by
Andi L Shane;
Michael D Cabana;
Stephane Vidry;
Dan Merenstein;
Ruben Hummelen;
Collin L Ellis;
James T Heimbach;
Susanne Hempel;
Susan V Lynch;
Mary Elle Sanders;
Daniel J Tancredi
The heterogeneity of human clinical trials to assess the effectiveness of probiotics presents challenges regarding interpretation and comparison. Evidence obtained from clinical trials among a population with a disease or specific risk factors may not be generalizable to healthy individuals. The evaluation of interventions in healthy persons requires careful selection of outcomes due to the absence of health indicators and the low incidence of preventable conditions. Given the tremendous resources invested in such trials, development of consistent approaches to assessing the effectiveness of probiotics would be beneficial. Furthermore, the reporting, presentation and communication of results may also affect the validity of the scientific evidence obtained from a trial. This review outlines the challenges associated with the design, implementation, data analysis and interpretation of clinical trials in humans involving probiotics. Best practices related to their design are offered along with recommendations for enhanced collaboration to advance research in this emerging field.
Objective:
To describe system failures potentially contributing to perinatal HIV transmission in the state of Georgia, United States, between 2005 and 2012.
Design:
A retrospective chart review of antenatal and postnatal records of HIV-infected infants between 1 January 2005 and 31 December 2012.
Methods:
Study participants included all HIV-infected infants referred for specialized management to the Ponce Family and Youth Clinic within Grady Health Systems in Atlanta. Main outcomes included identification of maternal, perinatal, and neonatal risk factors associated with vertical transmission.
Results:
Twenty-seven cases were identified; 89% of mothers were African–American between 16 and 30 years of age. Seventy-four percent of women knew their HIV status prior to pregnancy, 44% had no prenatal care, and 52% did not receive combination antiretroviral therapy during pregnancy or intrapartum zidovudine. HIV-1 RNA near the time of delivery was available in only 10 of 27 mothers, and of those, only three had an undetectable HIV-1 RNA level. Caesarean section was performed in 70% of women. Of the 27 children, the mean gestational age was 37 (SD: 2.9) weeks, with 33% requiring neonatal ICU admission. Fifty-nine percent were men, and only 67% received postnatal zidovudine prophylaxis.
Conclusion:
Mother-to-child transmission of HIV continues to occur in Georgia at unacceptable levels. Increased education with adherence to existing national guidelines, as well as coordinated efforts between healthcare and public health providers to improve linkage and retention in medical care are urgently needed to prevent further vertical transmission events in Georgia.
ABSTRACT: This is a summary from a workshop convened as part of the 13thannual meeting of the International Scientific Association for Probiotics and Prebiotics. A group of 24 stakeholders, including clinical experts, researchers, federal government officials, funding agencies, lawyers and industry experts met to review the challenges of the current regulatory approach to human research on probiotics in the USA and to discuss ways to move research forward. There was agreement that some of the current regulatory requirements imposed on probiotic research in the United States hindered research progress and increased cost without improving study subject safety. Many situations were outlined by clinical investigators demonstrating the impact of regulatory delays on research progress. Additionally, research is compromised when study designs and outcomes require manipulation so as to invoke less burdensome regulatory requirements. These responses by investigators to regulatory requirements have placed United States' researchers at a disadvantage. The public ultimately suffer when research to clarify the role of these products on health is stalled. Workshop participants concurred that regulatory oversight should balance study subject vulnerability with documented safety for the intended use for the probiotic strain, and that human research on foods and supplements should not be be regulated as drug research. Challenges and potential improvement strategies are discussed.
