Modification of the Antibiotic, Colistin, with Dextrin Causes Enhanced Cytotoxicity and Triggers Apoptosis in Myeloid Leukemia.

Introduction: Acute myeloid leukemia (AML) remains difficult to treat due to its heterogeneity in molecular landscape, epigenetics and cell signaling alterations. Precision medicine is a major goal in AML therapy towards developing agents that can be used to treat patients with different 'subtypes' in combination with current chemotherapies. We have previously developed dextrin-colistin conjugates to combat the rise in multi-drug resistant bacterial infections and overcome dose-limiting nephrotoxicity. Recent evidence of colistin's anticancer activity, mediated through inhibition of intracellular lysine-specific histone demethylase 1 (LSD1/KDM1A), suggests that dextrin-colistin conjugates could be used to treat cancer cells, including AML. This study aimed to evaluate whether dextrin conjugation (which reduces in vivo toxicity and prolongs plasma half-life) could enhance colistin's cytotoxic effects in myeloid leukemia cell lines and compare the intracellular uptake and localization of the free and conjugated antibiotic. Results: Our results identified a conjugate (containing 8000 g/mol dextrin with 1 mol% succinoylation) that caused significantly increased toxicity in myeloid leukemia cells, compared to free colistin. Dextrin conjugation altered the mechanism of cell death by colistin, from necrosis to caspase 3/7-dependent apoptosis. In contrast, conjugation via a reversible ester linker, instead of an amide, had no effect on the mechanism of the colistin-induced cell death. Live cell confocal microscopy of fluorescently labelled compounds showed both free and dextrin-conjugated colistins were endocytosed and co-localized in lysosomes, and increasing the degree of modification by succinoylation of dextrin significantly reduced colistin internalization. Discussion: Whilst clinical translation of dextrin-colistin conjugates for the treatment of AML is unlikely due to the potential to promote antimicrobial resistance (AMR) and the relatively high colistin concentrations required for anticancer activity, the ability to potentiate the effectiveness of an anticancer drug by polymer conjugation, while reducing side effects and improving biodistribution of the drug, is very attractive, and this approach warrants further investigation.

Dextrin conjugation to colistin inhibits its toxicity, cellular uptake and acute kidney injury in vivo.

The acute kidney injury (AKI) and dose-limiting nephrotoxicity, which occurs in 20-60% of patients following systemic administration of colistin, represents a challenge in the effective treatment of multi-drug resistant Gram-negative infections. To reduce clinical toxicity of colistin and improve targeting to infected/inflamed tissues, we previously developed dextrin-colistin conjugates, whereby colistin is designed to be released by amylase-triggered degradation of dextrin in infected and inflamed tissues, after passive targeting by the enhanced permeability and retention effect. Whilst it was evident in vitro that polymer conjugation can reduce toxicity and prolong plasma half-life, without significant reduction in antimicrobial activity of colistin, it was unclear how dextrin conjugation would alter cellular uptake and localisation of colistin in renal tubular cells in vivo. We discovered that dextrin conjugation effectively reduced colistin's toxicity towards human kidney proximal tubular epithelial cells (HK-2) in vitro, which was mirrored by significantly less cellular uptake of Oregon Green (OG)-labelled dextrin-colistin conjugate, when compared to colistin. Using live-cell confocal imaging, we revealed localisation of both, free and dextrin-bound colistin in endolysosome compartments of HK-2 and NRK-52E cells. Using a murine AKI model, we demonstrated dextrin-colistin conjugation dramatically diminishes both proximal tubular injury and renal accumulation of colistin. These findings reveal new insight into the mechanism by which dextrin conjugation can overcome colistin's renal toxicity and show the potential of polymer conjugation to improve the side effect profile of nephrotoxic drugs.

Food pattern modeling to inform global guidance on complementary feeding of infants.

