Hospitals in Africa Mapping Project survey was developed and implemented to assess the readiness of hospitals in sub-Saharan African to respond to emergencies, epidemics, and pandemics affecting children. Methods. This sub-study analyzed 56 survey questions that characterized the hospitals and assessed resources for diagnosis, treatment, and prevention of community-acquired infections and healthcare-associated infections (HAIs). Results. Twenty-four sites were recruited and 20 (from 15 countries) completed the survey in 2018 to 2019. Overall, 90% to 100% of sites reported that diagnostic assays were available for malaria, tuberculosis, and HIV. Periodic shortages of antibiotics, antimalarial drugs, and vaccines were reported by 45%, 25%, and 20% of sites, respectively. Sites reported formal programs for infection prevention and control (79%), monitoring HAIs (17%), and antimicrobial stewardship (53%). Conclusions. Opportunities to improve care for hospitalized African children were identified. These included resources for HAI surveillance and antimicrobial stewardship which can facilitate epidemic and pandemic preparedness.

Acceptability of optical coherence tomography and abstinence requirements among women participating in microbicide safety trials.

BACKGROUND: Developing effective and safe microbicides requires study procedures (e.g., technology used, abstinence requirements, and product use) that are acceptable to participants. METHODS: Thirty women completed 4 study visits including pelvic examination, colposcopy, optical coherence tomography (OCT), and semistructured, qualitative interviews. Additional requirements included abstinence (for approximately 16 days) and twice daily vaginal product use (for 5.5 days). Interviews were audio-recorded, transcribed, and analyzed using framework analysis. Themes addressing OCT experiences, acceptability of abstinence, and vaginal product use were examined. RESULTS: OCT was viewed favorably as an imaging technology. Some women reported feeling the fiber-optic probe "poking" them and more than one-third spontaneously reported feeling pressure or pinching upon rotation of the speculum in connection with the OCT evaluation. Compliance with vaginal gel use was high, but for many women assigned to use a product containing nonoxynol-9 (vs. placebo), the postproduct use examination was more uncomfortable, relative to the initial examination or 1 week following product discontinuation. Nearly all women experienced product leakage; acceptability of leakage varied. Two women were not abstinent and several more found abstinence challenging. Some women involved their partner in decision making regarding trial enrollment. Strategies to remain abstinent included participating when the partner was away, avoiding early intimacy, and engaging in alternative sexual activities. CONCLUSIONS: Qualitative interviews in early-phase studies provide insights and capture information that would be missed by behavioral inference alone. Understanding participant's experiences is important in order to provide anticipatory guidance and plan future microbicide studies that facilitate adherence with trial requirements.

Treatment with a novel topical nanoemulsion (NB-001) speeds time to healing of recurrent cold sores.

BACKGROUND: Current topical therapies for cold sores are only marginally beneficial due to poor skin penetration. We assessed the safety and efficacy of a novel topical antiviral nanoemulsion (NB-001) with high tissue bioavailability. OBJECTIVES: The primary endpoint was the time to lesion healing. METHODS: 482 subjects with recurrent cold sores were randomized to self-initiate treatment with either vehicle or NB-001 (0.1%, 0.3% or 0.5%) at the first signs or symptoms of a cold sore episode. Lotion was applied 5 times per day, approximately 3 to 4 hours apart, for 4 days. Time to lesion healing was correlated with NB-001 bioavailability determined in human cadaver skin. RESULTS: Subjects treated with 0.3% NB-001 showed a 1.3-day improvement in the mean time to healing compared to vehicle (P=0.006). This was consistent with human cadaver skin data indicating that the 0.3% nanoemulsion had the highest bioavailability, compared to 0.1% and 0.5% emulsions. No significant safety or dermal irritation concerns or systemic absorption were noted with any of the doses. CONCLUSIONS: Topical NB-001 (0.3%) was well tolerated and highly efficacious in shortening the time to healing of cold sores. The improvement in time to healing was similar to that reported for oral nucleoside analogues, but without systemic exposure. Topical agents for recurrent herpes labialis (cold sores) reduce healing time by one half day, compared to oral therapies that speed healing by a day or more. A topical antiviral nanoemulsion was well tolerated and improved cold sore healing time by over a day compared to vehicle control. Nanoemulsion (NB-001) could represent a more efficacious topical treatment for recurrent cold sores.

Parental reasons for utilization of an urban pediatric emergency department during the 2009 H1N1 influenza epidemic.

