Multilevel Follow-up of Cancer Screening (mFOCUS): Protocol for a multilevel intervention to improve the follow-up of abnormal cancer screening test results.

INTRODUCTION: While substantial attention is focused on the delivery of routine preventive cancer screening, less attention has been paid to systematically ensuring that there is timely follow-up of abnormal screening test results. Barriers to completion of timely follow-up occur at the patient, provider, care team and system levels. METHODS: In this pragmatic cluster randomized controlled trial, primary care sites in three networks are randomized to one of four arms: (1) standard care, (2) "visit-based" reminders that appear in a patient's electronic health record (EHR) when it is accessed by either patient or providers (3) visit based reminders with population health outreach, and (4) visit based reminders, population health outreach, and patient navigation with systematic screening and referral to address social barriers to care. Eligible patients in participating practices are those overdue for follow-up of an abnormal results on breast, cervical, colorectal and lung cancer screening tests. RESULTS: The primary outcome is whether an individual receives follow-up, specific to the organ type and screening abnormality, within 120 days of becoming eligible for the trial. Secondary outcomes assess the effect of intervention components on the patient and provider experience of obtaining follow-up care and the delivery of the intervention components. CONCLUSIONS: This trial will provide evidence for the role of a multilevel intervention on improving the follow-up of abnormal cancer screening test results. We will also specifically assess the relative impact of the components of the intervention, compared to standard care. TRIAL REGISTRATION: ClinicalTrials.gov NCT03979495.

Sialic acid levels in breast milk from HIV-positive Tanzanian women and impact of maternal diet.

OBJECTIVE: To quantify total sialic acid in milk from HIV-positive Tanzanian mothers and to determine the impact of maternal diet on milk sialic acid levels. DESIGN: Milk samples were analyzed from 74 HIV-positive, Tanzanian women enrolled in a randomized, controlled clinical study of a dietary macronutrient supplement. Women were provided with a daily protein-calorie supplement and a micronutrient supplement or micronutrient supplement only during the last trimester of pregnancy and up to the first 6 months of breastfeeding. METHODS: Milk samples were collected at approximately 2 weeks and at least 3 months postpartum and assayed for total sialic acid. Milk sialic acid was assessed relative to maternal macronutrient intake, age, BMI, CD4+ cell count and infant birth weight. RESULTS: The mean concentration of milk sialic acid was highest in the first 2 weeks postpartum (6.89 ±â€Š2.79 mmol/l) and declined rapidly by 3 months (2.49 ±â€Š0.60 mmol/l). Sialic acid content in milk was similar between both treatment arms of the study, and did not correlate with maternal macronutrient intake. No correlation was found between maternal age, BMI, CD4+ cell count or infant birth weight and total milk sialic acid concentration. CONCLUSION: Milk sialic acid levels in HIV-positive, Tanzanian women without malnutrition are comparable with reported values for women of European descent and show a similar temporal decline during early lactation. These findings suggest that total milk sialic acid is maintained despite macronutrient deficiencies in maternal diet and support a conserved role for milk sialic acid in neonatal development.

The premature infant gut microbiome during the first 6 weeks of life differs based on gestational maturity at birth.

BACKGROUND: The impact of degree of prematurity at birth on premature infant gut microbiota has not been extensively studied in comparison to term infants in large cohorts. METHODS: To determine the effect of gestational age at birth and postnatal exposures on gut bacterial colonization in infants, we analyzed 65 stool samples from 17 premature infants in the neonatal intensive care unit, as well as 13 samples from 13 mostly moderate-to-late premature infants and 189 samples from 176 term infants in the New Hampshire Birth Cohort Study. Gut colonization patterns were determined with 16S rDNA microbiome profiling. RESULTS: Gut bacterial alpha-diversity differed between premature and term infants at 6 weeks of age, after adjusting for exposures (p = 0.027). Alpha-diversity varied between extremely premature (<28 weeks gestation) and very premature infants (≥28 but <32 weeks, p = 0.011), as well as between extremely and moderate-to-late premature infants (≥32 and <37 weeks, p = 0.004). Newborn antibiotic use among premature infants was associated with lower Bifidobacterium and Bacteroides abundance (p = 0.015 and p = 0.041). CONCLUSION: Gestational age at birth and early antibiotic exposure have significant effects on the premature infant gut microbiota.

