A systematic review and meta-analysis of 24-h urinary output of children and adolescents: impact on the assessment of iodine status using urinary biomarkers.

PURPOSE: Urinary iodine concentration (UIC (µg/ml) from spot urine samples collected from school-aged children is used to determine the iodine status of populations. Some studies further extrapolate UIC to represent daily iodine intake, based on the assumption that children pass approximately 1 L urine over 24-h, but this has never been assessed in population studies. Therefore, the present review aimed to collate and produce an estimate of the average 24-h urine volume of children and adolescents (> 1 year and < 19 years) from published studies. METHODS: EBSCOHOST and EMBASE databases were searched to identify studies which reported the mean 24-h urinary volume of healthy children (> 1 year and < 19 years). The overall mean (95% CI) estimate of 24-h urine volume was determined using a random effects model, broken down by age group. RESULTS: Of the 44 studies identified, a meta-analysis of 27 studies, with at least one criterion for assessing the completeness of urine collections, indicated that the mean urine volume of 2-19 year olds was 773 (654, 893) (95% CI) mL/24-h. When broken down by age group, mean (95% CI) 24-h urine volume was 531 mL/day (454, 607) for 2-5 year olds, 771 mL/day (734, 808) for 6-12 year olds, and 1067 mL/day (855, 1279) for 13-19 year olds. CONCLUSIONS: These results demonstrate that the average urine volume of children aged 2-12 years is less than 1 L, therefore, misclassification of iodine intakes may occur when urine volumes fall below or above 1 L. Future studies utilizing spot urine samples to assess iodine status should consider this when extrapolating UIC to represent iodine intakes of a population.

HLA-B*14:02-Restricted Env-Specific CD8+ T-Cell Activity Has Highly Potent Antiviral Efficacy Associated with Immune Control of HIV Infection.

Immune control of human immunodeficiency virus type 1 (HIV) infection is typically associated with effective Gag-specific CD8+ T-cell responses. We here focus on HLA-B*14, which protects against HIV disease progression, but the immunodominant HLA-B*14-restricted anti-HIV response is Env specific (ERYLKDQQL, HLA-B*14-EL9). A subdominant HLA-B*14-restricted response targets Gag (DRYFKTLRA, HLA-B*14-DA9). Using HLA-B*14/peptide-saporin-conjugated tetramers, we show that HLA-B*14-EL9 is substantially more potent at inhibiting viral replication than HLA-B*14-DA9. HLA-B*14-EL9 also has significantly higher functional avidity (P < 0.0001) and drives stronger selection pressure on the virus than HLA-B*14-DA9. However, these differences were HLA-B*14 subtype specific, applying only to HLA-B*14:02 and not to HLA-B*14:01. Furthermore, the HLA-B*14-associated protection against HIV disease progression is significantly greater for HLA-B*14:02 than for HLA-B*14:01, consistent with the superior antiviral efficacy of the HLA-B*14-EL9 response. Thus, although Gag-specific CD8+ T-cell responses may usually have greater anti-HIV efficacy, factors independent of protein specificity, including functional avidity of individual responses, are also critically important to immune control of HIV.IMPORTANCE In HIV infection, although cytotoxic T lymphocytes (CTL) play a potentially critical role in eradication of viral reservoirs, the features that constitute an effective response remain poorly defined. We focus on HLA-B*14, unique among HLAs associated with control of HIV in that the dominant CTL response is Env specific, not Gag specific. We demonstrate that Env-specific HLA-B*14-restricted activity is substantially more efficacious than the subdominant HLA-B*14-restricted Gag response. Env immunodominance over Gag and strong Env-mediated selection pressure on HIV are observed only in subjects expressing HLA-B*14:02, and not HLA-B*14:01. This reflects the increased functional avidity of the Env response over Gag, substantially more marked for HLA-B*14:02. Finally, we show that HLA-B*14:02 is significantly more strongly associated with viremic control than HLA-B*14:01. These findings indicate that, although Gag-specific CTL may usually have greater anti-HIV efficacy than Env responses, factors independent of protein specificity, including functional avidity, may carry greater weight in mediating effective control of HIV.

Hepcidin is a Better Predictor of Iron Stores in Premenopausal Women than Blood Loss or Dietary Intake.

