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The greatest risk factor for kidney stones is hypercalciuria, the etiology of which is largely unknown. A recent genome-wide association study (GWAS) linked hypercalciuria and kidney stones to a claudin-14 (CLDN14) risk haplotype. However, the underlying molecular mechanism was not delineated. Recently, renal CLDN14 expression was found to increase in response to increased plasma calcium, thereby inducing calciuria. We hypothesized therefore that some children with hypercalciuria and kidney stones harbor a CLDN14 variant that inappropriately increases gene expression. To test this hypothesis, we sequenced the CLDN14 risk haplotype in a cohort of children with idiopathic hypercalciuria and kidney stones. An intronic SNP was more frequent in affected children. Dual luciferase and cell-based assays demonstrated increased reporter or CLDN14 expression when this polymorphism was introduced. In silico studies predicted the SNP introduced a novel insulinoma-associated 1 (INSM1) transcription factor binding site. Consistent with this, repeating the dual luciferase assay in the presence of INSM1 further increased reporter expression. Our data suggest that children with the INSM1 binding site within the CLDN14 risk haplotype have a higher likelihood of hypercalciuria and kidney stones. Enhanced CLDN14 expression may play a role in the pathophysiology of their hypercalciuria.

Congenital syphilis is one of the preventable diseases caused by the gram-negative bacteria Treponema pallidum; yet, it imposes a serious global health and economic burden, with more than half of the cases resulting in serious adverse outcomes, including infant mortality. Mother-to-child transmission (MTCT) of syphilis is estimated at 3.6 million adjusted life years (DALYs) and around $309 million in medical costs. In 2006, an estimated 9.7 million children of age less than five years died in developing countries; almost four million were neonatal deaths. There were 3.2 million stillbirths globally, among whom 95% were in the developing countries. In sub-Saharan Africa, there is an estimated 2.7% (0.1%-10.3%) of pregnant women infected with syphilis, representing more than 900,000 pregnancies at risk each year. There were many non-specific and specific diagnostic tests used in the past, which required laboratory equipment and electricity, but there are many newer tests available now that provide rapid results with high sensitivity and specificity, e.g., the immunochromatographic strip (ICS) and rapid syphilis tests (RST). Early syphilis can be completely eliminated with a single injection of penicillin, which is readily available, cheap, and highly effective, and treating pregnant women with penicillin is 98% effective at preventing congenital syphilis. Targeting women at a high risk of having syphilis makes universal screening in antenatal programs the most efficacious way to prevent syphilis-associated morbidity and mortality. The potential for a program to prevent congenital syphilis in the perinatal, neonatal, and postnatal periods is evident. While considering resource allocation to child survival programs in areas where the prevalence of syphilis is high, officials need to include antenatal syphilis screening, using rapid tests and treatment at the first contact of the mother with the health care system. In countries like Zambia and other resource-limited settings, a same-day test and treatment with penicillin should be prioritized to achieve the goal of eliminating congenital syphilis. Eliminating MTCT of syphilis through screening and treatment in antenatal care (ANC) is highly cost-effective in a wide range of settings, especially in countries with a high prevalence.

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