Nutrient needs are difficult to meet during infancy due to high nutrient requirements and the small quantities of food consumed. Guidelines to support food choice decisions are critical to promoting optimal infant health, growth and development and food pattern modeling can be used to inform guideline development. We employed the Optifood modeling system to determine if unfortified complementary foods could meet 13 nutrient targets for breastfed infants (6-11 months), and to describe food patterns that met, or came as close as possible to meeting targets. We also examined the impacts of eliminating food groups, increasing starchy staple foods or adding sentinel unhealthy foods. We collated a global food list from dietary studies in 37 countries and used this list to develop nutrient values for a set of 35 food subgroups. We analyzed infant dietary intakes from studies in eight countries to inform maximum quantities and frequencies of consumption for these subgroups in weekly food patterns. We found that unfortified foods could meet targets for most infants for 12 nutrients, but not for iron. For the smallest and youngest infants, with the lowest energy intakes, there were additional deficits for minerals. Best-case food patterns that met targets or came as close as possible to meeting targets included ample amounts of diverse vegetables, diverse plant- and animal-source protein foods, small amounts of whole grain foods and dairy and no refined grains or added fats or sugar. There were nutrient deficits if animal-source foods or vegetables were eliminated or if unhealthy foods were included.

Dietary selenium intake among Ethiopian children in areas known for selenium spatial variability.

Introduction: There is spatial variability of selenium (Se) in soil and crops in Ethiopia. We assessed the Se content of food items, breast milk, and urine among infants in Ethiopia from two areas with contrasting Se concentrations in soils. Methods: Dietary Se intakes among children (6-23 months) were evaluated using a weighed food record on two non-consecutive days. Also, spot urine samples from children and breast milk samples from their mothers were collected to determine Se concentration. Selenium concentrations in the samples were analyzed using an inductively coupled plasma mass spectrometer (ICP-MS). Results: Injera (prepared from teff and mixtures of other cereals) with a legume-based stew were the most frequently consumed foods by the children in both areas, followed by pasta. Overall, the Se concentration (mean ± SD) of food items, breast milk (12.2 ± 3.9 µg/L vs. 3.39 ± 1.5 µg/L), and urine samples (22.5 ± 11.5 µg/L vs. 3.0 ± 1.9 µg/L) from East Amhara were significantly higher than the corresponding samples from West Amhara (p < 0.001). The total Se intakes by the study children from East Amhara and West Amhara were 30.2 [IQ 25%, 14.2; IQ 75%, 54.1] and 7.4 [IQR 25%, 4.2; IQ 75%, 10.6] µg day-1, respectively; 31.5% of children from East Amhara and 92% of children from West Amhara were at risk of inadequate Se intakes. Urinary Se excretion accounted for 53 and 39% of daily dietary Se intake in East Amhara and West Amhara, respectively. Dietary Se intake was positively correlated with urinary Se excretion in East Amhara (r = 0.56; p < 0.001) but not among samples from West Amhara (r = 0.16; p ≥ 0.05), suggesting greater physiological Se conservation in a state of deficiency. Conclusion: There is spatial variability of Se in foods, breast milk, and urine in Ethiopia, suggesting the need for implementation of targeted agronomic interventions that enhance Se concentrations in the edible portion of plant foods.

High unhealthy food and beverage consumption is associated with poor diet quality among 12-35-month-olds in Guédiawaye Department, Senegal.

Background: High consumption of unhealthy foods and beverages (UFB) during early childhood is cause for concern, with growing evidence from low- and middle-income countries finding associations with poor diet quality and malnutrition. Research from sub-Saharan Africa remains limited, with no studies quantifying the contribution of UFB to total energy intakes among young children or exploring the relationship between such intakes and diet quality or anthropometric outcomes. Objectives: Assess UFB consumption patterns and their contribution to total energy intake from non-breastmilk foods/beverages (TEI-NBF), assess the association between high UFB consumption and dietary/nutrition outcomes, and explore drivers of unhealthy food choice among young children in Guédiawaye Department, Senegal. Methods: We conducted a cross-sectional study of a representative sample of 724 primary caregivers and their 12-35.9-month-old children. The study included a questionnaire, a quantitative four-pass 24-h dietary recall, and anthropometric measurements. The contribution of UFB to TEI-NBF was calculated and terciles generated. Logistic and linear models were used to compare outcomes of high versus low UFB consumption terciles. Results: UFB contributed on average 22.2% of TEI-NBF, averaging 5.9% for the lowest tercile and 39.9% for the highest. Diets of high UFB consumers, as compared to low, were significantly less dense in protein, fiber, and seven of the 11 micronutrients assessed and significantly denser in total fat, saturated fat, and total sugar. No associations were found with anthropometric outcomes. High UFB consumers were older and more likely to be living in food insecurity. The most common drivers of commercial UFB consumption were related to child preference, the use of these products as behavior management tools, treats, or gifts, and the sharing of these products by someone else eating them. Conclusion: High UFB consumption is associated with poor diet quality among 12-35-month-olds in Guédiawaye Department, Senegal. Addressing high UFB consumption during this critical developmental period should be prioritized in young child nutrition research, programming, and policy development.