Objective: To evaluate if routine supplementation of Lactobacillus rhamnosus GG ATCC 53103 (LGG) is associated with a decreased risk of necrotizing enterocolitis in very low birth weight (VLBW) infants. Study design: Retrospective observational cohort study of VLBW (<1500 g) infants at a single center from 2008 to 2016. LGG supplementation with Culturelle at a dose of 2.5 to 5 × 10 9 CFU/day began in 2014. We used multivariable logistic regression to evaluate the association between LGG supplementation and necrotizing enterocolitis (modified Bell stage IIA or greater), after adjusting for potential confounders. We also compared changes in necrotizing enterocolitis incidence before and after implementation of LGG using a statistical process control chart. Results: We evaluated 640 VLBW infants with a median gestational age of 28.7 weeks (IQR 26.3-30.6); 78 (12%) developed necrotizing enterocolitis. The median age at first dose of LGG was 6 days (IQR 3-10), and duration of supplementation was 32 days (IQR 18-45). The incidence of necrotizing enterocolitis in the epoch before LGG implementation was 10.2% compared with 16.8% after implementation. In multivariable analysis, LGG supplementation was associated with a higher risk of necrotizing enterocolitis (aOR 2.10, 95 % CI 1.25-3.54, P =.005). We found no special cause variation in necrotizing enterocolitis after implementation of LGG supplementation. There were no episodes of Lactobacillus sepsis during 5558 infant days of LGG supplementation. Conclusions: In this study, routine LGG supplementation was not associated with a decreased risk of necrotizing enterocolitis. Our findings do not support the use of the most common probiotic preparation currently supplemented to VLBW infants in the US.
The advent of virus reverse genetics has enabled the incorporation of genetically encoded reporter proteins into replication-competent viruses. These reporters include fluorescent proteins which have intrinsic chromophores that absorb light and re-emit it at lower wavelengths, and bioluminescent proteins which are luciferase enzymes that react with substrates to produce visible light. The incorporation of these reporters into replication-competent viruses has revolutionized our understanding of molecular virology and aspects of viral tropism and transmission. Reporter viruses have also enabled the development of high-throughput assays to screen antiviral compounds and antibodies and to perform neutralization assays. However, there remain technical challenges with the design of replication-competent reporter viruses, and each reporter has unique advantages and disadvantages for specific applications. This review describes currently available reporters, design strategies for incorporating reporters into replication-competent paramyxoviruses and orthomyxoviruses, and the variety of applications for which these tools can be utilized both in vitro and in vivo.
Rotavirus and norovirus are important etiologies of gastroenteritis among hospitalized children. During 2012-2013, we tested 207 residual stool specimens from children with healthcareassociated vomiting and/or diarrhea for rotavirus and norovirus. Twenty (10%) were rotavirus positive, and 3 (3%) were norovirus positive, stressing the importance of these pathogens in hospitalized children.
Background: Live oral rotavirus vaccines have been less immunogenic and efficacious among children in poor developing countries compared with middle income and industrialized countries for reasons that are not yet completely understood. We assessed whether the neutralizing activity of breast milk could lower the titer of vaccine virus and explain this difference in vitro. Methods: Breast milk samples were collected from mothers who were breast-feeding infants 4 to 29 weeks of age (ie, vaccine eligible age) in India (N = 40), Vietnam (N = 77), South Korea (N = 34), and the United States (N = 51). We examined breast milk for rotavirus-specific IgA and neutralizing activity against 3 rotavirus vaccine strains-RV1, RV5 G1, and 116E using enzyme immunoassays. The inhibitory effect of breast milk on RV1 was further examined by a plaque reduction assay. FINDINGS:: Breast milk from Indian women had the highest IgA and neutralizing titers against all 3 vaccine strains, while lower but comparable median IgA and neutralizing titers were detected in breast milk from Korean and Vietnamese women, and the lowest titers were seen in American women. Neutralizing activity was greatest against the 2 vaccine strains of human origin, RV1 and 116E. This neutralizing activity in one half of the breast milk specimens from Indian women could reduce the effective titer of RV1 by ∼2 logs, of 116E by 1.5 logs, and RV5 G1 strain by ∼1 log more than that of breast milk from American women. INTERPRETATION:: The lower immunogenicity and efficacy of rotavirus vaccines in poor developing countries could be explained, in part, by higher titers of IgA and neutralizing activity in breast milk consumed by their infants at the time of immunization that could effectively reduce the potency of the vaccine. Strategies to overcome this negative effect, such as delaying breast-feeding at the time of immunization, should be evaluated.
