Zinc-enriched fertilisers as a potential public health intervention in Africa

Background In this review, we examine the potential of Zn-enriched fertilisers to alleviate human dietary Zn deficiency. The focus is on ten African countries where dietary Zn supply is low and where fertiliser subsidies are routinely deployed on cereal crops. Scope Dietary Zn supply and deficiency prevalence were quantified from food supply and composition data. Typical effects of soil (granular) and foliar Zn applications on Zn concentrations in maize (Zea mays L.), rice (Oryza sativa L.) and wheat (Triticum aestivum L.) grains were based on a systematic literature review. Reductions in disease burdens attributable to Zn deficiency and cost-effectiveness were estimated using a disability-adjusted life years (DALYs) approach. Conclusions Baseline Zn supply in 2009 ranged from 7.1 (Zambia) to 11.9 (Mali) mg capita−1 day−1; prevalence of Zn deficiency ranged from 24 (Nigeria) to 66 % (Zambia). In reviewed studies, soil Zn application led to an increase in median Zn concentration in maize, rice and wheat grains of 23, 7 and 19 %; foliar application led to increases of 30, 25 and 63 %. Enriching granular fertilisers within current subsidy schemes would be most effective in Malawi, reducing DALYs lost due to Zn deficiency by 10 %. The cost per DALY saved ranged from US$624 to 5893 via granular fertilisers and from US$ 46 to 347 via foliar fertilisers. Foliar applications are likely to be more cost effective than soil applications due to fixation of Zn in the soil but may be more difficult to deploy. Zinc fertilisation is likely to be less cost-effective than breeding in the longer term although other micronutrients such as selenium could be incorporated

Confirmation of the genetic association of CTLA4 and PTPN22 with ANCA-associated vasculitis.

BACKGROUND: The genetic contribution to the aetiology of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is not well defined. Across different autoimmune diseases some genes with immunomodulatory roles, such as PTPN22, are frequently associated with multiple diseases, whereas specific HLA associations, such as HLA-B27, tend to be disease restricted. We studied ten candidate loci on the basis of their immunoregulatory role and prior associations with type 1 diabetes (T1D). These included PTPN22, CTLA4 and CD226, which have previously been associated with AAV. METHODS: We genotyped the following 11 SNPs, from 10 loci, in 641 AAV patients using TaqMan genotyping: rs2476601 in PTPN22, rs1990760 in IFIH1, rs3087243 in CTLA4, rs2069763 in IL2, rs10877012 in CYP27B1, rs2292239 in ERBB3, rs3184504 in SH2B3, rs12708716 in CLEC16A, rs1893217 and rs478582 in PTPN2 and rs763361 in CD226. Where possible, we performed a meta-analysis with previous analyses. RESULTS: Both CTLA4 rs3087243 and PTPN22 rs2476601 showed association with AAV, P = 6.4 x 10-3 and P = 1.4 x 10-4 respectively. The minor allele (A) of CTLA4 rs3087243 is protective (odds ratio = 0.84), whereas the minor allele (A) of PTPN22 rs2476601 confers susceptibility (odds ratio = 1.40). These results confirmed previously described associations with AAV. After meta-analysis, the PTPN22 rs2476601 association was further strengthened (combined P = 4.2 x 10-7, odds ratio of 1.48 for the A allele). The other 9 SNPs, including rs763361 in CD226, showed no association with AAV. CONCLUSION: Our study of T1D associated SNPs in AAV has confirmed CTLA4 and PTPN22 as susceptibility loci in AAV. These genes encode two key regulators of the immune response and are associated with many autoimmune diseases, including T1D, autoimmune thyroid disease, celiac disease, rheumatoid arthritis, and now AAV

Africa’s oesophageal cancer corridor: geographic variations in incidence correlate with certain micronutrient deficiencies