Including calcium-fortified water or flour in modeled diets based on local foods could improve calcium intake for women, adolescent girls, and young children in Bangladesh, Uganda, and Guatemala.

Adequate calcium intake is essential for health, especially for infants, children, adolescents, and women, yet is difficult to achieve with local foods in many low- and middle-income countries. Previous analysis found it was not always possible to identify food-based recommendations (FBRs) that reached the calcium population recommended intake (PRI) for these groups in Bangladesh, Guatemala, and Uganda. We have modeled the potential contribution of calcium-fortified drinking water or wheat flour to FBR sets, to fill the remaining intake gaps. Optimized diets containing fortified products, with calcium-rich local foods, achieved the calcium PRI for all target groups. Combining fortified water or flour with FBRs met dietary intake targets for adolescent girls in all geographies and allowed a reduction from 3-4 to the more feasible 1-2 FBRs. Water with a calcium concentration of 100 mg/L with FBRs was sufficient to meet calcium targets in Uganda, but higher concentrations (400-500 mg/L) were mostly required in Guatemala and Bangladesh. Combining calcium-fortified wheat flour at 400 mg/100 g of flour and the FBR for small fish resulted in diets meeting the calcium PRI in Bangladesh. Calcium-fortified water or flour could improve calcium intake for vulnerable populations, especially when combined with FBRs based on locally available foods.

Could local foods achieve recommended calcium intakes for nutritionally vulnerable populations in Uganda, Guatemala, and Bangladesh?

Globally, dietary intake of calcium is often insufficient, and it is unclear if adequacy could be achieved by promoting calcium-rich local foods. This study used linear programming and household consumption data from Uganda, Bangladesh, and Guatemala to assess whether local foods could meet calcium population reference intakes (Ca PRIs). The most promising food-based approaches to promote dietary calcium adequacy were identified for 12- to 23-month-old breastfed children, 4- to 6-year-old children, 10- to 14-year-old girls, and nonpregnant and nonbreastfeeding (NPNB) women of reproductive age living in two regions of each country. Calcium-optimized diets achieved 75-253% of the Ca PRI, depending on the population, and were <100% for 4- to 6-year-olds in one region of each country and 10- to 14-year-old girls in Sylhet, Bangladesh. The best food sources of calcium were green leafy vegetables and milk, across geographic locations, and species of small fish, nixtamalized (lime-treated) maize products, sesame seeds, and bean varieties, where consumed. Food-based recommendations (FBRs) achieving the minimum calcium threshold were identified for 12- to 23-month-olds and NPNB women across geographic locations, and for 4- to 6-year-olds and 10-to 14-year-old girls in Uganda. However, for 4- to 6-year-olds and 10- to 14-year-old girls in Bangladesh and Guatemala, calcium-adequate FBRs could not be identified, indicating a need for alternative calcium sources or increased access to and consumption of local calcium-rich foods.

High consumption of unhealthy commercial foods and beverages tracks across the complementary feeding period in rural/peri-urban Cambodia.

