A novel nano-iron supplement to safely combat iron deficiency and anaemia in young children: The IHAT-GUT double-blind, randomised, placebo-controlled trial protocol.

Background: Iron deficiency and its associated anaemia (IDA) are the leading forms of micronutrient malnutrition worldwide. Here we describe the rationale and design of the first clinical trial evaluating the efficacy and safety of an innovative nano iron supplement, iron hydroxide adipate tartrate (IHAT), for the treatment of IDA in young children (IHAT-GUT trial). Oral iron is often ineffective due to poor absorption and/or gastrointestinal adverse effects. IHAT is novel since it is effectively absorbed whilst remaining nanoparticulate in the gut, therefore should enable supplementation with fewer symptoms. Methods: IHAT-GUT is a three-arm, double-blind, randomised, placebo-controlled phase II trial conducted in Gambian children 6-35 months of age. The intervention consists of a 12-week supplementation with either IHAT, ferrous sulphate (both at doses bioequivalent to 12.5 mg Fe/day) or placebo. The trial aims to include 705 children with IDA who will be randomly assigned (1:1:1) to each arm. The primary objectives are to test non-inferiority of IHAT in relation to ferrous sulphate at treating IDA, and to test superiority of IHAT in relation to ferrous sulphate and non-inferiority in relation to placebo in terms of diarrhoea incidence and prevalence. Secondary objectives are mechanistic assessments, to test whether IHAT reduces the burden of enteric pathogens, morbidity, and intestinal inflammation, and that it does not cause detrimental changes to the gut microbiome, particularly in relation to Lactobacillaceae, Bifidobacteriaceae and Enterobacteriaceae. Discussion: This trial will test the hypothesis that supplementation with IHAT eliminates iron deficiency and improves haemoglobin levels without inducing gastrointestinal adverse effects. If shown to be the case, this would open the possibility for further testing and use of IHAT as a novel iron source for micronutrient intervention strategies in resource-poor countries, with the ultimate aim to help reduce the IDA global burden. Registration: This trial is registered at clinicaltrials.gov ( NCT02941081)

A novel nano-iron supplement to safely combat iron deficiency and anaemia in young children: The IHAT-GUT double-blind, randomised, placebo-controlled trial protocol.

Background: Iron deficiency and its associated anaemia (IDA) are the leading forms of micronutrient malnutrition worldwide. Here we describe the rationale and design of the first clinical trial evaluating the efficacy and safety of an innovative nano iron supplement, iron hydroxide adipate tartrate (IHAT), for the treatment of IDA in young children (IHAT-GUT trial). Oral iron is often ineffective due to poor absorption and/or gastrointestinal adverse effects. IHAT is novel since it is effectively absorbed whilst remaining nanoparticulate in the gut, therefore should enable supplementation with fewer symptoms. Methods: IHAT-GUT is a three-arm, double-blind, randomised, placebo-controlled phase II trial conducted in Gambian children 6-35 months of age. The intervention consists of a 12-week supplementation with either IHAT, ferrous sulphate (both at doses bioequivalent to 12.5 mg Fe/day) or placebo. The trial aims to include 705 children with IDA who will be randomly assigned (1:1:1) to each arm. The primary objectives are to test non-inferiority of IHAT in relation to ferrous sulphate at treating IDA, and to test superiority of IHAT in relation to ferrous sulphate and non-inferiority in relation to placebo in terms of diarrhoea incidence and prevalence. Secondary objectives are mechanistic assessments, to test whether IHAT reduces the burden of enteric pathogens, morbidity, and intestinal inflammation, and that it does not cause detrimental changes to the gut microbiome, particularly in relation to Lactobacillaceae, Bifidobacteriaceae and Enterobacteriaceae. Discussion: This trial will test the hypothesis that supplementation with IHAT eliminates iron deficiency and improves haemoglobin levels without inducing gastrointestinal adverse effects. If shown to be the case, this would open the possibility for further testing and use of IHAT as a novel iron source for micronutrient intervention strategies in resource-poor countries, with the ultimate aim to help reduce the IDA global burden. Registration: This trial is registered at clinicaltrials.gov ( NCT02941081)

Consideration of antimicrobial resistance and contextual factors in infectious disease guidelines: a systematic survey.