OBJECTIVE: The objective of the study was to understand the utilization of the pediatric emergency department (PED) of an academic hospital during regular primary care office hours during the 2009 H1N1 epidemic. Children with a usual source of care presenting for influenza-like illness (ILI) symptoms were compared with those presenting with other symptoms. METHODS: During the 2009 H1N1 outbreak, parents visiting a PED in a low-income area in New York City in June 2009 were surveyed using open- and close-ended questions. Sociodemographic factors and reasons for seeking care in the PED rather than their usual source of care were compared between groups. RESULTS: There were no sociodemographic differences among children brought to the PED for ILI and those brought for other presenting symptoms. Those families with a child with ILI symptoms were less likely to report urgency as the primary reason they brought their child to the PED. A common reason reported for coming to the PED was limited access to care. In further exploration of limited access, parents with a child with ILI symptoms were more likely to report that their usual source of care did not have any evening and/or weekend hours, and they did not know how to reach their provider after hours. CONCLUSIONS: Enhancing access to primary care settings and encouraging parents to use their primary care providers might reduce the utilization of the PED for nonurgent problems during epidemics.

Seroprevalence of cytomegalovirus (CMV) and risk factors for infection in adolescent males.

BACKGROUND: Congenital cytomegalovirus (CMV) is a leading cause of disability, including sensorineural hearing loss, developmental delay, and mental retardation. Although the seroprevalence of CMV and associated exposure and behavioral risk factors have been reported in adolescent females, few data exist about males. METHODS: Serum samples were obtained from males aged 12-17 years from June 2006 through July 2007 in Cincinnati, Ohio; Galveston, Texas; and Nashville, Tennessee. The samples were tested for CMV immunoglobulin G antibody with a commercial assay. Participants completed a computer-assisted screening interview to assess 7 risk categories. RESULTS: A total of 397 adolescent males were screened, and 165 (47%) were seropositive. African American race, older age, and exposure to children ≤ 3 years of age in the home were significant predictors of CMV infection in the univariate analysis. Hispanic ethnicity, group living situations, saliva-sharing behaviors, and intimate sexual contact were not associated with CMV infection. However, among those with a history of sexual contact, the number of life-time partners was associated with CMV. In the final multivariate model, CMV seroprevalence was significantly higher in African American subjects (odds ratio [OR], 1.93; 95% confidence interval [CI], 1.27-2.95) and subjects ≥ 14 years of age (OR, 1.1; 95% CI, 1.0-1.28). With each additional risk factor, males had a 1.6 times increased risk of CMV. CONCLUSIONS: CMV infections are common in adolescent males and are associated with African American race and increasing age. Further study is needed to understand these risk factors in preparation for a CMV vaccine targeted at both adolescent males and females.

Benzalkonium chloride causes colposcopic changes and increased susceptibility to genital herpes infection in mice.

BACKGROUND: Colposcopy is widely used in clinical microbicide safety testing but not in preclinical small animal studies. Endoscopic colposcopy could be employed in small animals allowing colposcopy to be used as one component in a multifactorial safety testing paradigm. STUDY DESIGN: We conducted dose-response studies in mice using 2%, 0.2%, or 0.02% benzalkonium chloride (BZK) as the test compound, and using multiple safety end points that included endoscopic colposcopy, susceptibility to vaginal HSV-2 infection, histology, and entry of inflammatory cells into the vagina. RESULTS: Animals treated with 0.2% or higher BZK experienced vaginal toxicities detectable by all tests used including colposcopy. In contrast, 0.02% BZK produced no significant changes except by histology in which a significant thinning of the vaginal epithelium was seen. CONCLUSION: Endoscopic colposcopy detected microbicide-elicited changes in the mouse vagina with similar sensitivity to the other endpoints used in these studies and would appear to be useful as part of a multifactorial microbicide safety testing paradigm in mice.

High resolution imaging of epithelial injury in the sheep cervicovaginal tract: a promising model for testing safety of candidate microbicides.