Background The aetiology of Africa’s easterly-lying corridor of squamous cell oesophageal cancer is poorly understood. Micronutrient deficiencies have been implicated in this cancer in other areas of the world, but their role in Africa is unclear. Without prospective cohorts, timely insights can instead be gained through ecological studies. Methods Across Africa we assessed associations between a country’s oesophageal cancer incidence rate and food balance sheet-derived estimates of mean national dietary supplies of 7 nutrients: calcium (Ca), copper (Cu), iron (Fe), iodine (I), magnesium (Mg), selenium (Se) and zinc (Zn). We included 32 countries which had estimates of dietary nutrient supplies and of better-quality GLOBCAN 2012 cancer incidence rates. Bayesian hierarchical Poisson lognormal models were used to estimate incidence rate ratios for oesophageal cancer associated with each nutrient, adjusted for age, gender, energy intake, phytate, smoking and alcohol consumption, as well as their 95% posterior credible intervals (CI). Adult dietary deficiencies were quantified using an estimated average requirements (EAR) cut-point approach. Results Adjusted incidence rate ratios for oesophageal cancer associated with a doubling of mean nutrient supply were: for Fe 0.49 (95% CI: 0.29–0.82); Mg 0.58 (0.31–1.08); Se 0.40 (0.18–0.90); and Zn 0.29 (0.11–0.74). There were no associations with Ca, Cu and I. Mean national nutrient supplies exceeded adult EARs for Mg and Fe in most countries. For Se, mean supplies were less than EARs (both sexes) in 7 of the 10 highest oesophageal cancer ranking countries, compared to 23% of remaining countries. For Zn, mean supplies were less than the male EARs in 8 of these 10 highest ranking countries compared to in 36% of other countries

Valuing increased zinc (Zn) fertiliser-use in Pakistan

Use of zinc (Zn) fertilisers may be cost-effective in increasing crop yields and in alleviating dietary Zn deficiency. However, Zn fertilisers are underutilised in many countries despite the widespread occurrence of Zn-deficient soils. Here, increased Zn fertiliser-use scenarios were simulated for wheat production in Punjab and Sindh Provinces, Pakistan. Inputs and outputs were valued in terms of both potential yield gains as well as health gains in the population. Methods The current dietary Zn deficiency risk of 23.9 % in Pakistan was based on food supply and wheat grain surveys. “Disability-adjusted life years (DALYs) lost” are a common metric of disease burden; an estimated 245,000 DALYs y−1 are lost in Punjab and Sindh due to Zn deficiency. Baseline Zn fertiliser-use of 7.3 kt y−1 ZnSO4.H2O was obtained from published and industry sources. The wheat area currently receiving Zn fertilisers, and grain yield responses of 8 and 14 % in Punjab and Sindh, respectively, were based on a recent survey of >2500 farmers. Increased grain Zn concentrations under Zn fertilisation were estimated from literature data and converted to improved Zn intake in humans and ultimately a reduction in DALYs lost

Heavily and fully modified RNAs guide efficient SpyCas9-mediated genome editing

RNA-based drugs depend on chemical modifications to increase potency and to decrease immunogenicity in vivo. Chemical modification will likely improve the guide RNAs involved in CRISPR-Cas9-based therapeutics as well. Cas9 orthologs are RNA-guided microbial effectors that cleave DNA. Here, we explore chemical modifications at all positions of the crRNA guide and tracrRNA cofactor. We identify several heavily modified versions of crRNA and tracrRNA that are more potent than their unmodified counterparts. In addition, we describe fully chemically modified crRNAs and tracrRNAs (containing no 2\u27-OH groups) that are functional in human cells. These designs will contribute to Cas9-based therapeutics since heavily modified RNAs tend to be more stable in vivo (thus increasing potency). We anticipate that our designs will improve the use of Cas9 via RNP and mRNA delivery for in vivo and ex vivo purposes

Heavily and Fully Modified RNAs Guide Efficient SpyCas9-Mediated Genome Editing [preprint]

RNA-based drugs depend on chemical modifications to increase potency and nuclease stability, and to decrease immunogenicity in vivo. Chemical modification will likely improve the guide RNAs involved in CRISPR-Cas9-based therapeutics as well. Cas9 orthologs are RNA-guided microbial effectors that cleave DNA. No studies have yet explored chemical modification at all positions of the crRNA guide and tracrRNA cofactor. Here, we have identified several heavily-modified versions of crRNA and tracrRNA that are more potent than their unmodified counterparts. In addition, we describe fully chemically modified crRNAs and tracrRNAs (containing no 2\u27-OH groups) that are functional in human cells. These designs demonstrate a significant breakthrough for Cas9-based therapeutics since heavily modified RNAs tend to be more stable in vivo (thus increasing potency). We anticipate that our designs will improve the use of Cas9 via RNP and mRNA delivery for in vivo and ex vivo purposes

Contrasting genetic association of IL2RA with SLE and ANCA-associated vasculitis.