Consumption of unhealthy commercial foods and beverages (UCFB) is common among infants and young children living in low- and middle-income countries. Such foods can displace other nutritious foods, however, there is limited evidence on how this consumption tracks across time. This study assessed and tracked UCFB consumption of children living in rural/peri-urban Cambodia during the complementary feeding period, identified UCFB consumption patterns of these children, and explored the association between UCFB consumption and growth. A 6-month longitudinal cohort study was implemented among 567 caregivers of children aged 10-14 months at recruitment. UCFB consumption was estimated each month via a telephone-administered 7-day food frequency questionnaire, and UCFB consumption patterns were identified based on changes in this frequency of consumption over time. The majority of children either maintained (45.7%, n = 246) or developed (43.5%, n = 234) an unhealthy consumption pattern and only 10.8% (n = 58) of children maintained/transitioned into a healthy consumption pattern. High consumers of UCFB at 10-14 months had a 4.7 (CI: 4.7 [3.1-7.2]) times odds of being high consumers of UCFB at 15-19 months (p < 0.001). There was a trend of lower length-for-age z-scores (LAZ) among children maintaining or developing an unhealthy consumption pattern (~-0. SD LAZ) compared to children maintaining/transitioning into a healthy consumption pattern, however, this association was not statistically significant. Findings indicate that high UCFB consumption begins during infancy and tracks into early childhood. National policies and programmes centred on early interventions addressing the use of UCFB for infant and young child feeding are needed.

Automated wearable cameras for improving recall of diet and time use in Uganda: a cross-sectional feasibility study.

BACKGROUND: Traditional recall approaches of data collection for assessing dietary intake and time use are prone to recall bias. Studies in high- and middle-income countries show that automated wearable cameras are a promising method for collecting objective health behavior data and may improve study participants' recall of foods consumed and daily activities performed. This study aimed to evaluate the feasibility of using automated wearable cameras in rural Eastern Ugandan to collect dietary and time use data. METHODS: Mothers of young children (n = 211) wore an automated wearable camera on 2 non-consecutive days while continuing their usual activities. The day after wearing the camera, participants' dietary diversity and time use was assessed using an image-assisted recall. Their experiences of the method were assessed via a questionnaire. RESULTS: Most study participants reported their experiences with the automated wearable camera and image-assisted recall to be good (36%) or very good (56%) and would participate in a similar study in the future (97%). None of the eight study withdrawals could be definitively attributed to the camera. Fifteen percent of data was lost due to device malfunction, and twelve percent of the images were "uncodable" due to insufficient lighting. Processing and analyzing the images were labor-intensive, time-consuming, and prone to human error. Half (53%) of participants had difficulty interpreting the images captured by the camera. CONCLUSIONS: Using an automated wearable camera in rural Eastern Uganda was feasible, although improvements are needed to overcome the challenges common to rural, low-income country contexts and reduce the burdens posed on both participants and researchers. To improve the quality of data obtained, future automated wearable camera-based image assisted recall studies should use a structured data format to reduce image coding time; electronically code the data in the field, as an output of the image review process, to eliminate ex post facto data entry; and, ideally, use computer-assisted personal interviews software to ensure completion and reduce errors. In-depth formative work in partnership with key local stakeholders (e.g., researchers from low-income countries, representatives from government and/or other institutional review boards, and community representatives and local leaders) is also needed to identify practical approaches to ensuring that the ethical rights of automated wearable camera study participants in low-income countries are adequately protected.

Validation of an Automated Wearable Camera-Based Image-Assisted Recall Method and the 24-h Recall Method for Assessing Women's Time Allocation in a Nutritionally Vulnerable Population: The Case of Rural Uganda.

Accurate data are essential for investigating relationships between maternal time-use patterns and nutritional outcomes. The 24 h recall (24HR) has traditionally been used to collect time-use data, however, automated wearable cameras (AWCs) with an image-assisted recall (IAR) may reduce recall bias. This study aimed to evaluate their concurrent criterion validity for assessing women's time use in rural Eastern Ugandan. Women's (n = 211) time allocations estimated via the AWC-IAR and 24HR methods were compared with direct observation (criterion method) using the Bland-Altman limits of agreement (LOA) method of analysis and Cronbach's coefficient alpha (time allocation) or Cohen's κ (concurrent activities). Systematic bias varied from 1 min (domestic chores) to 226 min (caregiving) for 24HR and 1 min (own production) to 109 min (socializing) for AWC-IAR. The LOAs were within 2 h for employment, own production, and self-care for 24HR and AWC-IAR but exceeded 11 h (24HR) and 9 h (AWC-IAR) for caregiving and socializing. The LOAs were within four concurrent activities for 24HR (-1.1 to 3.7) and AWC-IAR (-3.2 to 3.2). Cronbach's alpha for time allocation ranged from 0.1728 (socializing) to 0.8056 (own production) for 24HR and 0.2270 (socializing) to 0.7938 (own production) for AWC-IAR. For assessing women's time allocations at the population level, the 24HR and AWC-IAR methods are accurate and reliable for employment, own production, and domestic chores but poor for caregiving and socializing. The results of this study suggest the need to revisit previously published research investigating the associations between women's time allocations and nutrition outcomes.