BACKGROUND: Access to readily available large animal models and sensitive noninvasive techniques that can be used for the evaluation of microbicide-induced changes in tissue could significantly facilitate preclinical evaluations of microbicide safety. The sheep cervicovaginal tract, with stratified squamous epithelium similar to humans, holds promise as a large animal model used before nonhuman primates. In addition, optical coherence tomography (OCT) could enable high resolution visualization of tissue morphology and noninvasive assessment of microbicide-induced epithelial injury. METHODS: We evaluated the dose response of sheep cervicovaginal tract to benzalkonium chloride (BZK). Twenty sheep received treatment with phosphate-buffered saline or BZK solution (2%, 0.2%, or 0.02%). Pre- and posttreatment colposcopy and OCT images were collected and graded based on World Health Organization criteria and a previously reported scoring system, respectively. Biopsies were collected and the degree of epithelial injury and its thickness was assessed based on histology and OCT. RESULTS: The sheep cervicovagina exhibited anatomic and microscopic features similar to the human. Extensive loss of the epithelium was noted on colposcopy and OCT after application of 2% BZK. Colposcopy detected findings in half of sheep and OCT in all sheep treated with 0.2% BZK. OCT detected differences in the 0.02% BZK-treated group compared with controls, whereas colposcopy failed to detect any changes. CONCLUSIONS: The sheep cervicovagina is similar to humans, and exhibits dose dependent epithelial changes after BZK treatment. These findings suggest that the sheep model and OCT may become valuable tools for the safety evaluation of candidate microbicides, and warrant continued development.

Glycoprotein-D-adjuvant vaccine to prevent genital herpes.

BACKGROUND: An effective prophylactic vaccine would help control the spread of genital herpes. METHODS: We conducted two double-blind, randomized trials of a herpes simplex virus type 2 (HSV-2) glycoprotein-D-subunit vaccine with alum and 3-O-deacylated-monophosphoryl lipid A in subjects whose regular sexual partners had a history of genital herpes. In Study 1, subjects were seronegative for herpes simplex virus type 1 (HSV-1) and HSV-2; in Study 2, subjects were of any HSV serologic status. At months 0, 1, and 6, subjects received either vaccine or a control injection and were evaluated for 19 months. The primary end point was the occurrence of genital herpes disease in all subjects in Study 1 and in HSV-2-seronegative female subjects in Study 2. RESULTS: A total of 847 subjects who were seronegative for both HSV-1 and HSV-2 (268 of them women, in Study 1) and 1867 subjects who were seronegative for HSV-2 (710 of them women, in Study 2) underwent randomization and received injections. Vaccination was well tolerated and elicited humoral and cellular responses. Overall, the efficacy of the vaccine was 38 percent in Study 1 (95 percent confidence interval, -18 to 68 percent; 15 cases occurred in the vaccine group and 24 in the control group), and efficacy in female subjects was 42 percent in Study 2 (95 percent confidence interval, -31 to 74 percent; 9 cases occurred in the vaccine group and 16 in the control group). In both studies, further analysis showed that the vaccine was efficacious in women who were seronegative for both HSV-1 and HSV-2: efficacy in Study 1 was 73 percent (95 percent confidence interval, 19 to 91 percent; P=0.01), and efficacy in Study 2 was 74 percent (95 percent confidence interval, 9 to 93 percent; P=0.02). It was not efficacious in women who were seropositive for HSV-1 and seronegative for HSV-2 at base line or in men. CONCLUSIONS: These studies suggest that the glycoprotein D vaccine has efficacy against genital herpes in women who are seronegative for both HSV-1 and HSV-2 at base line but not in those who are seropositive for HSV-1 and seronegative for HSV-2. It had no efficacy in men, regardless of their HSV serologic status.

Pregnant women's attitudes about topical microbicides for the prevention and treatment of bacterial vaginosis during pregnancy.

We sought to understand pregnant women's product preference and likelihood of use of topical microbicides for bacterial vaginosis (BV) prevention and treatment. Pregnant women (N = 196) in a obstetrics clinic completed a survey between June 2014 and January 2015 about vaginal product use for BV. This cross-sectional study explored product preferences, likelihood of product use for BV management and father of the baby (FOB) involvement. Most participants were under 30 (68%) and underrepresented minorities (47% Hispanic, 21% African-American). Most women preferred the gel (69%). Only 30% were likely to use either product for prevention of BV; 76% if high risk for BV; 83% treatment of BV. Anticipated FOB involvement in decision-making included that 46% would ask his opinion, 38% would inform him of the decision and 7% would need approval. Most (87%) would ask the FOB for reminders and 66% for insertion help. Those under 30 were more likely to agree to ask the FOB for reminders (p < 0.01) and insertion help (p = 0.05). African-American women were less likely to have their FOB help with insertion (p < 0.01). Product preferences may be less critical than risk perception. Involvement of the FOB in decision-making may be vital.

Prevalence of herpes simplex virus types 1 and 2 among children and adolescents attending a sexual abuse clinic.

