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Hypertension affects 10%–15% of pregnancies worldwide and can lead to serious adverse fetal and maternal outcomes. In addition, women with hypertension in pregnancy are at greater risk of developing stroke and renal disease later in life, while hypertensive pregnancy complications can also affect the long-term health of the child. The identification of strategies to maintain healthy blood pressure in women before and during pregnancy should therefore be prioritised. Emerging research points to an important role for folate, one-carbon metabolism and the related B vitamin, riboflavin, in blood pressure. In particular, evidence from clinical and genome-wide association studies links the C677T polymorphism in the gene encoding the folate-metabolising enzyme methylenetetrahydrofolate reductase (MTHFR) with blood pressure and an increased risk of hypertension and hypertensive disorders of pregnancy. Riboflavin (in the form of flavin adenine dinucleotide) is required as a cofactor for MTHFR, and notably, randomised trials show that supplemental riboflavin can effectively lower blood pressure specifically in individuals with the variant MTHFR 677TT genotype, independently of antihypertensive medications. The evidence that better riboflavin status modifies the blood pressure phenotype in these genetically at-risk individuals has important public health implications, especially for populations worldwide with the highest frequencies of the variant TT genotype in MTHFR, including Guatemala (up to 66%), Mexico (32%) and Northern China (20%). This novel gene–nutrient interaction warrants particular attention in the context of blood pressure before and during pregnancy. Furthermore, the biological mechanisms require investigation, whereby one-carbon metabolism is linked with blood pressure and how riboflavin, a much-overlooked nutrient in health and research settings, can modulate the excess genetic risk of hypertension in affected individuals. Here, we review the generally unrecognised role of riboflavin as a novel personalised solution to prevent hypertension and hypertensive disorders of pregnancy in genetically at-risk women. This article should stimulate current thinking, with potentially important impacts for public health nutrition strategies to promote better pregnancy outcomes in women.

Anaemia affects more than 36 % of all pregnancies globally and is associated with significant maternal and neonatal morbidity and mortality. Iron deficiency is widely recognised as the most common nutritional cause of anaemia but other nutrient deficiencies are also implicated, including the B vitamin riboflavin, albeit its role is largely under-investigated and thus typically overlooked. Riboflavin, in its co-factor forms flavin adenine dinucleotide (FAD) and flavin mononucleotide (FMN), is required for numerous oxidation-reduction reactions, antioxidant function and in the metabolism of other B vitamins and iron. While clinical deficiency of riboflavin is largely confined to low-income countries, sub-clinical (functional) deficiency is much more widespread, including in high-income countries, and is particularly common among women of reproductive age and during pregnancy. Limited observational evidence from high-income populations suggests that suboptimal riboflavin status contributes to an increased risk of anaemia. Furthermore, randomised controlled trials in pregnant women from low- and middle-income countries have demonstrated beneficial effects of riboflavin on haematological status and anaemia. Various mechanisms have been proposed to explain the contribution of riboflavin deficiency to anaemia, with the strongest evidence pointing to an adverse effect on iron metabolism, given that riboflavin co-factors are required for the release of iron from storage ferritin in the production of red blood cells. Overall, this review investigates riboflavin intakes and status during pregnancy in different populations and evaluates the available evidence for the under-recognised role of riboflavin in the maintenance of haemoglobin concentrations together with its potential to protect against the development of anaemia during pregnancy.

The immune response after ocular exposure to foreign antigens varies substantially from that of a typical systemic response. Anterior chamber associated immune deviation (ACAID) has been well documented. The immune response of the subretinal space has not been studied in as much detail. Here, we characterized the immune response of the subretinal space when it encounters the antigens AdV-GFP and AAV-GFP (recombinant adenovirus or adeno-associated virus, respectively), each delivering the reporter gene encoding green fluorescent protein (GFP). Results indicate that the subretinal space possesses an immune-deviant property similar to ACAID. AdV-elicited immune responses following subretinal injections are significantly reduced compared with systemic responses elicited by intradermal injections of the same virus. Furthermore, subretinal AdV administration results in transduction of retinal pigment epithelial cells (RPE), which are the potential antigen presenting cells of the retina. This subsequently generates a population of immunosuppressive Th2-type, cytokine-secreting, splenic T cells. This response may be advantageous to the development of ocular gene therapy.

Placental accumulation of Plasmodium falciparum infected erythrocytes results in maternal anemia, low birth weight, and pregnancy loss. The parasite protein VAR2CSA facilitates the accumulation of infected erythrocytes in the placenta through interaction with the host receptor chondroitin sulfate A (CSA). Antibodies that prevent the VAR2CSA-CSA interaction correlate with protection from placental malaria, and VAR2CSA is a high-priority placental malaria vaccine antigen. Here, structure-guided design leveraging the full-length structures of VAR2CSA produced a stable immunogen that retains the critical conserved functional elements of VAR2CSA. The design expressed with a six-fold greater yield than the full-length protein and elicited antibodies that prevent adhesion of infected erythrocytes to CSA. The reduced size and adaptability of the designed immunogen enable efficient production of multiple variants of VAR2CSA for use in a cocktail vaccination strategy to increase the breadth of protection. These designs form strong foundations for the development of potent broadly protective placental malaria vaccines.

