Adaptive foraging behaviours in the Horn of Africa during Toba supereruption.

Although modern humans left Africa multiple times over 100,000 years ago, those broadly ancestral to non-Africans dispersed less than 100,000 years ago1. Most models hold that these events occurred through green corridors created during humid periods because arid intervals constrained population movements2. Here we report an archaeological site-Shinfa-Metema 1, in the lowlands of northwest Ethiopia, with Youngest Toba Tuff cryptotephra dated to around 74,000 years ago-that provides early and rare evidence of intensive riverine-based foraging aided by the likely adoption of the bow and arrow. The diet included a wide range of terrestrial and aquatic animals. Stable oxygen isotopes from fossil mammal teeth and ostrich eggshell show that the site was occupied during a period of high seasonal aridity. The unusual abundance of fish suggests that capture occurred in the ever smaller and shallower waterholes of a seasonal river during a long dry season, revealing flexible adaptations to challenging climatic conditions during the Middle Stone Age. Adaptive foraging along dry-season waterholes would have transformed seasonal rivers into 'blue highway' corridors, potentially facilitating an out-of-Africa dispersal and suggesting that the event was not restricted to times of humid climates. The behavioural flexibility required to survive seasonally arid conditions in general, and the apparent short-term effects of the Toba supereruption in particular were probably key to the most recent dispersal and subsequent worldwide expansion of modern humans.

A NPAS4-NuA4 complex couples synaptic activity to DNA repair.

Neuronal activity is crucial for adaptive circuit remodelling but poses an inherent risk to the stability of the genome across the long lifespan of postmitotic neurons1-5. Whether neurons have acquired specialized genome protection mechanisms that enable them to withstand decades of potentially damaging stimuli during periods of heightened activity is unknown. Here we identify an activity-dependent DNA repair mechanism in which a new form of the NuA4-TIP60 chromatin modifier assembles in activated neurons around the inducible, neuronal-specific transcription factor NPAS4. We purify this complex from the brain and demonstrate its functions in eliciting activity-dependent changes to neuronal transcriptomes and circuitry. By characterizing the landscape of activity-induced DNA double-strand breaks in the brain, we show that NPAS4-NuA4 binds to recurrently damaged regulatory elements and recruits additional DNA repair machinery to stimulate their repair. Gene regulatory elements bound by NPAS4-NuA4 are partially protected against age-dependent accumulation of somatic mutations. Impaired NPAS4-NuA4 signalling leads to a cascade of cellular defects, including dysregulated activity-dependent transcriptional responses, loss of control over neuronal inhibition and genome instability, which all culminate to reduce organismal lifespan. In addition, mutations in several components of the NuA4 complex are reported to lead to neurodevelopmental and autism spectrum disorders. Together, these findings identify a neuronal-specific complex that couples neuronal activity directly to genome preservation, the disruption of which may contribute to developmental disorders, neurodegeneration and ageing.

Bidirectional perisomatic inhibitory plasticity of a Fos neuronal network.

Behavioural experiences activate the FOS transcription factor in sparse populations of neurons that are critical for encoding and recalling specific events1-3. However, there is limited understanding of the mechanisms by which experience drives circuit reorganization to establish a network of Fos-activated cells. It is also not known whether FOS is required in this process beyond serving as a marker of recent neural activity and, if so, which of its many gene targets underlie circuit reorganization. Here we demonstrate that when mice engage in spatial exploration of novel environments, perisomatic inhibition of Fos-activated hippocampal CA1 pyramidal neurons by parvalbumin-expressing interneurons is enhanced, whereas perisomatic inhibition by cholecystokinin-expressing interneurons is weakened. This bidirectional modulation of inhibition is abolished when the function of the FOS transcription factor complex is disrupted. Single-cell RNA-sequencing, ribosome-associated mRNA profiling and chromatin analyses, combined with electrophysiology, reveal that FOS activates the transcription of Scg2, a gene that encodes multiple distinct neuropeptides, to coordinate these changes in inhibition. As parvalbumin- and cholecystokinin-expressing interneurons mediate distinct features of pyramidal cell activity4-6, the SCG2-dependent reorganization of inhibitory synaptic input might be predicted to affect network function in vivo. Consistent with this prediction, hippocampal gamma rhythms and pyramidal cell coupling to theta phase are significantly altered in the absence of Scg2. These findings reveal an instructive role for FOS and SCG2 in establishing a network of Fos-activated neurons via the rewiring of local inhibition to form a selectively modulated state. The opposing plasticity mechanisms acting on distinct inhibitory pathways may support the consolidation of memories over time.