Alginate oligosaccharides enhance diffusion and activity of colistin in a mucin-rich environment.

In a number of chronic respiratory diseases e.g. cystic fibrosis (CF) and chronic obstructive pulmonary disease (COPD), the production of viscous mucin reduces pulmonary function and represents an effective barrier to diffusion of inhaled therapies e.g. antibiotics. Here, a 2-compartment Transwell model was developed to study impaired diffusion of the antibiotic colistin across an artificial sputum (AS) matrix/medium and to quantify its antimicrobial activity against Pseudomonas aeruginosa NH57388A biofilms (alone and in combination with mucolytic therapy). High-performance liquid chromatography coupled with fluorescence detection (HPLC-FLD) revealed that the presence of AS medium significantly reduced the rate of colistin diffusion (> 85% at 48 h; p < 0.05). Addition of alginate oligosaccharide (OligoG CF-5/20) significantly improved colistin diffusion by 3.7 times through mucin-rich AS medium (at 48 h; p < 0.05). Increased diffusion of colistin with OligoG CF-5/20 was shown (using confocal laser scanning microscopy and COMSTAT image analysis) to be associated with significantly increased bacterial killing (p < 0.05). These data support the use of this model to study drug and small molecule delivery across clinically-relevant diffusion barriers. The findings indicate the significant loss of colistin and reduced effectiveness that occurs with mucin binding, and support the use of mucolytics to improve antimicrobial efficacy and lower antibiotic exposure.

A food-based approach could improve dietary adequacy for 12-23-month-old Eastern Ugandan children.

Little is known about dietary adequacy, for young Ugandan children, or context-specific food choices to improve it. This study estimated the percentage of breastfed 12-23-month-old rural Eastern Ugandan children (n = 114) at risk of inadequate intakes of 12 nutrients; and identified realistic food choices for improving it. In this cross-sectional survey, dietary (weighed food records), anthropometric and socioeconomic data were collected. The percentages of children at risk of inadequate nutrient intakes were estimated, assuming 541 g/day of breast milk was consumed. The median nutrient densities of their complementary feeding diets were also compared with desired levels. Linear programming analyses were used to identify 'problem nutrients' (where requirements will be difficult to meet given dietary practices) and model food choices to improve dietary adequacy. Overall, 21.2% of children were stunted and 3.8% were wasted. A high percentage (>45%) of children were at risk of inadequate intakes, for nine of the 12 nutrients assessed, and dietary nutrient densities were below desired levels for seven of the 12 nutrients. Iron, calcium, thiamine and niacin were 'problem nutrients'. Through careful selection of foods, modelling indicates that population level dietary adequacy can be achieved for eight of the 12 nutrients modelled. These choices include cows' milk, legumes, green leafy vegetables, sweet potatoes and fruits. Overall results suggest these high percentages of children at risk of inadequate nutrient intakes can be reduced through behaviour change interventions, although additional interventions may be required to ensure population-level dietary adequacy for iron, thiamine and niacin.

Systematic review of metrics used to characterise dietary nutrient supply from household consumption and expenditure surveys.

OBJECTIVE: To review existing publications using Household Consumption and Expenditure Survey (HCES) data to estimate household dietary nutrient supply to (1) describe scope of available literature, (2) identify the metrics reported and parameters used to construct these metrics, (3) summarise comparisons between estimates derived from HCES and individual dietary assessment data and (4) explore the demographic and socio-economic sub-groups used to characterise risks of nutrient inadequacy. DESIGN: This study is a systematic review of publications identified from online databases published between 2000 to 2019 that used HCES food consumption data to estimate household dietary nutrient supply. Further publications were identified by 'snowballing' the references of included database-identified publications. SETTING: Publications using data from low- and lower-middle income countries. RESULTS: In total, fifty-eight publications were included. Three metrics were reported that characterised household dietary nutrient supply: apparent nutrient intake per adult-male equivalent per day (n 35), apparent nutrient intake per capita per day (n 24) and nutrient density (n 5). Nutrient intakes were generally overestimated using HCES food consumption data, with several studies finding sizeable discrepancies compared with intake estimates based on individual dietary assessment methods. Sub-group analyses predominantly focused on measuring variation in household dietary nutrient supply according to socio-economic position and geography. CONCLUSION: HCES data are increasingly being used to assess diets across populations. More research is needed to inform the development of a framework to guide the use of and qualified interpretation of dietary assessments based on these data.

