Immunogenicity of NVX-CoV2373 heterologous boost against SARS-CoV-2 variants.

As part of a multicenter study evaluating homologous and heterologous COVID-19 booster vaccines, we assessed the magnitude, breadth, and short-term durability of binding and pseudovirus-neutralizing antibody (PsVNA) responses following a single booster dose of NVX-CoV2373 in adults primed with either Ad26.COV2.S, mRNA-1273, or BNT162b2 vaccines. NVX-CoV2373 as a heterologous booster was immunogenic and associated with no safety concerns through Day 91. Fold-rises in PsVNA titers from baseline (Day 1) to Day 29 were highest for prototypic D614G variant and lowest for more recent Omicron sub-lineages BQ.1.1 and XBB.1. Peak humoral responses against all SARS-CoV-2 variants were lower in those primed with Ad26.COV2.S than with mRNA vaccines. Prior SARS CoV-2 infection was associated with substantially higher baseline PsVNA titers, which remained elevated relative to previously uninfected participants through Day 91. These data support the use of heterologous protein-based booster vaccines as an acceptable alternative to mRNA or adenoviral-based COVID-19 booster vaccines. This trial was conducted under ClinicalTrials.gov: NCT04889209.

A randomized trial of safety, acceptability and adherence of three rectal microbicide placebo formulations among young sexual and gender minorities who engage in receptive anal intercourse (MTN-035).

Efforts to develop a range of HIV prevention products that can serve as behaviorally congruent viable alternatives to consistent condom use and oral pre-exposure prophylaxis (PrEP) remain crucial. MTN-035 was a randomized crossover trial seeking to evaluate the safety, acceptability, and adherence to three placebo modalities (insert, suppository, enema) prior to receptive anal intercourse (RAI). If participants had no RAI in a week, they were asked to use their assigned product without sex. We hypothesized that the modalities would be acceptable and safe for use prior to RAI, and that participants would report high adherence given their behavioral congruence with cleansing practices (e.g., douches and/or enemas) and their existing use to deliver medications (e.g., suppositories; fast-dissolving inserts) via the rectum. Participants (N = 217) were sexual and gender minorities enrolled in five different countries (Malawi, Peru, South Africa, Thailand, and the United States of America). Mean age was 24.9 years (range 18-35 years). 204 adverse events were reported by 98 participants (45.2%); 37 (18.1%) were deemed related to the study products. The proportion of participants reporting "high acceptability" was 72% (95%CI: 65% - 78%) for inserts, 66% (95%CI: 59% - 73%) for suppositories, and 73% (95%CI: 66% - 79%) for enemas. The proportion of participants reporting fully adherent per protocol (i.e., at least one use per week) was 75% (95%CI: 69% - 81%) for inserts, 74% (95%CI: 68% - 80%) for suppositories, and 83% (95%CI: 77% - 88%) for enemas. Participants fully adherent per RAI-act was similar among the three products: insert (n = 99; 58.9%), suppository (n = 101; 58.0%) and enema (n = 107; 58.8%). The efficacy and effectiveness of emerging HIV prevention drug depends on safe and acceptable delivery modalities that are easy to use consistently. Our findings demonstrate the safety and acceptability of, and adherence to, enemas, inserts, and suppositories as potential modalities through which to deliver a rectal microbicide.

MTN-033: a Phase 1 Study Comparing Applicator versus "as Lubricant" Delivery of Rectal Dapivirine Gel.