Climate impacts of alternative beef production systems depend on the functional unit used: Weight or monetary value.

Beef production has been identified as a significant source of anthropogenic greenhouse gas (GHG) emissions in the agricultural sector. United States and Canada account for about a quarter of the world's beef supply. To compare the GHG emission contributions of alternative beef production systems, we conducted a meta-analysis of 32 studies that were conducted between 2001 and 2023. Results indicated that GHG emissions from beef production in North America varied almost fourfold from 10.2 to 37.6 with an average of 21.4 kg CO2e/kg carcass weight (CW). Studies that considered soil C sequestration (C-seq) reported the highest mitigation potential in GHG emissions (80%), followed by growth enhancement technology (16%), diet modification (6%), and grazing management improvement (7%). Our study highlights the implications of using carbon intensity per economic activity (i.e., GHG emissions per monetary unit), compared to the more common metric of intensity on per weight of product basis (GHG emissions per kg CW) for comparisons across differentiated beef cattle products. While a positive association was found between the proportion of lifespan on grassland and the conventional weight-based indicator, grass-finished beef was found to have lower carbon intensity per economic activity than feedlot-finished beef. Our study emphasizes the need to incorporate land use and management effects and soil C-seq as fundamental aspects of beef GHG emissions and mitigation assessments.

Phase separation of Polycomb-repressive complex 1 is governed by a charged disordered region of CBX2.

Mammalian development requires effective mechanisms to repress genes whose expression would generate inappropriately specified cells. The Polycomb-repressive complex 1 (PRC1) family complexes are central to maintaining this repression. These include a set of canonical PRC1 complexes, each of which contains four core proteins, including one from the CBX family. These complexes have been shown previously to reside in membraneless organelles called Polycomb bodies, leading to speculation that canonical PRC1 might be found in a separate phase from the rest of the nucleus. We show here that reconstituted PRC1 readily phase-separates into droplets in vitro at low concentrations and physiological salt conditions. This behavior is driven by the CBX2 subunit. Point mutations in an internal domain of Cbx2 eliminate phase separation. These same point mutations eliminate the formation of puncta in cells and have been shown previously to eliminate nucleosome compaction in vitro and generate axial patterning defects in mice. Thus, the domain of CBX2 that is important for phase separation is the same domain shown previously to be important for chromatin compaction and proper development, raising the possibility of a mechanistic or evolutionary link between these activities.

Comparison of stochastic and deterministic models for gambiense sleeping sickness at different spatial scales: A health area analysis in the DRC.