Modeling food fortification contributions to micronutrient requirements in Malawi using Household Consumption and Expenditure Surveys.

Large-scale food fortification may be a cost-effective intervention to increase micronutrient supplies in the food system when implemented under appropriate conditions, yet it is unclear if current strategies can equitably benefit populations with the greatest micronutrient needs. This study developed a mathematical modeling framework for comparing fortification scenarios across different contexts. It was applied to model the potential contributions of three fortification vehicles (oil, sugar, and wheat flour) toward meeting dietary micronutrient requirements in Malawi through secondary data analyses of a Household Consumption and Expenditure Survey. We estimated fortification vehicle coverage, micronutrient density of the diet, and apparent intake of nonpregnant, nonlactating women for nine different micronutrients, under three food fortification scenarios and stratified by subpopulations across seasons. Oil and sugar had high coverage and apparent consumption that, when combined, were predicted to improve the vitamin A adequacy of the diet. Wheat flour contributed little to estimated dietary micronutrient supplies due to low apparent consumption. Potential contributions of all fortification vehicles were low in rural populations of the lowest socioeconomic position. While the model predicted large-scale food fortification would contribute to reducing vitamin A inadequacies, other interventions are necessary to meet other micronutrient requirements, especially for the rural poor.

A physicochemical assessment of the thermal stability of dextrin-colistin conjugates.

Attachment of polysaccharide carriers is increasingly being used to achieve precision delivery and improved effectiveness of protein and peptide drugs. Although it is clear that their clinical effectiveness relies on the purity and integrity of the conjugate in storage, as well as following administration, instability of polysaccharide-based conjugates can reduce the protective efficacy of the polymer, which may adversely affect the bioactive's potency. As a model, these studies used dextrin-colistin conjugates, with varying degrees of polymer modification (1, 2.5 and 7.5 mol% succinoylation) to assess the effect of storage temperature (- 20, 4, 21 and 37 °C) and duration (up to 12 months) on saccharide and colistin release and antimicrobial activity. Estimation of the proportion of saccharide release (by comparison of area under the curve from size exclusion chromatograms) was more pronounced at higher temperatures (up to 3 and 35% at - 20 °C and 37 °C, respectively after 12 months), however, repeated freeze-thaw did not produce any measurable release of saccharides, while addition of amylase (20, 100, 500 IU/L) caused rapid release of saccharides (> 70% total within 24 h). At all temperatures, conjugates containing the lowest degree of succinoylation released the highest proportion of free colistin, which increased with storage temperature, however no trend in saccharide release was observed. Despite the clear physical effects of prolonged storage, antimicrobial activity of all samples was only altered after storage at 37 °C for 12 months (> threefold decreased activity). These results demonstrate significant release of saccharides from dextrin-colistin conjugates during prolonged storage in buffered solution, especially at elevated temperature, which, in most cases, did not affect antimicrobial activity. These findings provide vital information about the structure-activity relationship of dextrin-colistin conjugates, prior to full-scale commercial development, which can subsequently be applied to other polysaccharide-protein and -peptide conjugates.

Validation of a life-logging wearable camera method and the 24-h diet recall method for assessing maternal and child dietary diversity.