BACKGROUND: Children and adolescents with a history of sexual abuse are at risk for acquiring herpes simplex virus (HSV) type 2. We evaluated the prevalence of HSV-1 and HSV-2 and the usefulness for this population of 2 commercially available tests. METHODS: Sera from 150 children seen in a sexual abuse clinic were analyzed for type-specific HSV antibodies using Focus HerpeSelect HSV-2 ELISA (Focus), Biokit HSV-2 Rapid Test (Biokit), and by Western blot (WB). RESULTS: The patient sample was 81% female, had a mean age of 11.6 years (range, 1 to 18 years), and was 46% Caucasian, 28% Hispanic, 25% African American, and 2% other. According to WB, 77 (51%) of the children were HSV-1 seropositive. For HSV-2, there was 1 "true positive" (positive by all 3 tests) and 1 patient whose serum had atypical HSV-2 bands by WB but was positive by Focus. There were 6 sera that were positive by Focus and negative by WB. Index values of these 6 Focus tests were not predictive of WB status. For the 105 samples for which Biokit data were available, all samples were concordant with WB. CONCLUSIONS: The findings of this study suggest that routine screening for HSV-2 in sexually abused children does not have a high yield. The Focus test has an unacceptably high rate of false-positive results in children; however, Biokit may be an acceptable substitute for WB in evaluating children for HSV-2 antibodies.

Vaccine hesitancy and healthcare providers.

While most people vaccinate according to the recommended schedule, this success is challenged by individuals and groups who delay or refuse vaccines. The aim of this article is to review studies on vaccine hesitancy among healthcare providers (HCPs), and the influences of their own vaccine confidence and vaccination behaviour on their vaccination recommendations to others. The search strategy was developed in Medline and then adapted across several multidisciplinary mainstream databases including Embase Classic & Embase, and PschInfo. All foreign language articles were included if the abstract was available in English. A total of 185 articles were included in the literature review. 66% studied the vaccine hesitancy among HCPs, 17% analysed concerns, attitudes and/or behaviour of HCPs towards vaccinating others, and 9% were about evaluating intervention(s). Overall, knowledge about particular vaccines, their efficacy and safety, helped to build HCPs own confidence in vaccines and their willingness to recommend vaccines to others. The importance of societal endorsement and support from colleagues was also reported. In the face of emerging vaccine hesitancy, HCPs still remain the most trusted advisor and influencer of vaccination decisions. The capacity and confidence of HCPs, though, are stretched as they are faced with time constraints, increased workload and limited resources, and often have inadequate information or training support to address parents' questions. Overall, HCPs need more support to manage the quickly evolving vaccine environment as well as changing public, especially those who are reluctant or refuse vaccination. Some recommended strategies included strengthening trust between HCPs, health authorities and policymakers, through more shared involvement in the establishment of vaccine recommendations.

Vaccine safety evaluation: Practical aspects in assessing benefits and risks.

Vaccines are different from most medicines in that they are administered to large and mostly healthy populations including infants and children, so there is a low tolerance for potential risks or side-effects. In addition, the long-term benefits of immunisation in reducing or eliminating infectious diseases may induce complacency due to the absence of cases. However, as demonstrated in recent measles outbreaks in Europe and United States, reappearance of the disease occurs as soon as vaccine coverage falls. Unfounded vaccine scares such as those associating the combined measles-mumps-rubella vaccine with autism, and whole-cell pertussis vaccines with encephalopathy, can also have massive impacts, resulting in reduced vaccine uptake and disease resurgence. The safety assessment of vaccines is exhaustive and continuous; beginning with non-clinical evaluation of their individual components in terms of purity, stability and sterility, continuing throughout the clinical development phase and entire duration of use of the vaccine; including post-approval. The breadth and depth of safety assessments conducted at multiple levels by a range of independent organizations increases confidence in the rigour with which any potential risks or side-effects are investigated and managed. Industry, regulatory agencies, academia, the medical community and the general public all play a role in monitoring vaccine safety. Within these stakeholder groups, the healthcare professional and vaccine provider have key roles in the prevention, identification, investigation and management of adverse events following immunisation (AEFI). Guidelines and algorithms aid in determining whether AEFI may have been caused by the vaccine, or whether it is coincidental to it. Healthcare providers are encouraged to rigorously investigate AEFIs and to report them via local reporting processes. The ultimate objective for all parties is to ensure vaccines have a favourable benefit-risk profile.