The relationship between dietary intake, circulating hepcidin and iron status in free-living premenopausal women has not been explored. This cross-sectional study aimed to identify dietary determinants of iron stores after accounting for blood loss and to determine whether iron intake predicts iron stores independently of hepcidin in a sample of Australian women. Three hundred thirty eight women aged 18-50 years were recruited. Total intake and food sources of iron were determined via food frequency questionnaire; the magnitude of menstrual losses was estimated by self-report; and blood donation volume was quantified using blood donation records and self-reported donation frequency. Serum samples were analysed for ferritin, hepcidin and C-reactive protein concentrations. Linear regression was used to investigate associations. Accounting for blood loss, each 1 mg/day increase in dietary iron was associated with a 3% increase in iron stores (p = 0.027); this association was not independent of hepcidin. Hepcidin was a more influential determinant of iron stores than blood loss and dietary factors combined (R² of model including hepcidin = 0.65; R² of model excluding hepcidin = 0.17, p for difference <0.001), and increased hepcidin diminished the positive association between iron intake and iron stores. Despite not being the biggest contributor to dietary iron intake, unprocessed meat was positively associated with iron stores, and each 10% increase in consumption was associated with a 1% increase in iron stores (p = 0.006). No other dietary factors were associated with iron stores. Interventions that reduce hepcidin production combined with dietary strategies to increase iron intake may be important means of improving iron status in women with depleted iron stores.

Mobile Phone App Aimed at Improving Iron Intake and Bioavailability in Premenopausal Women: A Qualitative Evaluation.

BACKGROUND: Low iron intake can lead to iron deficiency, which can result in impaired health and iron-deficiency anemia. A mobile phone app, combining successful dietary strategies to increase bioavailable iron with strategies for behavior change, such as goal setting, monitoring, feedback, and resources for knowledge acquisition, was developed with the aim to increase bioavailable iron intake in premenopausal women. OBJECTIVE: To evaluate the content, usability, and acceptability of a mobile phone app designed to improve intake of bioavailable dietary iron. METHODS: Women aged 18-50 years with an Android mobile phone were invited to participate. Over a 2-week period women were asked to interact with the app. Following this period, semistructured focus groups with participants were conducted. Focus groups were audio recorded and analyzed via an inductive open-coding method using the qualitative analysis software NVivo 10. Themes were identified and frequency of code occurrence was calculated. RESULTS: Four focus groups (n=26) were conducted (age range 19-36 years, mean 24.7, SD 5.2). Two themes about the app's functionality were identified (frequency of occurrence in brackets): interface and design (134) and usability (86). Four themes about the app's components were identified: goal tracker (121), facts (78), photo diary (40), and games (46). A number of suggestions to improve the interface and design of the app were provided and will inform the ongoing development of the app. CONCLUSIONS: This research indicates that participants are interested in iron and their health and are willing to use an app utilizing behavior change strategies to increase intake of bioavailable iron. The inclusion of information about the link between diet and health, monitoring and tracking of the achievement of dietary goals, and weekly reviews of goals were also seen as valuable components of the app and should be considered in mobile health apps aimed at adult women.

Disease progression despite protective HLA expression in an HIV-infected transmission pair.

BACKGROUND: The precise immune responses mediated by HLA class I molecules such as HLA-B*27:05 and HLA-B*57:01 that protect against HIV disease progression remain unclear. We studied a CRF01_AE clade HIV infected donor-recipient transmission pair in which the recipient expressed both HLA-B*27:05 and HLA-B*57:01. RESULTS: Within 4.5 years of diagnosis, the recipient had progressed to meet criteria for antiretroviral therapy initiation. We employed ultra-deep sequencing of the full-length virus genome in both donor and recipient as an unbiased approach by which to identify specific viral mutations selected in association with progression. Using a heat map method to highlight differences in the viral sequences between donor and recipient, we demonstrated that the majority of the recipient's mutations outside of Env were within epitopes restricted by HLA-B*27:05 and HLA-B*57:01, including the well-studied Gag epitopes. The donor, who also expressed HLA alleles associated with disease protection, HLA-A*32:01/B*13:02/B*14:01, showed selection of mutations in parallel with disease progression within epitopes restricted by these protective alleles. CONCLUSIONS: These studies of full-length viral sequences in a transmission pair, both of whom expressed protective HLA alleles but nevertheless failed to control viremia, are consistent with previous reports pointing to the critical role of Gag-specific CD8+ T cell responses restricted by protective HLA molecules in maintaining immune control of HIV infection. The transmission of subtype CRF01_AE clade infection may have contributed to accelerated disease progression in this pair as a result of clade-specific sequence differences in immunodominant epitopes.

Associations between dietary iron and zinc intakes, and between biochemical iron and zinc status in women.