The intensification of intervention activities against the fatal vector-borne disease gambiense human African trypanosomiasis (gHAT, sleeping sickness) in the last two decades has led to a large decline in the number of annually reported cases. However, while we move closer to achieving the ambitious target of elimination of transmission (EoT) to humans, pockets of infection remain, and it becomes increasingly important to quantitatively assess if different regions are on track for elimination, and where intervention efforts should be focused. We present a previously developed stochastic mathematical model for gHAT in the Democratic Republic of Congo (DRC) and show that this same formulation is able to capture the dynamics of gHAT observed at the health area level (approximately 10,000 people). This analysis was the first time any stochastic gHAT model has been fitted directly to case data and allows us to better quantify the uncertainty in our results. The analysis focuses on utilising a particle filter Markov chain Monte Carlo (MCMC) methodology to fit the model to the data from 16 health areas of Mosango health zone in Kwilu province as a case study. The spatial heterogeneity in cases is reflected in modelling results, where we predict that under the current intervention strategies, the health area of Kinzamba II, which has approximately one third of the health zone's cases, will have the latest expected year for EoT. We find that fitting the analogous deterministic version of the gHAT model using MCMC has substantially faster computation times than fitting the stochastic model using pMCMC, but produces virtually indistinguishable posterior parameterisation. This suggests that expanding health area fitting, to cover more of the DRC, should be done with deterministic fits for efficiency, but with stochastic projections used to capture both the parameter and stochastic variation in case reporting and elimination year estimations.

Delayed Mucosal Antiviral Responses Despite Robust Peripheral Inflammation in Fatal COVID-19.

BACKGROUND: While inflammatory and immune responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in peripheral blood are extensively described, responses at the upper respiratory mucosal site of initial infection are relatively poorly defined. We sought to identify mucosal cytokine/chemokine signatures that distinguished coronavirus disease 2019 (COVID-19) severity categories, and relate these to disease progression and peripheral inflammation. METHODS: We measured 35 cytokines and chemokines in nasal samples from 274 patients hospitalized with COVID-19. Analysis considered the timing of sampling during disease, as either the early (0-5 days after symptom onset) or late (6-20 days after symptom onset) phase. RESULTS: Patients that survived severe COVID-19 showed interferon (IFN)-dominated mucosal immune responses (IFN-γ, CXCL10, and CXCL13) early in infection. These early mucosal responses were absent in patients who would progress to fatal disease despite equivalent SARS-CoV-2 viral load. Mucosal inflammation in later disease was dominated by interleukin 2 (IL-2), IL-10, IFN-γ, and IL-12p70, which scaled with severity but did not differentiate patients who would survive or succumb to disease. Cytokines and chemokines in the mucosa showed distinctions from responses evident in the peripheral blood, particularly during fatal disease. CONCLUSIONS: Defective early mucosal antiviral responses anticipate fatal COVID-19 but are not associated with viral load. Early mucosal immune responses may define the trajectory of severe COVID-19.

Accelerating Progress Towards the 2030 Neglected Tropical Diseases Targets: How Can Quantitative Modeling Support Programmatic Decisions?

Over the past decade, considerable progress has been made in the control, elimination, and eradication of neglected tropical diseases (NTDs). Despite these advances, most NTD programs have recently experienced important setbacks; for example, NTD interventions were some of the most frequently and severely impacted by service disruptions due to the coronavirus disease 2019 (COVID-19) pandemic. Mathematical modeling can help inform selection of interventions to meet the targets set out in the NTD road map 2021-2030, and such studies should prioritize questions that are relevant for decision-makers, especially those designing, implementing, and evaluating national and subnational programs. In September 2022, the World Health Organization hosted a stakeholder meeting to identify such priority modeling questions across a range of NTDs and to consider how modeling could inform local decision making. Here, we summarize the outputs of the meeting, highlight common themes in the questions being asked, and discuss how quantitative modeling can support programmatic decisions that may accelerate progress towards the 2030 targets.

Repeated High-Dose Vitamin A Supplements, Standard of Care for Treating Xerophthalmia, Leads to Hypervitaminosis A in Piglets.