Fetal exposures and perinatal influences on the stool microbiota of premature infants.

OBJECTIVE: To test the hypothesis that maternal complications significantly affect gut colonization patterns in very low birth weight infants. METHODS: Forty-nine serial stool samples were obtained weekly from nine extremely premature infants enrolled in a prospective longitudinal study. Sequencing of the bacterial 16S rRNA gene from stool samples was performed to approximate the intestinal microbiome. Linear mixed effects models were used to evaluate relationships between perinatal complications and intestinal microbiome development. RESULTS: Subjects with prenatal exposure to a non-sterile intrauterine environment, i.e. prolonged preterm premature rupture of membranes (PPPROM) and chorioamnionitis exposure, were found to have a relatively higher abundance of potentially pathogenic bacteria in the stool across all time points compared to subjects without those exposures, irrespective of exposure to postnatal antibiotics. Compared with those delivered by Caesarean section, vaginally delivered subjects were found to have significantly lower diversity of stool microbiota across all time points, with lower abundance of many genera, most in the family Enterobacteriaceae. CONCLUSIONS: We identified persistently increased potential pathogen abundance in the developing stool microbiota of subjects exposed to a non-sterile uterine environment. Maternal complications appear to significantly influence the diversity and bacterial composition of the stool microbiota of premature infants, with findings persisting over time.

Associations between Gut Microbial Colonization in Early Life and Respiratory Outcomes in Cystic Fibrosis.

OBJECTIVE: To examine patterns of microbial colonization of the respiratory and intestinal tracts in early life in infants with cystic fibrosis (CF) and their associations with breastfeeding and clinical outcomes. STUDY DESIGN: A comprehensive, prospective longitudinal analysis of the upper respiratory and intestinal microbiota in a cohort of infants and young children with CF followed from birth was performed. Genus-level microbial community composition was characterized using 16S-targeted pyrosequencing, and relationships with exposures and outcomes were assessed using linear mixed-effects models, time-to-event analysis, and principal components analysis. RESULTS: Sequencing of 120 samples from 13 subjects collected from birth to 34 months revealed relationships between breastfeeding, microbial diversity in the respiratory and intestinal tracts, and the timing of onset of respiratory complications, including exacerbations and colonization with Pseudomonas aeruginosa. Fluctuations in the abundance of specific bacterial taxa preceded clinical outcomes, including a significant decrease in bacteria of the genus Parabacteroides within the intestinal tract prior to the onset of chronic P aeruginosa colonization. Specific assemblages of bacteria in intestinal samples, but not respiratory samples, were associated with CF exacerbation in early life, indicating that the intestinal microbiome may play a role in lung health. CONCLUSIONS: Our findings relating breastfeeding to respiratory outcomes, gut diversity to prolonged periods of health, and specific bacterial communities in the gut prior to respiratory complications in CF highlight a connection between the intestinal microbiome and health and point to potential opportunities for antibiotic or probiotic interventions. Further studies in larger cohorts validating these findings are needed.

Live attenuated and inactivated influenza vaccines in children.

BACKGROUND: Live attenuated influenza vaccine (LAIV) and inactivated influenza vaccine (IIV) are available for children. Local and systemic immunity induced by LAIV followed a month later by LAIV and IIV followed by LAIV were investigated with virus recovery after LAIV doses as surrogates for protection against influenza on natural exposure. METHODS: Fifteen children received IIV followed by LAIV, 13 an initial dose of LAIV, and 11 a second dose of LAIV. The studies were done during autumn 2009 and autumn 2010 with the same seasonal vaccine (A/California/07/09 [H1N1], A/Perth/16/09 [H3N2], B/Brisbane/60/08). RESULTS: Twenty-eight of 39 possible influenza viral strains were recovered after the initial dose of LAIV. When LAIV followed IIV, 21 of 45 viral strains were identified. When compared to primary LAIV infection, the decreased frequency of shedding with the IIV-LAIV schedule was significant (P = .023). With LAIV-LAIV, the fewest viral strains were recovered (3/33)--numbers significantly lower (P < .001) than shedding after initial LAIV and after IIV-LAIV (P < .001). Serum hemagglutination inhibition antibody responses were more frequent after IIV than LAIV (P = .02). In contrast, more mucosal immunoglobulin A responses were seen with LAIV. CONCLUSIONS: LAIV priming induces greater inhibition of virus recovery on LAIV challenge than IIV priming. The correlate(s) of protection are the subject of ongoing analysis. CLINICAL TRIALS REGISTRATION: NCT01246999.