Iron and zinc are found in similar foods and absorption of both may be affected by food compounds, thus biochemical iron and zinc status may be related. This cross-sectional study aimed to: (1) describe dietary intakes and biochemical status of iron and zinc; (2) investigate associations between dietary iron and zinc intakes; and (3) investigate associations between biochemical iron and zinc status in a sample of premenopausal women aged 18-50 years who were recruited in Melbourne and Sydney, Australia. Usual dietary intakes were assessed using a 154-item food frequency questionnaire (n = 379). Iron status was assessed using serum ferritin and hemoglobin, zinc status using serum zinc (standardized to 08:00 collection), and presence of infection/inflammation using C-reactive protein (n = 326). Associations were explored using multiple regression and logistic regression. Mean (SD) iron and zinc intakes were 10.5 (3.5) mg/day and 9.3 (3.8) mg/day, respectively. Median (interquartile range) serum ferritin was 22 (12-38) µg/L and mean serum zinc concentrations (SD) were 12.6 (1.7) µmol/L in fasting samples and 11.8 (2.0) µmol/L in nonfasting samples. For each 1 mg/day increase in dietary iron intake, zinc intake increased by 0.4 mg/day. Each 1 µmol/L increase in serum zinc corresponded to a 6% increase in serum ferritin, however women with low serum zinc concentration (AM fasting < 10.7 µmol/L; AM nonfasting < 10.1 µmol/L) were not at increased risk of depleted iron stores (serum ferritin <15 µg/L; p = 0.340). Positive associations were observed between dietary iron and zinc intakes, and between iron and zinc status, however interpreting serum ferritin concentrations was not a useful proxy for estimating the likelihood of low serum zinc concentrations and women with depleted iron stores were not at increased risk of impaired zinc status in this cohort.

Increasing iron and zinc in pre-menopausal women and its effects on mood and cognition: a systematic review.

Iron and zinc are essential minerals often present in similar food sources. In addition to the adverse effects of frank iron and zinc-deficient states, iron insufficiency has been associated with impairments in mood and cognition. This paper reviews current literature on iron or zinc supplementation and its impact on mood or cognition in pre-menopausal women. Searches included MEDLINE complete, Excerpta Medica Database (EMBASE), psychINFO, psychARTICLES, pubMED, ProQuest Health and Medical Complete Academic Search complete, Scopus and ScienceDirect. Ten randomized controlled trials and one non-randomized controlled trial were found to meet the inclusion criteria. Seven studies found improvements in aspects of mood and cognition after iron supplementation. Iron supplementation appeared to improve memory and intellectual ability in participants aged between 12 and 55 years in seven studies, regardless of whether the participant was initially iron insufficient or iron-deficient with anaemia. The review also found three controlled studies providing evidence to suggest a role for zinc supplementation as a treatment for depressive symptoms, as both an adjunct to traditional antidepressant therapy for individuals with a diagnosis of major depressive disorder and as a therapy in its own right in pre-menopausal women with zinc deficiency. Overall, the current literature indicates a positive effect of improving zinc status on enhanced cognitive and emotional functioning. However, further study involving well-designed randomized controlled trials is needed to identify the impact of improving iron and zinc status on mood and cognition.

Programmed death-1 expression on HIV-1-specific CD8+ T cells is shaped by epitope specificity, T-cell receptor clonotype usage and antigen load.

OBJECTIVES: Although CD8+ T cells play a critical role in the control of HIV-1 infection,their antiviral efficacy can be limited by antigenic variation and immune exhaustion.The latter phenomenon is characterized by the upregulation of multiple inhibitory receptors, such as programmed death-1 (PD-1), CD244 and lymphocyte activation gene-3 (LAG-3), which modulate the functional capabilities of CD8+ T cells. DESIGN AND METHODS: Here, we used an array of different human leukocyte antigen(HLA)-B*15:03 and HLA-B*42:01 tetramers to characterize inhibitory receptor expression as a function of differentiation on HIV-1-specific CD8+ T-cell populations(n = 128) spanning 11 different epitope targets. RESULTS: Expression levels of PD-1, but not CD244 or LAG-3, varied substantially across epitope specificities both within and between individuals. Differential expression of PD-1 on T-cell receptor (TCR) clonotypes within individual HIV-1-specific CD8+ T-cell populations was also apparent, independent of clonal dominance hierarchies. Positive correlations were detected between PD-1 expression and plasma viral load, which were reinforced by stratification for epitope sequence stability and dictated by effector memory CD8+ T cells. CONCLUSION: Collectively, these data suggest that PD-1 expression on HIV-1-specific CD8+ T cells tracks antigen load at the level of epitope specificity and TCR clonotype usage. These findings are important because they provide evidence that PD-1 expression levels are influenced by peptide/HLA class I antigen exposure.