Placental malaria (PM) is a deadly syndrome most frequent and severe in first pregnancies. PM results from accumulation of Plasmodium falciparum -infected erythrocytes (IE) that express the surface antigen VAR2CSA and bind to chondroitin sulfate A (CSA) in the placenta. Women become PM-resistant over successive pregnancies as they develop anti-adhesion and anti-VAR2CSA antibodies, supporting VAR2CSA as the leading PM-vaccine candidate. However, the first VAR2CSA subunit vaccines failed to induce broadly neutralizing antibody and it is known that naturally acquired antibodies target both variant-specific and conserved epitopes. It is crucial to determine whether effective vaccines will require incorporation of many or only a single VAR2CSA variants. Here, IgG from multigravidae was sequentially purified on five full-length VAR2CSA ectodomain variants, thereby depleting IgG reactivity to each. The five VAR2CSA variants purified ~0.7% of total IgG and yielded both strain-transcending and strain-specific reactivity to VAR2CSA and IE-surface antigen. In two independent antibody purification/depletion experiments with permutated order of VAR2CSA variants, IgG purified on the first VAR2CSA antigen displayed broad cross-reactivity to both recombinant and native VAR2CSA variants, and inhibited binding of all isolates to CSA. IgG remaining after depletion on all variants showed significantly reduced binding-inhibition activity compared to initial total IgG. These findings demonstrate that a single VAR2CSA ectodomain variant displays conserved epitopes that are targeted by neutralizing (or binding-inhibitory) antibodies shared by multiple parasite strains, including maternal isolates. This suggests that a broadly effective PM-vaccine can be achieved with a limited number of VAR2CSA variants. Contracting malaria during pregnancy – especially a first pregnancy – can lead to a severe, placental form of the disease that is often fatal. Red blood cells infected with the malaria parasite Plasmodium falciparum display a protein, VAR2CSA, which can recognize and bind CSA molecules present on placental cells and in placental blood spaces. This leads to the infected blood cells accumulating in the placenta and inducing harmful inflammation. Having been exposed to the parasite in prior pregnancies generates antibodies that target VAR2CSA, stopping the infected blood cells from latching onto placental CSA or tagging them for immune destruction. Overall, this makes placental malaria less severe in following pregnancies, and suggests that vaccines could be developed based on VAR2CSA. However, this protein has regions that can vary in structure, meaning that P. falciparaum can generate many VAR2CSA variants. Individuals exposed to the parasite naturally generate antibodies that block a wide array of variants from attaching to CSA. In contrast, first-generation vaccines based on VAR2CSA fragments have only induced variant-specific antibodies, therefore offering limited protection against infection. As a response, Doritchamou et al. set out to find VAR2CSA structures that could be recognized by antibodies targeting an array of variants. Blood was obtained from women who had had multiple pregnancies and were immune to malaria. Their plasma was passed over five different large VAR2CSA variants in order to isolate and purify antibodies that attached to these structures. Doritchamou et al. found that antibodies binding to individual VAR2CSA structures could also recognise a wide array of VAR2CSA variants and blocked all tested parasites from sticking to CSA. While further research is needed, these findings highlight antibodies that cross-react to diverse VAR2CSA variants and could be used to design more effective vaccines targeting placental malaria.

Malaria elimination requires tools that interrupt parasite transmission. Here, we characterize B cell receptor responses among Malian adults vaccinated against the first domain of the cysteine-rich 230 kDa gamete surface protein Pfs230, a key protein in sexual stage development of P. falciparum parasites. Among nine Pfs230 human monoclonal antibodies (mAbs) that we generated, one potently blocks transmission to mosquitoes in a complement-dependent manner and reacts to the gamete surface; the other eight show only low or no blocking activity. The structure of the transmission-blocking mAb in complex with vaccine antigen reveals a large discontinuous conformational epitope, specific to domain 1 of Pfs230 and comprising six structural elements in the protein. The epitope is conserved, suggesting the transmission-blocking mAb is broadly functional. This study provides a rational basis to improve malaria vaccines and develop therapeutic antibodies for malaria elimination. Vaccines that interrupt malaria transmission will be important tools for malaria elimination. Here the authors identify a human monoclonal antibody from Pfs230 vaccinated individuals that blocks transmission of Plasmodium falciparum to mosquitoes in a complement-dependent manner and reacts with gamete surface.