Data to inform behaviorally congruent delivery of rectal microbicides as lubricants are scant. Dapivirine (DPV) is a nonnucleoside reverse transcriptase inhibitor which has been demonstrated to be well-tolerated and efficacious in multiple clinical trials when used in a vaginal ring formulation. DPV gel administered rectally with an applicator was found to be well-tolerated in a phase 1 clinical trial. MTN-033, a single site, open label, sequence randomized, crossover study, enrolled HIV-negative men to receive 0.05% DPV gel intrarectally using an applicator (2.5 g) and self-administered on an artificial phallus as lubricant (up to 10 g). The study evaluated the pharmacokinetics (in plasma, rectal fluid, and mucosal rectal tissue), safety, acceptability, and pharmacodynamics of DPV gel when applied rectally. Statistical comparisons between methods of application were performed using mixed effects models or Wilcoxon's signed rank tests. Sixteen participants used DPV gel by applicator and 15/16 participants used gel as lubricant (mean, 1.8 g; SD, 0.8). DPV plasma AUC0-24h after use as lubricant was estimated to be 0.41 times the AUC0-24h (95% CI 0.24, 0.88) after use with applicator. While DPV was quantifiable in plasma and luminal fluid, it was not quantifiable in tissue for both applicator and as lubricant administration. No related adverse events (AE) were reported, and 15/15 participants felt the gel was easy to use. Evidence of local delivery and systemic absorption of DPV when dosed as an anal lubricant supports the feasibility and potential for development of lubricant-delivered rectal microbicides. There were no safety concerns associated with use of DPV gel and participants reported finding it easy to use. However, lower DPV exposure in plasma and lack of quantifiable DPV in rectal tissue indicate that higher potency, concentration, and longer half-life antiretrovirals with optimized formulations will be needed to achieve protective tissue concentrations.

Consumption of Micronutrient Powder, Syrup or Fortified Food Significantly Improves Zinc and Iron Status in Young Mexican Children: A Cluster Randomized Trial.

The objective of this study was to compare the effect of three micronutrient products on biomarkers of iron and zinc status of Mexican children 6−12 months of age. As part of research to improve the impact of a national program, 54 communities were randomly assigned to receive: (1) fortified food (FF), provided by the program at the time, or (2) micronutrient powders (MNP) or (3) syrup. Each product contained 10 mg each of zinc and iron, plus other micronutrients. Children consumed the product 6 days/week for four months. Primary outcomes were changes in serum zinc, ferritin, soluble transferrin receptor, hemoglobin concentrations, and their deficiencies. Zinc concentration increased significantly from baseline to follow-up in all groups, with the largest change in the syrup group (geometric mean difference: +4.4 µmol/L; 95%CI: 3.2, 5.5), followed by MNP (+2.9 µmol/L; 95%CI: 2.1, 3.6) and FF (+0.9 µmol/L; 95%CI: 0.3, 1.6). There was a significant increase in hemoglobin concentration (+5.5 g/L; 2.5, 8.4) and a significant reduction in anemia prevalence (44.2% to 26.8%, p < 0.01) only in the MNP group. Compliance differed significantly among groups (MNP vs. FF, p = 0.04; MNP vs. syrup, p = 0.04), but may not fully explain the greater improvement in zinc and iron status in the syrup and MNP groups. The food matrix may influence nutrient utilization from supplements.

Bayesian approaches to fixed effects meta-analysis.

Bayesian methods seem a natural choice for combining sources of evidence in meta-analyses. However, in practice, their sensitivity to the choice of prior distribution is much less attractive, particularly for parameters describing heterogeneity. A recent non-Bayesian approach to fixed-effects meta-analysis provides novel ways to think about estimation of an average effect and the variability around this average. In this paper, we describe the Bayesian analogs of those results, showing how Bayesian inference on fixed-effects parameters-properties of the study populations at hand-is more stable and less sensitive than standard random-effects approaches. As well as these practical insights, our development also clarifies different ways in which prior beliefs like homogeneity and correlation can be reflected in prior distributions. We also carefully distinguish how random-effects models can be used to reflect sampling uncertainty versus their use reflecting a priori exchangeability of study-specific effects, and how subsequent inference depends on which motivation is used. With some important theoretical results, illustrated in an applied meta-analysis example, we show the robustness of the fixed effects even for small numbers of studies.

Homologous and Heterologous Covid-19 Booster Vaccinations.