Breast milk from Tanzanian women has divergent effects on cell-free and cell-associated HIV-1 infection in vitro.

Transmission of HIV-1 during breastfeeding is a significant source of new pediatric infections in sub-Saharan Africa. Breast milk from HIV-positive mothers contains both cell-free and cell-associated virus; however, the impact of breast milk on HIV-1 infectivity remains poorly understood. In the present study, breast milk was collected from HIV-positive and HIV-negative Tanzanian women attending antenatal clinics in Dar es Salaam. Milk was analyzed for activity in vitro against both cell-free and cell-associated HIV-1. Potent inhibition of cell-free R5 and X4 HIV-1 occurred in the presence of milk from all donors regardless of HIV-1 serostatus. Inhibition of cell-free HIV-1 infection positively correlated with milk levels of sialyl-Lewis(X) from HIV-positive donors. In contrast, milk from 8 of 16 subjects enhanced infection with cell-associated HIV-1 regardless of donor serostatus. Milk from two of these subjects contained high levels of multiple pro-inflammatory cytokines including TNFα, IL-1ß, IL-6, IL-8, MIP-1α, MIP-1ß, MCP-1 and IP-10, and enhanced cell-associated HIV-1 infection at dilutions as high as 1∶500. These findings indicate that breast milk contains innate factors with divergent activity against cell-free and cell-associated HIV-1 in vitro. Enhancement of cell-associated HIV-1 infection by breast milk may be associated with inflammatory conditions in the mother and may contribute to infant infection during breastfeeding.

Bacterial growth kinetics in ACD-A apheresis platelets: comparison of plasma and PAS III storage.

BACKGROUND: Our objective was to determine the growth kinetics of bacteria in leukoreduced apheresis platelets (LR-AP) in a platelet (PLT) additive solution (PAS; InterSol, Fenwal, Inc.) compared to LR-AP stored in plasma. STUDY DESIGN AND METHODS: Hyperconcentrated, double-dose LR-AP were collected from healthy donors with a separator (AMICUS, Fenwal, Inc.). LR-AP were evenly divided, InterSol was added to half (65% InterSol:35% plasma [PAS]), and PLTs in autologous plasma were used for a paired control (PL). Bacteria were inoculated into each LR-AP PAS/PL pair (0.5-1.6 colony-forming units [CFUs]/mL), and bacterial growth was followed for up to 7 days. Time to the end of the lag phase, doubling times, maximum concentration (conc-max), and time to maximum concentration (time-max) were estimated. RESULTS: Streptococcus viridans did not grow to detectable levels in either PAS or PL units. The other bacteria had no significant overall difference in the conc-max (p = 0.47) or time-max (p = 0.7) between PL and PAS LR-AP; PL had a 0.14 hours faster doubling rate (p = 0.023); and PAS had a 4.7 hours shorter lag time (p = 0.016). CONCLUSION: We observed that five index organisms will grow in LR-AP stored in a 35%:65% ratio of plasma to InterSol where initial bacterial concentrations are 0.5 to 1.6 CFUs/mL. The more rapid initiation of log-phase growth for bacteria within a PAS storage environment resulted in a bacterial concentration up to 4 logs higher in the PAS units compared to the plasma units at 24 hours, but with no difference in the conc-max. This may present an early bacterial detection advantage for PAS-stored PLTs.