Iron status and dietary iron intake of female blood donors.

BACKGROUND: The aim was to assess iron status and dietary iron intake in a sample of premenopausal female regular and new blood donors. STUDY DESIGN AND METHODS: Premenopausal women blood donors were invited to participate. Blood samples were analyzed for serum ferritin and hemoglobin. An iron checklist assessed dietary iron intake. Donors were classified as regular donors or new donors. RESULTS: Twenty-one new donors (mean [SD] age, 28.6 [6.0] years; body mass index [BMI], 25.6 [4.5] kg/m(2) ) and 172 regular donors (mean age, 29.4 [5.5] years; BMI, 24.7 [3.8] kg/m(2) ) participated. Fifty percent of regular donors and 24% of new donors had depleted iron stores (serum ferritin <15 µg/L; difference p = 0.036). Dietary iron intake was higher in regular donors (mean [SE], 12.6 [0.7] mg/day) compared to new donors (9.9 [0.4] mg/day; p = 0.006). Eighty-five percent of regular donors and 79% of new donors met the estimated average requirement for iron. CONCLUSIONS: Despite the fact that most of these donors had an adequate dietary iron intake, more than half of the blood donors had depleted iron stores. Increasing dietary iron intake through supplements and/or dietary means is expected to be necessary to maintain adequate iron status in this group.

Iron and zinc nutrition in the economically-developed world: a review.

This review compares iron and zinc food sources, dietary intakes, dietary recommendations, nutritional status, bioavailability and interactions, with a focus on adults in economically-developed countries. The main sources of iron and zinc are cereals and meat, with fortificant iron and zinc potentially making an important contribution. Current fortification practices are concerning as there is little regulation or monitoring of intakes. In the countries included in this review, the proportion of individuals with iron intakes below recommendations was similar to the proportion of individuals with suboptimal iron status. Due to a lack of population zinc status information, similar comparisons cannot be made for zinc intakes and status. Significant data indicate that inhibitors of iron absorption include phytate, polyphenols, soy protein and calcium, and enhancers include animal tissue and ascorbic acid. It appears that of these, only phytate and soy protein also inhibit zinc absorption. Most data are derived from single-meal studies, which tend to amplify impacts on iron absorption in contrast to studies that utilize a realistic food matrix. These interactions need to be substantiated by studies that account for whole diets, however in the interim, it may be prudent for those at risk of iron deficiency to maximize absorption by reducing consumption of inhibitors and including enhancers at mealtimes.

HLA-A*68:02-restricted Gag-specific cytotoxic T lymphocyte responses can drive selection pressure on HIV but are subdominant and ineffective.

BACKGROUND: Human leukocyte allele (HLA) class I polymorphism has the greatest impact of human genetic variation on viral load set point. A substantial part of this effect is due to the action of HLA-B and HLA-C alleles. With few exceptions the role of HLA-A molecules in immune control of HIV is unclear. METHODS: We here study HLA-A*68:02, one of the most highly prevalent HLA-A alleles in C-clade infected sub-Saharan African populations, and one that plays a prominent role in the HIV-specific CD8 T-cell responses made against the virus. RESULTS: We define eight epitopes restricted by this allele and propose the peptide binding motif for HLA-A*68:02. Although one of these epitopes almost exactly overlaps an HLA-B*57-restricted epitope in Gag linked with immune control of HIV, this HLA-A*68:02-restricted Gag-TA10 response imposed only weak selection pressure on the virus and was not associated with significantly lower viral setpoint. The only HLA-A*68:02-restricted responses imposing strong selection pressure on HIV were in the flanking regions of Pol-EA8 and Pol-EA11 and within the Vpr-EV10 epitope (P  =  8 × 10). However, targeting of this latter epitope was associated with significantly higher viral loads (P  =  0.003), suggesting lack of efficacy. CONCLUSION: This study is consistent with previous data showing that HLA-A-restricted Gag-specific responses can impose selection pressure on HIV. In the case of HLA-A*68:02 the Gag response is subdominant, and apparently has little impact in natural infection. However, these data suggest the potential for high frequency vaccine-induced Gag responses restricted by this allele to have significant antiviral efficacy in vaccine recipients.

Differential clade-specific HLA-B*3501 association with HIV-1 disease outcome is linked to immunogenicity of a single Gag epitope.