BACKGROUND: Although the three vaccines against coronavirus disease 2019 (Covid-19) that have received emergency use authorization in the United States are highly effective, breakthrough infections are occurring. Data are needed on the serial use of homologous boosters (same as the primary vaccine) and heterologous boosters (different from the primary vaccine) in fully vaccinated recipients. METHODS: In this phase 1-2, open-label clinical trial conducted at 10 sites in the United States, adults who had completed a Covid-19 vaccine regimen at least 12 weeks earlier and had no reported history of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection received a booster injection with one of three vaccines: mRNA-1273 (Moderna) at a dose of 100 µg, Ad26.COV2.S (Johnson & Johnson-Janssen) at a dose of 5×1010 virus particles, or BNT162b2 (Pfizer-BioNTech) at a dose of 30 µg. The primary end points were safety, reactogenicity, and humoral immunogenicity on trial days 15 and 29. RESULTS: Of the 458 participants who were enrolled in the trial, 154 received mRNA-1273, 150 received Ad26.COV2.S, and 153 received BNT162b2 as booster vaccines; 1 participant did not receive the assigned vaccine. Reactogenicity was similar to that reported for the primary series. More than half the recipients reported having injection-site pain, malaise, headache, or myalgia. For all combinations, antibody neutralizing titers against a SARS-CoV-2 D614G pseudovirus increased by a factor of 4 to 73, and binding titers increased by a factor of 5 to 55. Homologous boosters increased neutralizing antibody titers by a factor of 4 to 20, whereas heterologous boosters increased titers by a factor of 6 to 73. Spike-specific T-cell responses increased in all but the homologous Ad26.COV2.S-boosted subgroup. CD8+ T-cell levels were more durable in the Ad26.COV2.S-primed recipients, and heterologous boosting with the Ad26.COV2.S vaccine substantially increased spike-specific CD8+ T cells in the mRNA vaccine recipients. CONCLUSIONS: Homologous and heterologous booster vaccines had an acceptable safety profile and were immunogenic in adults who had completed a primary Covid-19 vaccine regimen at least 12 weeks earlier. (Funded by the National Institute of Allergy and Infectious Diseases; DMID 21-0012 ClinicalTrials.gov number, NCT04889209.).

Acceptability and Preference for 3-Month Versus 1-Month Vaginal Rings for HIV-1 Risk Reduction Among Participants in a Phase 1 Trial.

Background: The monthly dapivirine vaginal ring provides partial protection against HIV, and a longer duration ring may reduce user burden and improve adherence. We examined acceptability and preference for 3-month versus 1-month rings for HIV-1 risk reduction in a phase 1 clinical trial. Materials and Methods: In Microbicide Trials Network-036/International Partnership for Microbicides 047, 49 HIV-negative participants aged 18-45 were randomized to one of two 3-month rings or the 1-month ring. Acceptability ratings were collected at enrollment, week 4, and study exit (week 13). At exit, ring preference was assessed quantitatively among all participants and a randomly selected subset of 24 participants completed in-depth interviews. Quantitative and qualitative findings were integrated to explore factors influencing acceptability and preference. Results: Acceptability of each ring was initially moderate and increased during the trial. Ratings were lower in the 3-month ring arms than the 1-month arm at each time point, including baseline. Most participants (34/47; 72%) preferred a 3-month ring at exit; however, this proportion was significantly lower within some subgroups characterized by site, education, race/ethnicity, and experiences with ring use. Qualitative interviews revealed reservations about hygiene and safety of the 3-month ring, including discomfort with use during menses, but these were usually outweighed by its increased convenience. Conclusions: Both ring durations were highly acceptable at study exit. Although most participants preferred a 3-month ring, preference was more divided in certain subgroups, highlighting the benefit of offering different duration options. Providing additional support to address concerns about hygiene and safety may improve acceptability of a 3-month vaginal ring.