BACKGROUND The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in late 2019 and spread globally, prompting an international effort to accelerate development of a vaccine. The candidate vaccine mRNA-1273 encodes the stabilized prefusion SARS-CoV-2 spike protein. METHODS We conducted a phase 1, dose-escalation, open-label trial including 45 healthy adults, 18 to 55 years of age, who received two vaccinations, 28 days apart, with mRNA-1273 in a dose of 25 μg, 100 μg, or 250 μg. There were 15 participants in each dose group. RESULTS After the first vaccination, antibody responses were higher with higher dose (day 29 enzyme-linked immunosorbent assay anti–S-2P antibody geometric mean titer [GMT], 40,227 in the 25-μg group, 109,209 in the 100-μg group, and 213,526 in the 250-μg group). After the second vaccination, the titers increased (day 57 GMT, 299,751, 782,719, and 1,192,154, respectively). After the second vaccination, serum-neutralizing activity was detected by two methods in all participants evaluated, with values generally similar to those in the upper half of the distribution of a panel of control convalescent serum specimens. Solicited adverse events that occurred in more than half the participants included fatigue, chills, headache, myalgia, and pain at the injection site. Systemic adverse events were more common after the second vaccination, particularly with the highest dose, and three participants (21%) in the 250-μg dose group reported one or more severe adverse events. CONCLUSIONS The mRNA-1273 vaccine induced anti–SARS-CoV-2 immune responses in all participants, and no trial-limiting safety concerns were identified. These findings support further development of this vaccine.
Background
Vitamin D deficiency is common in HIV-infected individuals. In adults, traditional and HIV-related factors play a role in vitamin D status, and deficiency appears to impair immune restoration and exacerbate HIV complications, like cardiovascular disease (CVD). This study sought to determine factors contributing to vitamin D status in HIV-infected youth and investigate the relationship with CVD risk, inflammation, and immune restoration.
Methods
HIV-infected subjects (1–25 years old) were enrolled prospectively along with healthy controls that were group-matched by age, sex, and race. HIV data were collected for the HIV-infected group, while traditional risk factors, including vitamin D intake, sun exposure, skin pigmentation, physical activity level, and body mass index (BMI) were collected for both groups. Fasting lipids, plasma 25-hydroxyvitamin D (25(OH)D), and inflammation markers were measured.
Results
200 HIV-infected subjects and 50 controls were enrolled. HIV group had 53% male, 95% black, and a mean age of 17.2±4.6 years. There was no difference in 25(OH)D between groups; 77% of HIV+ and 74% of controls had 25(OH)D <20 ng/mL. Only Fitzpatrick skin type was independently associated with 25(OH)D. No HIV variables were associated with 25(OH)D, even when HIV sub-populations were examined. Inflammation, CVD risk factors, and immune restoration were not independently associated with 25(OH)D.
Conclusions
Vitamin D deficiency is common among HIV-infected youth. However, HIV factors, CVD risk, inflammation, and immune restoration do not appear to have the same relationship with vitamin D as has been shown in adults. Supplementation trials are needed to determine if increasing 25(OH)D concentrations could better elucidate these relationships.
Objective Anal cancer rates are increasing among HIV-infected persons. Although an efficacious human papillomavirus (HPV) vaccine is available, HPV vaccination rates remain low. Therefore, providers perform anal cancer screening, but there is no consensus on the optimal methods or timing of screening. This study was performed to determine the prevalence of and factors associated with anal squamous intraepithelial lesions in sexually active HIV-infected young men who have sex with men and transgender women. Materials and Methods We performed a single-center, retrospective study of sexually active HIV-infected young men who have sex with men and transgender women aged 13 to 24 years at an HIV clinic in Atlanta GA from 2009 to 2016. We used analysis of variance and χ2 tests of independence to evaluate bivariate associations and identify demographic, behavioral, and clinical risk factors. Results Of 314 subjects with a mean (SD) age of 20.4 (2.1) years at initial anal cytology testing, 5% had completed the HPV vaccine series at or before the time that cytology was obtained. Ninety-five percent of the anal cytology tests obtained were abnormal, and 72 (29%) of those subjects returned for diagnostic testing either by intraoperative biopsy or high-resolution anoscopy. Fifty-seven percent of those who underwent biopsy had histologic high-grade squamous intraepithelial lesions including 2 cases of carcinoma in situ. A history of greater than 20 lifetime sexual partners was associated with abnormal histology (probability < 0.001, p =.017). Conclusions Our study highlights the value of early, standardized screening to avoid missing anal dysplasia or cancer, particularly in unvaccinated persons with high numbers of sexual partners.