An in vitro model of human ovarian follicles would greatly benefit the study of female reproduction. Ovarian development requires the combination of germ cells and several types of somatic cells. Among these, granulosa cells play a key role in follicle formation and support for oogenesis. Whereas efficient protocols exist for generating human primordial germ cell-like cells (hPGCLCs) from human induced pluripotent stem cells (hiPSCs), a method of generating granulosa cells has been elusive. Here, we report that simultaneous overexpression of two transcription factors (TFs) can direct the differentiation of hiPSCs to granulosa-like cells. We elucidate the regulatory effects of several granulosa-related TFs and establish that overexpression of NR5A1 and either RUNX1 or RUNX2 is sufficient to generate granulosa-like cells. Our granulosa-like cells have transcriptomes similar to human fetal ovarian cells and recapitulate key ovarian phenotypes including follicle formation and steroidogenesis. When aggregated with hPGCLCs, our cells form ovary-like organoids (ovaroids) and support hPGCLC development from the premigratory to the gonadal stage as measured by induction of DAZL expression. This model system will provide unique opportunities for studying human ovarian biology and may enable the development of therapies for female reproductive health.

Ready-to-use therapeutic food (RUTF) containing less dairy may be a lower-cost treatment option for severe acute malnutrition (SAM). The objective was to understand the effectiveness of RUTF containing alternative sources of protein (nondairy), or <50% of protein from dairy products, compared with standard RUTF in children with SAM. The Cochrane Library, MEDLINE, Embase, CINAHL, and Web of Science were searched using terms relating to RUTF. Studies were eligible if they included children with SAM and evaluated RUTF with <50% of protein from dairy products compared with standard RUTF. Meta-analysis and meta-regression were completed to assess the effectiveness of intervention RUTF on a range of child outcomes. The quality of the evidence across outcomes was assessed using the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach. A total of 5868 studies were identified, of which 8 articles of 6 studies met the inclusion criteria evaluating 7 different intervention RUTF recipes. Nondairy or lower-dairy RUTF showed less weight gain (standardized mean difference: −0.20; 95% CI: −0.26, −0.15; P < 0.001), lower recovery (relative risk ratio: 0.93; 95% CI: 0.87, 1.00; P = 0.046), and lower weight-for-age z scores (WAZ) near program discharge (mean difference: −0.10; 95% CI: −0.20, 0.0; P = 0.047). Mortality, time to recovery, default (consecutive absences from outpatient therapeutic feeding program visits), nonresponse, and other anthropometric measures did not differ between groups. The certainty of evidence was high for weight gain and ranged from very low to moderate for other outcomes. RUTF with lower protein from dairy or dairy-free RUTF may not be as effective as standard RUTF for treatment of children with SAM based on weight gain, recovery, and WAZ evaluated using meta-analysis, although further research is required to explore the potential of alternative formulations. This review was registered at https://www.crd.york.ac.uk/prospero/ as CRD42020160762.

An in vitro model of human ovarian follicles would greatly benefit the study of female reproduction. Ovarian development requires the combination of germ cells and their supporting somatic cells, known as granulosa cells. Whereas efficient protocols exist for generating human primordial germ cell-like cells (hPGCLCs) from human iPSCs, a method of generating granulosa cells has been elusive. Here we report that simultaneous overexpression of two transcription factors (TFs) can direct the differentiation of human iPSCs to granulosa-like cells. We elucidate the regulatory effects of several granulosa-related TFs, and establish that overexpression of NR5A1 and either RUNX1 or RUNX2 is necessary and sufficient to generate granulosa-like cells. Our granulosa-like cells form ovary-like organoids (ovaroids) when aggregated with hPGCLCs, and recapitulate key ovarian phenotypes including support of germ cell maturation, follicle formation, and steroidogenesis. This model system will provide unique opportunities for studying human ovarian biology, and may enable the development of therapies for female reproductive health.

Treatment of acute malnutrition typically requires the provision of ready-to-use food (RUF). Common RUF is effective but expensive, being manufactured from costly ingredients, and shipped worldwide from few global suppliers. I developed a linear programming tool to create RUF optimized for low cost using locally grown crops while maintaining necessary nutritional goals and other constraints. My tool utilizes a database of the nutritional value, price, and water efficiency of suitable ingredients and allows adjustment of constraints, including nutrients, flavour, and crop water efficiency. It is designed to (a) address nutrient requirements conforming to current standards and practice; (b) optimize RUF formulae for low cost using a wide range of ingredients for nutritional value and acceptability improvement; (c) ensure protein quality through protein digestibility corrected amino acid score; and (d) adjust RUF formulae according to locally grown crop selection, local prices, and crop water footprint. The tool creates formulae free of expensive dairy ingredients, ensuring desired protein digestibility corrected amino acid score by automatically balancing proteins with complementary quantities of essential amino acids. Using publicly available data with an application to Nigeria, my tool created RUF formulae suitable for local production using local crops to meet all nutrient requirements at a fraction of the ingredient cost and water footprint of current formulae, demonstrating the tool's effectiveness. Optimization of RUF for low cost using locally grown crops will facilitate local production and reduce ingredient as well as transport costs, so more patients can receive lifesaving treatment.