A Randomized, Double Blind, Placebo-Controlled, Phase 1 Safety, and Pharmacokinetic Study of Dapivirine Gel (0.05%) Administered Rectally to HIV-1 Seronegative Adults (MTN-026).

Dapivirine (DPV), formulated as vaginal ring, demonstrated HIV risk reduction. MTN-026 explored DPV, formulated as rectal gel, for safety, pharmacokinetics (PK), and acceptability. HIV-uninfected men and women aged 18-45 years were enrolled at United States and Thailand sites and randomized 2:1 to receive DPV 0.05% or placebo gel via rectal applicator. A single-dose phase was followed by seven observed daily doses. Plasma and fluid and tissue from both rectum and cervix were collected at baseline and after the final dose over 72 h for PK, ex-vivo HIV-1 biopsy challenge, histology, and flow cytometry. Twenty-eight participants were randomized; 2 terminated early; 9 were female and 19 male; 12 were white, 11 Asian, 4 black, and 1 other race/ethnicity. Mean age was 28.5 and 34.2 years in the DPV and placebo arms, respectively. Thirty adverse events occurred (all Grade 1 or 2, except one unrelated Grade 3) without study arm differences. DPV rectal tissue concentrations [median (interquartile range)] 0.5-1 and 2 h after a single dose were 256 ng/g [below the lower limit of quantification (BLQ)-666] and BLQ (BLQ-600), respectively, then BLQ (BLQ-BLQ) from 24 to 72 h; concentrations following multiple doses were similar. The largest median DPV plasma concentrations were 0.33 ng/mL (0.15-0.48) after one dose and 0.40 (0.33-0.49) after seven doses. The DPV rectal gel was acceptable and without safety concerns. While DPV plasma concentrations were similar to the vaginal ring, rectal tissue concentrations were well below vaginal ring tissue concentrations, suggesting need for reformulation. Clinical trial number: NCT03239483.

Acceptability of a Dapivirine Gel Administered Rectally to HIV-1 Seronegative Adults (MTN-033 Study).

We triangulated quantitative and qualitative assessments to evaluate participants' acceptability of 0.05% dapivirine rectal microbicide (RM) gel administered via two separate modalities (a rectal applicator and an artificial phallus for use as a coital simulation device) as part of a Phase I trial (N = 14) among men who have sex with men (MSM) randomized using a 1:1 ratio. Overall, participants reported favorable acceptability of the gel (n = 11; 78.6%), the same or more at the end of the study compared to when they started the study. Additionally, when discussing their preferred administration modality, they noted that both methods had positive qualities but also potential areas of improvement. Our findings underscore the need to create multiple delivery methods for a future microbicide gel (i.e., with and without the need for an applicator) and highlight the importance of offering MSM choices in how biomedical HIV prevention strategies are delivered.

Heterologous SARS-CoV-2 Booster Vaccinations - Preliminary Report.

Background: While Coronavirus disease 2019 (Covid-19) vaccines are highly effective, breakthrough infections are occurring. Booster vaccinations have recently received emergency use authorization (EUA) for certain populations but are restricted to homologous mRNA vaccines. We evaluated homologous and heterologous booster vaccination in persons who had received an EUA Covid-19 vaccine regimen. Methods: In this phase 1/2 open-label clinical trial conducted at ten U.S. sites, adults who received one of three EUA Covid-19 vaccines at least 12 weeks prior to enrollment and had no reported history of SARS-CoV-2 infection received a booster injection with one of three vaccines (Moderna mRNA-1273 100-µg, Janssen Ad26.COV2.S 5×1010 virus particles, or Pfizer-BioNTech BNT162b2 30-µg; nine combinations). The primary outcomes were safety, reactogenicity, and humoral immunogenicity on study days 15 and 29. Results: 458 individuals were enrolled: 154 received mRNA-1273, 150 received Ad26.CoV2.S, and 153 received BNT162b2 booster vaccines. Reactogenicity was similar to that reported for the primary series. Injection site pain, malaise, headache, and myalgia occurred in more than half the participants. Booster vaccines increased the neutralizing activity against a D614G pseudovirus (4.2-76-fold) and binding antibody titers (4.6-56-fold) for all combinations; homologous boost increased neutralizing antibody titers 4.2-20-fold whereas heterologous boost increased titers 6.2-76-fold. Day 15 neutralizing and binding antibody titers varied by 28.7-fold and 20.9-fold, respectively, across the nine prime-boost combinations. Conclusion: Homologous and heterologous booster vaccinations were well-tolerated and immunogenic in adults who completed a primary Covid-19 vaccine regimen at least 12 weeks earlier.