BACKGROUND: Vitamin A (VA) deficiency and excess negatively affect development, growth, and bone health. The World Health Organization's standard of care for xerophthalmia due to VA deficiency, is 3 high-dose VA supplements of 50,000-200,000 IU, based on age, which may cause hypervitaminosis A in some individuals. OBJECTIVES: This study measured VA status following 3 VA doses in 2 piglet studies. METHODS: In Study 1, 5 groups of piglets (n = 10/group) were weaned 10 d postbirth to VA-free feed and orally administered 0; 25,000; 50,000; 100,000; or 200,000 IU VA ester on days 0, 1, and 7. On days 14 and 15, the piglets underwent the modified relative dose-response (MRDR) test for VA deficiency, and were killed. Tissues were collected for high-pressure liquid chromatography analysis. Study 2 used the same design in 3 groups (n = 13/group) weaned at 16 d and administered 0; 25,000; and 200,000 IU doses. RESULTS: In Study 1 (final weight: 3.6 ± 0.7 kg), liver VA concentration was hypervitaminotic in 40%, 90%, and 100% of 50,000; 100,000; and 200,000 IU groups, respectively. The 25,000 IU group was 100% adequate, and the placebo group was 40% deficient. In Study 2 (final weight: 8.7 ± 0.8 kg), where 200,000 IU could be prescribed to infants with a similar body weight, 31% of the piglets were hypervitaminotic, the 25,000 IU group was 100% VA adequate, and the placebo group was 100% deficient. The MRDR test measured deficiency in 50% and 70% of the placebo group in each study but had 3 false positives among hypervitaminotic piglets in Study 1. CONCLUSIONS: Repeated high-dose VA may cause hypervitaminosis, indicating dose sizes may need reduction. The MRDR resulted in false positives in a hypervitaminotic state during malnutrition and should be paired with serum retinyl ester evaluation to enhance VA status assessment in populations with overlapping interventions.

Ileocolic Intussusception: Iterative Quality Improvement to Address a Recurring Problem.

INTRODUCTION: Recent quality improvement (QI) initiatives indicate that pediatric patients with uncomplicated ileocolic intussusception can be safely discharged from the emergency department (ED) after fluoroscopic reduction. These programs improve patient experience and reduce cost. We sought to build on these efforts by developing a QI initiative at our own institution that included patients transferred from a satellite campus and focused on iterative improvement of our treatment pathway based on continual reassessment of our processes and data. MATERIALS AND METHODS: We formed a multidisciplinary team, established a collaborative open-access clinical pathway, and implemented educational plans for each participating division. Data were tracked prospectively, and process adjustments were made as clinically indicated. In this report, we compare patients treated before and after the QI initiative. RESULTS: There were 155 patients treated before the QI initiative (January 1, 2018-June 30, 2022) and 87 after the initiative began (July 1, 2022-October 31, 2023). There were significant improvements in the rate of ED discharge (4/155 (2.6%) versus 51/87 (59%), P < 0.001) and mean time to discharge (40.7 versus 23.1 h, P = 0.002), while the average cost of a visit fell by 30% (P = 0.012). The mean time to discharge from the ED increased (6.9 versus 11.0 h, P < 0.001), and the rate of readmission was unchanged. For patients transferred from the satellite campus, time to fluoroscopic reduction significantly improved during the initiative (9.4 versus 6.5 h, P = 0.048). CONCLUSIONS: We implemented a QI program for patients with fluoroscopically reduced ileocolic intussusception that was serially adjusted based on continual reassessment of data. The protocol was associated with a decreased admission rate, total cost, and time to hospital discharge.

Self-concealment, secrecy, and guilt.

OBJECTIVE: Individuals with a tendency to conceal unflattering information about themselves are more likely to be preoccupied by their secrets and tend to report more negative affect. According to theory, this negative affect is due to self-concealers' conflicting motivation to be authentic in their relationship but fear the negative consequences should they reveal their secrets, which promotes ill-fated attempts to suppress. The purpose of the current study was to test a central component of this model. METHODS: Two studies of adults who were in a romantic relationship and keeping a secret from their partner (combined N = 635; 67.2% women; Mage  = 39.6, SD = 11.9) were surveyed on four biweekly occasions. Multilevel mediation analyses were conducted to test whether preoccupation and suppression mediated the link between self-concealing and negative affect and guilt. RESULTS: The data support the hypotheses. Self-concealers were more preoccupied with and prone to suppress their secret than those low on the trait, which, in turn, predicted greater negative affect and guilt. CONCLUSION: The findings suggest that self-concealers' insecurities and fear of the relational consequences of disclosure set the stage for the debilitating cycle of suppression and preoccupation that leaves them feeling anxious and guilty.