Accurate and timely data are essential for identifying populations at risk for undernutrition due to poor-quality diets, for implementing appropriate interventions and for evaluating change. Life-logging wearable cameras (LLWC) have been used to prospectively capture food/beverage consumed by adults in high-income countries. This study aimed to evaluate the concurrent criterion validity, for assessing maternal and child dietary diversity scores (DDS), of a LLWC-based image-assisted recall (IAR) and 24-h recall (24HR). Direct observation was the criterion method. Food/beverage consumption of rural Eastern Ugandan mothers and their 12-23-month-old child (n 211) was assessed, for the same day for each method, and the IAR and 24HR DDS were compared with the weighed food record DDS using the Bland-Altman limits of agreement (LOA) method of analysis and Cohen's κ. The relative bias was low for the 24HR (-0·1801 for mothers; -0·1358 for children) and the IAR (0·1227 for mothers; 0·1104 for children), but the LOA were wide (-1·6615 to 1·3012 and -1·6883 to 1·4167 for mothers and children via 24HR, respectively; -2·1322 to 1·8868 and -1·7130 to 1·4921 for mothers and children via IAR, respectively). Cohen's κ, for DDS via 24HR and IAR, was 0·68 and 0·59, respectively, for mothers, and 0·60 and 0·59, respectively, for children. Both the 24HR and IAR provide an accurate estimate of median dietary diversity, for mothers and their young child, but non-differential measurement error would attenuate associations between DDS and outcomes, thereby under-estimating the true associations between DDS - where estimated via 24HR or IAR - and outcomes measured.

Biofortified Maize Improves Selenium Status of Women and Children in a Rural Community in Malawi: Results of the Addressing Hidden Hunger With Agronomy Randomized Controlled Trial.

Background: Selenium deficiency is widespread in the Malawi population. The selenium concentration in maize, the staple food crop of Malawi, can be increased by applying selenium-enriched fertilizers. It is unknown whether this strategy, called agronomic biofortification, is effective at alleviating selenium deficiency. Objectives: The aim of the Addressing Hidden Hunger with Agronomy (AHHA) trial was to determine whether consumption of maize flour, agronomically-biofortified with selenium, affected the serum selenium concentrations of women, and children in a rural community setting. Design: An individually-randomized, double-blind placebo-controlled trial was conducted in rural Malawi. Participants were randomly allocated in a 1:1 ratio to receive either intervention maize flour biofortified with selenium through application of selenium fertilizer, or control maize flour not biofortified with selenium. Participant households received enough flour to meet the typical consumption of all household members (330 g capita -1 day-1) for a period of 8 weeks. Baseline and endline serum selenium concentration (the primary outcome) was measured by inductively coupled plasma mass spectrometry (ICP-MS). Results: One woman of reproductive age (WRA) and one school-aged child (SAC) from each of 180 households were recruited and households were randomized to each group. The baseline demographic and socioeconomic status of participants were well-balanced between arms. No serious adverse events were reported. In the intervention arm, mean (standard deviation) serum selenium concentration increased over the intervention period from 57.6 (17.0) µg L-1 (n = 88) to 107.9 (16.4) µg L-1 (n = 88) among WRA and from 46.4 (14.8) µg L-1 (n = 86) to 97.1 (16.0) µg L-1 (n = 88) among SAC. There was no evidence of change in serum selenium concentration in the control groups. Conclusion: Consumption of maize flour biofortified through application of selenium-enriched fertilizer increased selenium status in this community providing strong proof of principle that agronomic biofortification could be an effective approach to address selenium deficiency in Malawi and similar settings. Clinical Trial Registration: http://www.isrctn.com/ISRCTN85899451, identifier: ISRCTN85899451.

Bi-Functional Alginate Oligosaccharide-Polymyxin Conjugates for Improved Treatment of Multidrug-Resistant Gram-Negative Bacterial Infections.