Phase 1 pharmacokinetics and safety study of extended duration dapivirine vaginal rings in the United States.

INTRODUCTION: Vaginal rings are a promising approach to provide a woman-centred, long-acting HIV prevention strategy. Prior trials of a 25 mg dapivirine (DPV) ring have shown a favourable safety profile and approximately 30% risk reduction of HIV-1 infection. Extended duration rings replaced every three months may encourage user adherence, improve health service efficiency and reduce cost overall. We evaluated safety, pharmacokinetics, adherence and acceptability of two three-month rings with different DPV dosages, compared with the monthly DPV ring. METHODS: From December 2017 to October 2018, MTN-036/IPM-047 enrolled 49 HIV-negative participant in Birmingham, Alabama and San Francisco, California into a phase 1, randomized trial comparing two extended duration (three-month) rings (100 or 200 mg DPV) to a monthly 25 mg DPV ring, each used over 13 weeks, with follow-up completed in January 2019. Safety was assessed by recording adverse events (AEs). DPV concentrations were quantified in plasma, cervicovaginal fluid (CVF) and cervical tissue, at nominal timepoints. Geometric mean ratios (GMRs) relative to the comparator ring were estimated from a regression model. RESULTS: There were no differences in the proportion of participants with grade ≥2 genitourinary AEs or grade ≥3 AEs in the extended duration versus monthly ring arms (p = 1.0). Plasma and CVF DPV concentrations were higher in the extended duration rings compared to the monthly ring. Plasma GMRs were 1.31 to 1.85 and 1.41 to 1.86 and CVF GMRs were 1.45 to 2.87 and 1.74 to 2.60 for the 100 and 200 mg ring respectively. Cervical tissue concentrations were consistently higher in the 200 mg ring (GMRs 2.36 to 3.97). The majority of participants (82%) were fully adherent (ring inserted at all times, with no product discontinuations/outages) with no differences between the monthly versus three-month rings. Most participants found the ring acceptable (median = 8 on 10-point Likert scale), with a greater proportion of participants reporting high acceptability (9 or 10) in the 25 mg arm (73%) compared with the 100 mg (25%) and 200 mg (44%) arms (p = 0.01 and p = 0.15 respectively). CONCLUSIONS: The extended duration DPV rings were well-tolerated and achieved higher DPV concentrations compared with the monthly DPV ring. These findings support further evaluation of three-month DPV rings for HIV prevention.

Incorporating external evidence on between-trial heterogeneity in network meta-analysis.

In a network meta-analysis, between-study heterogeneity variances are often very imprecisely estimated because data are sparse, so standard errors of treatment differences can be highly unstable. External evidence can provide informative prior distributions for heterogeneity and, hence, improve inferences. We explore approaches for specifying informative priors for multiple heterogeneity variances in a network meta-analysis. First, we assume equal heterogeneity variances across all pairwise intervention comparisons (approach 1); incorporating an informative prior for the common variance is then straightforward. Models allowing unequal heterogeneity variances are more realistic; however, care must be taken to ensure implied variance-covariance matrices remain valid. We consider three strategies for specifying informative priors for multiple unequal heterogeneity variances. Initially, we choose different informative priors according to intervention comparison type and assume heterogeneity to be proportional across comparison types and equal within comparison type (approach 2). Next, we allow all heterogeneity variances in the network to differ, while specifying a common informative prior for each. We explore two different approaches to this: placing priors on variances and correlations separately (approach 3) or using an informative inverse Wishart distribution (approach 4). Our methods are exemplified through application to two network metaanalyses. Appropriate informative priors are obtained from previously published evidence-based distributions for heterogeneity. Relevant prior information on between-study heterogeneity can be incorporated into network meta-analyses, without needing to assume equal heterogeneity across treatment comparisons. The approaches proposed will be beneficial in sparse data sets and provide more appropriate intervals for treatment differences than those based on imprecise heterogeneity estimates.