OBJECTIVES: Guidelines that include antimicrobial recommendations should explicitly consider contextual factors that influence antimicrobial resistance and their downstream effects on resistance selection. The objectives were to analyse (1) how, and to what extent, tuberculosis, gonorrhoea and respiratory tract infection guidelines are considering antimicrobial resistance; (2) are of acceptable quality and (3) if they can be easily contextualised to fit the needs of specific populations and health systems. METHODS: We conducted a systematic review and searched Ovid MEDLINE and Embase from 1 January 2007 to 7 June 2019 for tuberculosis, gonorrhoea and respiratory tract infection guidelines published in English. We also searched guideline databases, key websites and reference lists. We identified guidelines and recommendations that considered contextual factors including antimicrobial resistance, values, resource use, equity, acceptability and feasibility. We assessed quality of the guidelines using the Appraisal of Guidelines for Research and Evaluation II tool focusing on the domains scope and purpose, rigour of development, and editorial independence. RESULTS: We screened 10 365 records, of which 74 guidelines met inclusion criteria. Of these guidelines, 39% (n=29/74) met acceptable quality scores. Approximately two-thirds of recommendations considered antimicrobial resistance at the population and/or outcome level. Five of the 29 guidelines reported all factors required for recommendation contextualisation. Equity was the least considered across guidelines. DISCUSSION: Relatively few guidelines for highly prevalent infectious diseases are considering resistance at a local level, and many do not consider contextual factors necessary for appropriate antimicrobial use. Improving the quality of guidelines targeting specific regional areas is required. PROSPERO REGISTRATION NUMBER: CRD42020145235

Enteric pathogens of food sellers in rural Gambia with incidental finding of Myxobolus species (Protozoa: Myxozoa).

BACKGROUND: Ongoing surveillance of enteric pathogens of public health significance among casual food sellers is undertaken in many resource-limited countries. We report the results of a survey in Kiang West province, The Gambia, and provide an exemplar methodology for such surveys in resource-limited laboratories. METHODS: Unpreserved, unrefrigerated stool samples were subjected to Salmonella, Shigella and agar plate culture for rhabditoid nematodes. Direct microscopy, formalin-ethyl acetate concentration and iron-hematoxylin staining was performed later, following preservation. RESULTS: Of 128 specimens received, no Shigella spp. was recovered, while four serovars of non-typhoidal Salmonella enterica, including Chandans, were isolated. Pathogenic parasitic infections were Necator americanus 10/128 (7.8%), Strongyloides stercoralis 3/128 (2.8%), Blastocystis species 45/128 (35.1%), Entamoeba histolytica complex 19/128 (14.8%) and Giardia intestinalis 4/128 (3.1%). A single case each of Hymenolepis diminuta and S. mansoni infection were detected. In one participant, myxozoan spores identical to those of Myxobolus species were found. CONCLUSIONS: Rare parasitoses and serovars of Salmonella enterica may occur relatively commonly in rural Africa. This paper describes intestinal pathogens found in a cohort of food sellers in such a setting. Furthermore, it describes two parasites rarely recovered from humans and demonstrates the need for methods other than microscopy to detect S. stercoralis infections

A novel nano-iron supplement versus standard treatment for iron deficiency anaemia in children 6-35 months (IHAT-GUT trial): a double-blind, randomised, placebo-controlled non-inferiority phase II trial in The Gambia.