The strongest genetic influence on immune control in HIV-1 infection is the HLA class I genotype. Rapid disease progression in B-clade infection has been linked to HLA-B*35 expression, in particular to the less common HLA-B*3502 and HLA-B*3503 subtypes but also to the most prevalent subtype, HLA-B*3501. In these studies we first demonstrated that whereas HLA-B*3501 is associated with a high viral set point in two further B-clade-infected cohorts, in Japan and Mexico, this association does not hold in two large C-clade-infected African cohorts. We tested the hypothesis that clade-specific differences in HLA associations with disease outcomes may be related to distinct targeting of critical CD8(+) T-cell epitopes. We observed that only one epitope was significantly targeted differentially, namely, the Gag-specific epitope NPPIPVGDIY (NY10, Gag positions 253 to 262) (P = 2 × 10(-5)). In common with two other HLA-B*3501-restricted epitopes, in Gag and Nef, that were not targeted differentially, a response toward NY10 was associated with a significantly lower viral set point. Nonimmunogenicity of NY10 in B-clade-infected subjects derives from the Gag-D260E polymorphism present in ∼90% of B-clade sequences, which critically reduces recognition of the Gag NY10 epitope. These data suggest that in spite of any inherent HLA-linked T-cell receptor repertoire differences that may exist, maximizing the breadth of the Gag-specific CD8(+) T-cell response, by the addition of even a single epitope, may be of overriding importance in achieving immune control of HIV infection. This distinction is of direct relevance to development of vaccines designed to optimize the anti-HIV CD8(+) T-cell response in all individuals, irrespective of HLA type.

Efficacious early antiviral activity of HIV Gag- and Pol-specific HLA-B 2705-restricted CD8+ T cells.

The association between HLA-B 2705 and the immune control of human immunodeficiency virus type 1 (HIV-1) has previously been linked to the targeting of the HLA-B 2705-restricted Gag epitope KRWIILGLNK (KK10) by CD8(+) T cells. In order to better define the mechanisms of the HLA-B 2705 immune control of HIV, we first characterized the CD8(+) T-cell responses of nine highly active antiretroviral therapy (HAART)-naïve B 2705-positive subjects. Unexpectedly, we observed a strong response to an HLA-B 2705-restricted Pol epitope, KRKGGIGGY (KY9), in 8/9 subjects. The magnitude of the KY9 response was only marginally lower than that of the KK10-specific response (median, 695 versus 867 spot-forming cells [SFC]/million peripheral blood mononuclear cells [PBMCs]; not significant [NS]), and viral escape mutants were observed in both KY9 and KK10, resulting from selection pressure driven by the respective CD8(+) T-cell response. By comparing inhibitions of viral replication by CD8(+) T cells specific for the Gag KK10, Pol KY9, and Vpr VL9 HLA-B 2705-restricted epitopes, we observed a consistent hierarchy of antiviral efficacy (Gag KK10 > Pol KY9 > Vpr VL9). This hierarchy was associated with early recognition of HIV-1-infected cells, within 6 h of infection, by KK10- and KY9-specific CD8(+) T cells but not until 18 h postinfection by VL9-specific CD8(+) T cells. There was no association between antiviral efficacy and proliferative capacity, cytotoxicity, polyfunctionality, or T-cell receptor (TCR) avidity. These data are consistent with previous studies indicating an important role for the B 2705-Gag KK10 response in the control of HIV but also suggest a previously unrecognized role played by the subdominant Pol-specific KY9 response in HLA-B 2705-mediated control of HIV and that the recognition of HIV-infected cells by CD8(+) T cells early in the viral life cycle may be important for viral containment in HIV-infected individuals.

Comparison of the effectiveness of commonly used clinic-based treatments for external genital warts.

We describe a prospective study designed to assess the effectiveness of the commonly used clinic-based treatments for genital warts individually and in combination. Patients presenting with new or recurrent genital warts were randomly allocated to one of five treatments on a weekly basis. The clinical endpoint was wart clearance or eight treatments, whichever occurred sooner. If there was not a good response by the eighth treatment, an alternate modality was offered. Four hundred and nine individuals were enrolled in the study. Almost no patients withdrew in any group due to adverse effects. Three-quarters of patients treated with podophyllin 25% and cryotherapy concurrently required only two treatments to clear their warts. All had clearance in less than eight treatments. Single therapy with either trichloracetic acid or podophyllin 25% resulted in longer time to wart clearance, and more persistent warts.