Addressing the estimation of standard errors in fixed effects meta-analysis.

Standard methods for fixed effects meta-analysis assume that standard errors for study-specific estimates are known, not estimated. While the impact of this simplifying assumption has been shown in a few special cases, its general impact is not well understood, nor are general-purpose tools available for inference under more realistic assumptions. In this paper, we aim to elucidate the impact of using estimated standard errors in fixed effects meta-analysis, showing why it does not go away in large samples and quantifying how badly miscalibrated standard inference will be if it is ignored. We also show the important role of a particular measure of heterogeneity in this miscalibration. These developments lead to confidence intervals for fixed effects meta-analysis with improved performance for both location and scale parameters.

Maternal and Fetal Outcomes of Anticoagulation in Pregnant Women With Mechanical Heart Valves.

BACKGROUND: Anticoagulation for mechanical heart valves during pregnancy is essential to prevent thromboembolic events. Each regimen has drawbacks with regard to maternal or fetal risk. OBJECTIVES: This meta-analysis sought to estimate and compare the risk of adverse maternal and fetal outcomes in pregnant women with mechanical heart valves who received different methods of anticoagulation. METHODS: Studies were identified using a Medline search including all publications up to June 5, 2016. Study inclusion required reporting of maternal death, thromboembolism, and valve failure, and/or fetal spontaneous abortion, death, and congenital defects in pregnant women treated with any of the following: 1) a vitamin K antagonist (VKA) throughout pregnancy; 2) low-molecular-weight heparin (LMWH) throughout pregnancy; 3) LMWH for the first trimester, followed by a VKA (LMWH and VKA); or 4) unfractionated heparin for the first trimester, followed by a VKA (UFH and VKA). RESULTS: A total of 800 pregnancies from 18 publications were included. Composite maternal risk was lowest with VKA (5%), compared with LMWH (16%; ratio of averaged risk [RAR]: 3.2; 95% confidence interval [CI]: 1.5 to 7.5), LMWH and VKA (16%; RAR: 3.1; 95% CI: 1.2 to 7.5), or UFH and VKA (16%; RAR: 3.1; 95% CI: 1.5 to 7.1). Composite fetal risk was lowest with LMWH (13%; RAR: 0.3; 95% CI: 0.1 to 0.8), compared with VKA (39%), LMWH and VKA (23%), or UFH and VKA (34%). No significant difference in fetal risk was observed between women taking ≤5 mg daily warfarin and those with an LMWH regimen (RAR: 0.9; 95% CI: 0.3 to 2.4). CONCLUSIONS: VKA treatment was associated with the lowest risk of adverse maternal outcomes, whereas the use of LMWH throughout pregnancy was associated with the lowest risk of adverse fetal outcomes. Fetal risk was similar between women taking ≤5 mg warfarin daily and women treated with LMWH.

Insulinlike Growth Factor Binding Protein-1 and Ghrelin Predict Health Outcomes Among Older Adults: Cardiovascular Health Study Cohort.