BACKGROUND: Iron deficiency anaemia (IDA) is the leading cause of years lost to disability in most sub-Saharan African countries and is especially common in young children. The IHAT-GUT trial assessed the efficacy and safety of a novel nano iron supplement, which is a dietary ferritin analogue termed iron hydroxide adipate tartrate (IHAT), for the treatment of IDA in children under 3 years of age. METHODS: In this single-country, randomised, double-blind, parallel, placebo-controlled, non-inferiority Phase II study in The Gambia, children 6-35 months with IDA (7≤Hb < 11 g/dL and ferritin<30 μg/L) were randomly assigned (1:1:1) to receive either IHAT, ferrous sulphate (FeSO4) or placebo daily for 3 months (85 days). The daily iron dose was 12.5 mg Fe equivalent for FeSO4 and the estimated dose with comparable iron-bioavailability for IHAT (20 mg Fe). The primary efficacy endpoint was the composite of haemoglobin response at day 85 and correction of iron deficiency. The non-inferiority margin was 0.1 absolute difference in response probability. The primary safety endpoint was moderate-severe diarrhoea analysed as incidence density and prevalence over the 3 months intervention. Secondary endpoints reported herein include hospitalisation, acute respiratory infection, malaria, treatment failures, iron handling markers, inflammatory markers, longitudinal prevalence of diarrhoea and incidence density of bloody diarrhoea. Main analyses were per-protocol (PP) and intention-to-treat (ITT) analyses. This trial is registered with clinicaltrials.gov (NCT02941081). FINDINGS: Between Nov 2017 and Nov 2018, 642 children were randomised into the study (214 per group) and included in the ITT analysis, the PP population included 582 children. A total of 50/177 (28.2%) children in the IHAT group achieved the primary efficacy endpoint, as compared with 42/190 (22.1%) in the FeSO4 group (OR 1.39, 80% CI 1.01-1.91, PP population) and with 2/186 (1.1%) in the placebo group. Diarrhoea prevalence was similar between groups, with 40/189 (21.2%) children in the IHAT group developing at least one episode of moderate-severe diarrhoea over the 85 days intervention, compared with 47/198 (23.7%) in the FeSO4 group (OR 1.18, 80% CI 0.86-1.62) and 40/195 (20.5%) in the placebo group (OR 0.96, 80% CI 0.7-1.33, PP population). Incidence density of moderate-severe diarrhoea was 2.66 in the IHAT group and 3.42 in the FeSO4 group (RR 0.76, 80% CI 0.59-0.99, CC-ITT population).There were 143/211 (67.8%) children with adverse events (AEs) in the IHAT group, 146/212 (68.9%) in the FeSO4 group and 143/214 (66.8%) in the placebo group. There were overall 213 diarrhoea-related AEs; 35 (28.5%) cases reported in the IHAT group compared with 51 (41.5%) cases in the FeSO4 group and 37 (30.1%) cases in the placebo group. INTERPRETATION: In this first Phase II study conducted in young children with IDA, IHAT showed sufficient non-inferiority compared to standard-of-care FeSO4, in terms of ID correction and haemoglobin response, to warrant a definitive Phase III trial. In addition, IHAT had lower incidence of moderate-severe diarrhoea than FeSO4, with no increased adverse events in comparison with placebo. FUNDING: The Bill & Melinda Gates Foundation (OPP1140952)

Approaches of integrating the development of guidelines and quality indicators: a systematic review

Contains fulltext : 225833.pdf (publisher's version ) (Open Access)BACKGROUND: Guidelines and quality indicators (for example as part of a quality assurance scheme) aim to improve health care delivery and health outcomes. Ideally, the development of quality indicators should be grounded in evidence-based, trustworthy guideline recommendations. However, anecdotally, guidelines and quality assurance schemes are developed independently, by different groups of experts who employ different methodologies. We conducted an extension and update of a previous systematic review to identify, describe and evaluate approaches to the integrated development of guidelines and related quality indicators. METHODS: On May 24th, 2019 we searched in Medline, Embase and CINAHL and included studies if they reported a methodological approach to guideline-based quality indicator development and were published in English, French, or German. RESULTS: Out of 16,034 identified records, we included 17 articles that described a method to integrate guideline recommendations development and quality indicator development. Added to the 13 method articles from original systematic review we included a total 30 method articles. We did not find any evaluation studies. In most approaches, guidelines were a source of evidence to inform the quality indicator development. The criteria to select recommendations (e.g. level of evidence or strength of the recommendation) and to generate, select and assess quality indicators varied widely. We found methodological approaches that linked guidelines and quality indicator development explicitly, however none of the articles reported a conceptual framework that fully integrated quality indicator development into the guideline process or where quality indicator development was part of the question formulation for developing the guideline recommendations. CONCLUSIONS: In our systematic review we found approaches which explicitly linked guidelines with quality indicator development, nevertheless none of the articles reported a comprehensive and well-defined conceptual framework which integrated quality indicator development fully into the guideline development process

The emerging threat of pre-extensively drug-resistant tuberculosis in West Africa: preparing for large-scale tuberculosis research and drug resistance surveillance