BACKGROUND: Autoimmune diseases are complex and have genetic and environmental susceptibility factors. The objective was to test the genetic association of systemic lupus erythematosus (SLE) and anti-neutrophil cytoplasmic antibody (ANCA) - associated systemic vasculitis (AAV) with SNPs in the IL2RA region and to correlate genotype with serum levels of IL-2RA. METHODS: Using a cohort of over 700 AAV patients, two SLE case-control studies and an SLE trio collection (totalling over 1000 SLE patients), and a TaqMan genotyping approach, we tested 3 SNPs in the IL2RA locus, rs11594656, rs2104286 & rs41295061, each with a prior association with autoimmune disease; rs11594656 and rs41295061 with type 1 diabetes (T1D) and rs2104286 with multiple sclerosis (MS) and T1D. RESULTS: We show that SLE is associated with rs11594656 (P = 3.87 x 10-7) and there is some evidence of association of rs41295061 with AAV (P = 0.0122), which both have prior association with T1D. rs2104286, an MS and T1D - associated SNP in the IL2RA locus, is not associated with either SLE or AAV. CONCLUSION: We have confirmed a previous suggestion that the IL2RA locus is associated with SLE and showed some evidence of association with AAV. Soluble IL-2RA concentrations correlate with rs11594656 genotype in quiescent disease in both AAV and SLE. Differential association of autoimmune diseases and SNPs within the IL2RA locus suggests that the IL2RA pathway may prove to play differing, as yet undefined, roles in each disease

Good soil management can reduce dietary zinc deficiency in Zimbabwe

Dietary zinc (Zn) deficiency is widespread in sub-Saharan Africa (SSA) with adverse impacts on human health. Agronomic biofortification with Zn fertilizers and improved soil fertility management, using mineral and organic nutrient resources, has previously been shown to increase Zn concentration of staple grain crops, including maize. Here, we show the potential of different soil fertility management options on maize crops to reduce dietary Zn deficiency in Zimbabwe using secondary data from a set of survey and field experiments. An ex-ante approach was used, informed by published evidence from studies in three contrasting smallholder production systems in Zimbabwe. To estimate current Zn deficiency in Zimbabwe, data on dietary Zn supply from non-maize sources from the Global Expanded Nutrient Supply (GENuS) data set were linked to maize grain Zn composition observed under typical current soil fertility management scenarios. A baseline dietary Zn deficiency prevalence of 68% was estimated from a reference maize grain Zn composition value of 16.6 mg kg-1 and an estimated dietary Zn intake of 9.3 mg capita-1 day-1 from all food sources. The potential health benefits of reducing Zn deficiency using different soil fertility management scenarios were quantified within a Disability Adjusted Life Years (DALYs) framework. A scenario using optimal mineral NPK fertilizers and locally available organic nutrient resources (i.e. cattle manure and leaf litter), but without additional soil Zn fertilizer applications, is estimated to increase maize grain Zn concentration to 19.3 mg kg-1. This would reduce the estimated prevalence of dietary Zn deficiency to 55%, potentially saving 2,238 DALYs year-1. Universal adoption of optimal fertilizers, to include soil Zn applications and locally available organic leaf litter, is estimated to increase maize grain Zn concentration to 32.4 mg kg-1 and reduce dietary Zn deficiency to 16.7%, potentially saving 9,119 DALYs year-1. Potential monetized yield gains from adopting improved soil fertility management range from 49-to 158-fold larger than the potential reduction in DALYs, if the latter are monetized using standard methods. Farmers should be incentivized to adopt improved soil fertility management to improve both crop yield and quality