Context: Multiple diseases may explain the association of the growth hormone/insulinlike growth factor-I (GH/IGF-I) axis with longevity. Objective: To relate circulating GH/IGF-I system protein levels with major health events. Design and Setting: This is a cohort study set in 4 US communities. Participants: Adults (N = 2268) 65 years and older free of diabetes and cardiovascular disease. Measurements: We assessed insulinlike growth factor binding protein-1 (IGFBP-1) and ghrelin in fasting and 2-hour oral glucose tolerance test (OGTT) blood samples, as well as fasting IGF-I and IGFBP-3. Hazard ratios for mortality and a composite outcome for first incident myocardial infarction, stroke, heart failure, hip fracture, or death were adjusted for sociodemographic, behavioral, and physiological covariates. Results: During 13,930 person-years of follow-up, 48.1% of individuals sustained one or more components of the composite outcome and 31.8% died. Versus the lowest quartiles, the highest quartiles of fasting and 2-hour ghrelin were associated with 27% higher (95% confidence interval [CI]: 6%, 53%) and 39% higher (95% CI: 14%, 71%) risks of the composite outcome, respectively. The highest quartile of 2-hour IGFBP-1 was associated with 35% higher (95% CI: 1%, 52%) risk of the composite end point. Similarly, higher mortality was significantly associated with higher fasting and 2-hour ghrelin levels and with 2-hour IGFBP-1 level. When examined together, 2-hour post-OGTT levels of IGFBP-1 and ghrelin tended to predict outcomes better than fasting levels. Conclusions: Circulating IGFBP-1 and ghrelin measured during an OGTT predicted major health events and death in older adults, which may explain the influence of the GH/IGF-I axis on lifespan and health.

Agreement between circulating IGF-I, IGFBP-1 and IGFBP-3 levels measured by current assays versus unavailable assays previously used in epidemiological studies.

OBJECTIVE: Levels of insulin-like growth factor (IGF) proteins are associated with the risk of cancer and mortality. IGF assays produced by Diagnostic Systems Laboratories (DSL) were widely used in epidemiological studies, were not calibrated against recommended standards and are no longer commercially available. DESIGN: In a split sample study among 1471 adults participating in the Cardiovascular Health Study, we compared values obtained using DSL assays with alternative assays for serum IGF-I (Immunodiagnostic Systems, IDS), IGFBP-1 (American Laboratory Products Company, ALPCO) and IGFBP-3 (IDS). RESULTS: Results were compared using kernel density estimation plots, quartile analysis with weighted kappa statistics and linear regression models to assess the concordance of data from the different assays. Participants had a mean age of 77years. Results between alternative assays were strongly correlated (IGF-I, r=0.93 for DSL versus IDS; log-IGFBP-1, r=0.90 for DSL versus ALPCO; IGFBP-3, r=0.92 for DSL versus IDS). Cross tabulations showed that participants were usually in the same quartile categories regardless of the assay used (overall agreement, 74% for IGF-I, 64% for IGFBP-1, 71% for IGFBP-3). Weighted kappa also showed substantial agreement between assays (kw, 0.78 for IGF-I, 0.69 for IGFBP-1, 0.76 for IGFBP-3). Regressions of levels obtained with DSL assays (denoted X) to alternative assays were, IGF-I: 0.52X+15.2ng/ml, log-IGFBP-1: 1.01X-1.73ng/ml IGFBP-3: 0.87X+791.1ng/ml. Serum values of IGF-I, IGFBP-1 and IGFBP-3 measured using alternative assays are moderately correlated. CONCLUSIONS: Care is needed in the interpretation of data sets involving IGF analytes if assay methodologies are not uniform.

Adapting group sequential methods to observational postlicensure vaccine safety surveillance: results of a pentavalent combination DTaP-IPV-Hib vaccine safety study.