Background Drug-resistant tuberculosis (TB) is a global public health problem. Adequate management requires baseline drug-resistance prevalence data. In West Africa, due to a poor laboratory infrastructure and inadequate capacity, such data are scarce. Therefore, the true extent of drug-resistant TB was hitherto undetermined. In 2008, a new research network, the West African Network of Excellence for Tuberculosis, AIDS and Malaria (WANETAM), was founded, comprising nine study sites from eight West African countries (Burkina Faso, The Gambia, Ghana, Guinea-Bissau, Mali, Nigeria, Senegal and Togo). The goal was to establish Good Clinical Laboratory Practice (GCLP) principles and build capacity in standardised smear microscopy and mycobacterial culture across partnering laboratories to generate the first comprehensive West African drug-resistance data. Methods Following GCLP and laboratory training sessions, TB isolates were collected at sentinel referral sites between 2009–2013 and tested for first- and second-line drug resistance. Results From the analysis of 974 isolates, an unexpectedly high prevalence of multi-drug-resistant (MDR) strains was found in new (6 %) and retreatment patients (35 %) across all sentinel sites, with the highest prevalence amongst retreatment patients in Bamako, Mali (59 %) and the two Nigerian sites in Ibadan and Lagos (39 % and 66 %). In Lagos, MDR is already spreading actively amongst 32 % of new patients. Pre-extensively drug-resistant (pre-XDR) isolates are present in all sites, with Ghana showing the highest proportion (35 % of MDR). In Ghana and Togo, pre-XDR isolates are circulating amongst new patients. Conclusions West African drug-resistance prevalence poses a previously underestimated, yet serious public health threat, and our estimates obtained differ significantly from previous World Health Organisation (WHO) estimates. Therefore, our data are reshaping current concepts and are essential in informing WHO and public health strategists to implement urgently needed surveillance and control interventions in West Africa

A novel nano-iron supplement versus standard treatment for iron deficiency anaemia in children 6–35 months (IHAT-GUT trial): a double-blind, randomised, placebo-controlled non-inferiority phase II trial in The Gambia

Background: Iron deficiency anaemia (IDA) is the leading cause of years lost to disability in most sub-Saharan African countries and is especially common in young children. The IHAT-GUT trial assessed the efficacy and safety of a novel nano iron supplement, which is a dietary ferritin analogue termed iron hydroxide adipate tartrate (IHAT), for the treatment of IDA in children under 3 years of age. Methods: In this single-country, randomised, double-blind, parallel, placebo-controlled, non-inferiority Phase II study in The Gambia, children 6–35 months with IDA (7≤Hb < 11 g/dL and ferritin<30 μg/L) were randomly assigned (1:1:1) to receive either IHAT, ferrous sulphate (FeSO4) or placebo daily for 3 months (85 days). The daily iron dose was 12.5 mg Fe equivalent for FeSO4 and the estimated dose with comparable iron-bioavailability for IHAT (20 mg Fe). The primary efficacy endpoint was the composite of haemoglobin response at day 85 and correction of iron deficiency. The non-inferiority margin was 0.1 absolute difference in response probability. The primary safety endpoint was moderate-severe diarrhoea analysed as incidence density and prevalence over the 3 months intervention. Secondary endpoints reported herein include hospitalisation, acute respiratory infection, malaria, treatment failures, iron handling markers, inflammatory markers, longitudinal prevalence of diarrhoea and incidence density of bloody diarrhoea. Main analyses were per-protocol (PP) and intention-to-treat (ITT) analyses. This trial is registered with clinicaltrials.gov (NCT02941081). Findings: Between Nov 2017 and Nov 2018, 642 children were randomised into the study (214 per group) and included in the ITT analysis, the PP population included 582 children. A total of 50/177 (28.2%) children in the IHAT group achieved the primary efficacy endpoint, as compared with 42/190 (22.1%) in the FeSO4 group (OR 1.39, 80% CI 1.01–1.91, PP population) and with 2/186 (1.1%) in the placebo group. Diarrhoea prevalence was similar between groups, with 40/189 (21.2%) children in the IHAT group developing at least one episode of moderate-severe diarrhoea over the 85 days intervention, compared with 47/198 (23.7%) in the FeSO4 group (OR 1.18, 80% CI 0.86–1.62) and 40/195 (20.5%) in the placebo group (OR 0.96, 80% CI 0.7–1.33, PP population). Incidence density of moderate-severe diarrhoea was 2.66 in the IHAT group and 3.42 in the FeSO4 group (RR 0.76, 80% CI 0.59–0.99, CC-ITT population). There were 143/211 (67.8%) children with adverse events (AEs) in the IHAT group, 146/212 (68.9%) in the FeSO4 group and 143/214 (66.8%) in the placebo group. There were overall 213 diarrhoea-related AEs; 35 (28.5%) cases reported in the IHAT group compared with 51 (41.5%) cases in the FeSO4 group and 37 (30.1%) cases in the placebo group. Interpretation: In this first Phase II study conducted in young children with IDA, IHAT showed sufficient non-inferiority compared to standard-of-care FeSO4, in terms of ID correction and haemoglobin response, to warrant a definitive Phase III trial. In addition, IHAT had lower incidence of moderate-severe diarrhoea than FeSO4, with no increased adverse events in comparison with placebo. Funding: The Bill & Melinda Gates Foundation ( OPP1140952)