BackgroundChildren’s potential exposures to chemical and biological agents in tribal childcare centers are not well characterized.Objectives(1) The environmental health of childcare centers in Portland Area Indian Country was characterized by measuring selected pesticides, polychlorinated biphenyls (PCBs), allergens, and lead (Pb) in outdoor soil and indoor dust. (2) We compared our results to other studies of childcare centers in both the United States and globally.MethodsAt 31 tribal childcare centers in Washington, Oregon, and Idaho, we collected indoor dust and outdoor soil samples from at least one classroom, multipurpose room, and outdoor play area. Number of rooms sampled depended on facility size. Surface wipes were collected from the floor, play/work surface, and windowsill and analyzed for selected pesticides and PCBs. Vacuum samples were collected from the floor and analyzed for selected allergens. Lead was measured in surface wipes and outdoor soil collected at 11 centers. A questionnaire collected information on demographics, cleaning habits, and pesticide usage.ResultsAt least one pesticide was measured at all childcare centers. cis-Permethrin (surface wipes: 0.003–180 ng/cm2), trans-permethrin (surface wipes: 0.002–200 ng/cm2) and piperonyl butoxide (surface wipes: 0.001–120 ng/cm2) were measured in all centers. Lead was measured in most surface wipes (<0.25–14 ng/cm2) and all outdoor soil samples (8.4–50 mg/kg). Aroclors 1242 and 1254 were detected on indoor surfaces in three centers at very low loadings. Allergen residues were measured at very low concentrations in vacuum dust samples (Der p 1: <0.012–0.12 µg/g; Der f 1: <0.012–0.09 µg/g; Mus m 1: <0.002–10.055 µg/g). In general, we observed lower levels of chemical and biological agents than what has been reported previously.SignificanceBy understanding the environmental health of childcare centers, we can better understand the role of child-specific environments in promoting children’s health and well-being.Impact statementTo our knowledge, this is the first study to characterize the environmental health of tribal childcare centers in the Pacific Northwest. Combined with the information we have on childcare centers from around the world, this study expands our knowledge on young children’s potential exposures to chemical and biological agents in locations where they spend significant amounts of time.

Background For many U.S. academic physicians, direct patient care is the primary focus of daily work and the most important professional responsibility. Concurrently, some degree of scholarly activity is often required for career advancement. Junior clinical faculty often face challenges that limit their success in this area such as heavy clinical workloads or other time constraints, a lack of personal expertise or experience, mentorship, and institutional infrastructure. Support systems and faculty development interventions may mitigate these challenges and contribute to increased academic productivity and promotion. The objective of this study was to perform a scoping review of literature on strategies which increase scholarly activity among junior clinical faculty in the United States to determine the extent to which this topic has been scientifically investigated, the form of the employed strategies for supporting junior clinical faculty scholarly activity, the types of scholarly activity measured, and the research methods used. Methods An online search of PubMed, CINAHL, Cochrane Library, Embase, ERIC and APA PsycINFO databases was conducted and supplemented by a manual search of references and citations. Articles published between January 1, 2012, and February 7, 2025, that described faculty development interventions designed to increase scholarly productivity of junior clinical faculty in the United States were included. We employed a structured data extraction algorithm, extracted data in dyads, and resolved any inconsistencies using a third extractor. Included publications were categorized by the primary intervention strategy they employed. Results Eighteen publications are included in this scoping review. The most common primary strategies for supporting scholarly activity were peer-mentoring (5/18, 28%) and traditional mentoring (5/18, 28%). Other strategies included grants and funding (4/18, 22%), faculty development and training (2/18, 11%), and protected time (1/18, 6%). Two of the 18 publications included a control group. Conclusions Mentoring was the most common strategy to support scholarly activity of junior clinical faculty followed by faculty development programs. Scholarly activity is often measured by publications, grant funding, and presentations. A major gap in the current literature is the absence of any high-quality research demonstrating a beneficial effect on the scholarly activity of junior clinical faculty.

We developed an epidemiological model of avian malaria ( Plasmodium relictum ) across an altitudinal gradient on the island of Hawaii that includes the dynamics of the host, vector, and parasite. This introduced mosquito-borne disease is hypothesized to have contributed to extinctions and major shifts in the altitudinal distribution of highly susceptible native forest birds. Our goal was to better understand how biotic and abiotic factors influence the intensity of malaria transmission and impact on susceptible populations of native Hawaiian forest birds. Our model illustrates key patterns in the malaria-forest bird system: high malaria transmission in low-elevation forests with minor seasonal or annual variation in infection; episodic transmission in mid-elevation forests with site-to-site, seasonal, and annual variation depending on mosquito dynamics; and disease refugia in high-elevation forests with only slight risk of infection during summer. These infection patterns are driven by temperature and rainfall effects on parasite incubation period and mosquito dynamics across an elevational gradient and the availability of larval habitat, especially in mid-elevation forests. The results from our model suggest that disease is likely a key factor in causing population decline or restricting the distribution of many susceptible Hawaiian species and preventing the recovery of other vulnerable species. The model also provides a framework for the evaluation of factors influencing disease transmission and alternative disease control programs, and to evaluate the impact of climate change on disease cycles and bird populations.