To address gaps in traditional postlicensure vaccine safety surveillance and to promote rapid signal identification, new prospective monitoring systems using large health-care database cohorts have been developed. We newly adapted clinical trial group sequential methods to this observational setting in an original safety study of a combination diphtheria and tetanus toxoids and acellular pertussis adsorbed (DTaP), inactivated poliovirus (IPV), and Haemophilus influenzae type b (Hib) conjugate vaccine (DTaP-IPV-Hib) among children within the Vaccine Safety Datalink population. For each prespecified outcome, we conducted 11 sequential Poisson-based likelihood ratio tests during September 2008-January 2011 to compare DTaP-IPV-Hib vaccinees with historical recipients of other DTaP-containing vaccines. No increased risk was detected among 149,337 DTaP-IPV-Hib vaccinees versus historical comparators for any outcome, including medically attended fever, seizure, meningitis/encephalitis/myelitis, nonanaphylactic serious allergic reaction, anaphylaxis, Guillain-Barré syndrome, or invasive Hib disease. In end-of-study prespecified subgroup analyses, risk of medically attended fever was elevated among 1- to 2-year-olds who received DTaP-IPV-Hib vaccine versus historical comparators (relative risk = 1.83, 95% confidence interval: 1.34, 2.50) but not among infants under 1 year old (relative risk = 0.83, 95% confidence interval: 0.73, 0.94). Findings were similar in analyses with concurrent comparators who received other DTaP-containing vaccines during the study period. Although lack of a controlled experiment presents numerous challenges, implementation of group sequential monitoring methods in observational safety surveillance studies is promising and warrants further investigation.

A randomized placebo-controlled trial of acetaminophen for prevention of post-vaccination fever in infants.

BACKGROUND: Fever is common following infant vaccinations. Two randomized controlled trials demonstrated the efficacy of acetaminophen prophylaxis in preventing fever after whole cell pertussis vaccination, but acetaminophen prophylaxis has not been evaluated for prevention of fever following contemporary vaccines recommended for infants in the United States. METHODS: Children six weeks through nine months of age were randomized 1:1 to receive up to five doses of acetaminophen (10-15 mg per kg) or placebo following routine vaccinations. The primary outcome was a rectal temperature ≥38°C within 32 hours following the vaccinations. Secondary outcomes included medical utilization, infant fussiness, and parents' time lost from work. Parents could request unblinding of the treatment assignment if the child developed fever or symptoms that would warrant supplementary acetaminophen treatment for children who had been receiving placebo. RESULTS: A temperature ≥38°C was recorded for 14% (25/176) of children randomized to acetaminophen compared with 22% (37/176) of those randomized to placebo but that difference was not statistically significant (relative risk [RR], 0.63; 95% CI, 0.40-1.01). Children randomized to acetaminophen were less likely to be reported as being much more fussy than usual (10% vs 24%) (RR, 0.42; 95% CI, 0.25-0.70) or to have the treatment assignment unblinded (3% vs 9%) (RR, 0.31; 95% CI, 0.11-0.83) than those randomized to placebo. In age-stratified analyses, among children ≥24 weeks of age, there was a significantly lower risk of temperature ≥38°C in the acetaminophen group (13% vs. 25%; p = 0.03). CONCLUSION: The results of this relatively small trial suggest that acetaminophen may reduce the risk of post-vaccination fever and fussiness. TRIAL REGISTRATION: Clinicaltrials.gov NCT00325819.

Anemia in Mexican women: results of two national probabilistic surveys.

OBJECTIVE: To describe the prevalence of anemia in Mexican women and analyze its trends with information from the last two national nutrition surveys. MATERIAL AND METHODS: The prevalence of anemia in women was analyzed. Anemia was adjusted by socioeconomic profile and by potentially explanatory variables. RESULTS: The overall prevalence of anemia for pregnant women was 20.2% (95% CI 15.9, 26.2%) and 15.5% for non-pregnant women (95% CI 14.7, 16.4%). The prevalence of anemia in women decreased from 1999 to 2006 in all socioeconomic profiles. Adolescent women living in the northern and in the southern regions had a greater risk of anemia than those in Mexico City (p= 0.05). Significant risk was found among low socioeconomic level (p< 0.06). Greater parity was a significant risk factor (p< 0.05) for being anemic. CONCLUSIONS: Although anemia in reproductive age women in Mexico decreased, it continues to be a public health problem.