The recent emergence of resistance to colistin, an antibiotic of last resort with dose-limiting toxicity, has highlighted the need for alternative approaches to combat infection. This study aimed to generate and characterise alginate oligosaccharide ("OligoG")-polymyxin (polymyxin B and E (colistin)) conjugates to improve the effectiveness of these antibiotics. OligoG-polymyxin conjugates (amide- or ester-linked), with molecular weights of 5200-12,800 g/mol and antibiotic loading of 6.1-12.9% w/w, were reproducibly synthesised. In vitro inflammatory cytokine production (tumour necrosis factor alpha (TNFα) ELISA) and cytotoxicity (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) of colistin (2.2-9.3-fold) and polymyxin B (2.9-27.2-fold) were significantly decreased by OligoG conjugation. Antimicrobial susceptibility tests (minimum inhibitory concentration (MIC), growth curves) demonstrated similar antimicrobial efficacy of ester- and amide-linked conjugates to that of the parent antibiotic but with more sustained inhibition of bacterial growth. OligoG-polymyxin conjugates exhibited improved selectivity for Gram-negative bacteria in comparison to mammalian cells (approximately 2-4-fold). Both OligoG-colistin conjugates caused significant disruption of Pseudomonas aeruginosa biofilm formation and induced bacterial death (confocal laser scanning microscopy). When conjugates were tested in an in vitro "time-to-kill" (TTK) model using Acinetobacter baumannii, only ester-linked conjugates reduced viable bacterial counts (~2-fold) after 4 h. Bi-functional OligoG-polymyxin conjugates have potential therapeutic benefits in the treatment of multidrug-resistant (MDR) Gram-negative bacterial infections, directly reducing toxicity whilst retaining antimicrobial and antibiofilm activities.

Iodine-fortified toddler milk improves dietary iodine intakes and iodine status in toddlers: a randomised controlled trial.

PURPOSE: We aimed to evaluate the effectiveness of consuming iodine-fortified toddler milk for improving dietary iodine intakes and biochemical iodine status in toddlers. METHODS: In a 20-week parallel randomised controlled trial, healthy 12-20-month-old children were assigned to: Fortified Milk [n = 45; iodine-fortified (21.1 µg iodine/100 g prepared drink) cow's milk], or Non-Fortified Milk (n = 90; non-fortified cow's milk). Food and nutrient intakes were assessed with 3-day weighed food records at baseline, and weeks 4 and 20. Urinary iodine concentration (UIC) was measured at baseline and 20 weeks. RESULTS: At baseline, toddlers' median milk intake was 429 g/day. There was no evidence that milk intakes changed within or between the groups during the intervention. Toddlers' baseline geometric mean iodine intake was 46.9 µg/day, and the median UIC of 43 µg/L in the Fortified Milk group and 55 µg/L in the Non-Fortified Milk group indicated moderate and mild iodine deficiency, respectively, with this difference due to chance. During the intervention, iodine intakes increased by 136% (p < 0.001) and UIC increased by 85 µg/L (p < 0.001) in the Fortified Milk group compared to the Non-Fortified Milk group. The 20-week median UIC was 91 µg/L in the Fortified Milk group and 49 µg/L in the Non-Fortified Milk group. CONCLUSIONS: Consumption of ≈ 1.7 cups of iodine-fortified toddler milk per day for 20 weeks can increase dietary iodine intakes and UIC in healthy iodine-deficient toddlers. This strategy alone is unlikely to provide sufficient intake to ensure adequate iodine status in toddlers at risk of mild-to-moderate iodine deficiency.

Exploratory Analysis of Nutritional Quality and Metrics of Snack Consumption among Nepali Children during the Complementary Feeding Period.

The World Health Organization recommends feeding snacks between meals to young children. This study explored nutritional quality of snacks consumed between meals and consumption metrics (% total energy intakes (%TEI) and amount of kcal from snacks) to understand correlations with dietary outcomes (total energy intakes and dietary adequacy) and body-mass-index-for-age z-scores (BMIZ). Data used were 24-h dietary recalls and anthropometric measurements among a representative sample (n = 679) of one-year-olds in Nepal. Nepali meal patterns for young children were identified through formative research and all foods/beverages consumed outside of meals were categorized as snacks. A nutrient profiling model was used to categorize snacks as healthy or unhealthy, based on positive and negative nutrient content. Snacks consumed between meals provided half of all energy consumed, and were associated with increased energy and nutrient intakes. The positive effect of snacks between meals on dietary adequacy was greater when these snacks were healthy, while increasing %TEI from unhealthy snacks consumed between meals was negatively associated with dietary adequacy. Consumption of snacks between meals was not associated with mean BMIZ among the children. These findings indicate that the provision of and nutritional quality of snacks are important considerations to communicate to caregivers. Discouragement of unhealthy, nutrient-poor snacks is critical for complementary feeding dietary guidelines in contexts experiencing nutrition transition.