Player-Facing Casino Employees: Engagement with Responsible Gambling Programming and its Association with Referring Players.

This research explores the engagement of player-facing casino employees with GameSense, a responsible gambling (RG) program, and referral of players to GameSense. We surveyed 280 employees across three casinos in Massachusetts that use this RG program as part of their RG strategy. We found that although most player-facing casino employees were aware of GameSense, slightly over half visited a GameSense Information Center, and about two-thirds interacted with a GameSense Advisor. In terms of the reason for visiting, Latent Class Analysis (LCA) revealed three distinct classes: Comprehensive Interests, RG Interests, and Focused Interests. As for those who have yet to visit, LCA two classes emerged: RG Proficiency Beliefs and Tempered RG Proficiency Beliefs. Engaged employees were more likely to refer players to GameSense, highlighting the need for targeted approaches addressing the diverse interests of player-facing employees for engaging or not engaging with GameSense. These findings underscore the importance of have player-facing casino employees engage with RG programming, and targeted approached for engagement, to enhance the efficacy of RG initiatives, and contribute to a more robust RG framework within the gambling industry.

Wilderness Medical Society Clinical Practice Guidelines for Medical Direction of Search and Rescue Teams.

The Wilderness Medical Society convened a panel to review available evidence supporting practices for medical direction of search and rescue teams. This panel included of members of the Wilderness Medical Society Search and Rescue Committee, the National Association of EMS Physicians Wilderness Committee, and leadership of the Mountain Rescue Association. Literature about definitions and terminology, epidemiology, currently accepted best practices, and regulatory and legal considerations was reviewed. The panel graded available evidence supporting practices according to the American College of Chest Physicians criteria and then made recommendations based on that evidence. Recommendations were based on the panel's collective clinical experience and judgment when published evidence was lacking.

Wilderness Medical Society Clinical Practice Guidelines for the Treatment and Prevention of Drowning: 2024 Update.

The Wilderness Medical Society convened a panel to review available evidence supporting practices for acute management of drowning in out-of-hospital and emergency care settings. Literature about definitions and terminology, epidemiology, rescue, resuscitation, acute clinical management, disposition, and drowning prevention was reviewed. The panel graded available evidence supporting practices according to the American College of Chest Physicians criteria and then made recommendations based on that evidence. Recommendations were based on the panel's collective clinical experience and judgment when published evidence was lacking. This is the second update to the original practice guidelines published in 2016 and updated in 2019.

The dynamics of drowning: Clarifying terminologies and response strategies.

ABSTRACT: Drowning is the process of respiratory impairment from immersion or submersion in a liquid. Worldwide, approximately 360,000 deaths annually can be attributed to drowning. Morbidity and mortality are a result of hypoxia, so the focus during resuscitation should be on airway management and optimizing oxygenation. This article describes several drowning scenarios and discusses appropriate response and treatment algorithms.

Copper-Catalyzed Dearomative 1,2-Hydroamination.

Catalytic olefin hydroamination reactions are some of the most atom-economical transformations that bridge readily available starting materials-olefins and high-value-added amines. Despite significant advances in this field over the last two decades, the formal hydroamination of nonactivated aromatic compounds remains an unsolved challenge. Herein, we report the extension of olefin hydroamination to aromatic π-systems by using arenophile-mediated dearomatization and Cu-catalysis to perform 1,2-hydroamination on nonactivated arenes. This strategy was applied to a variety of substituted arenes and heteroarenes to provide general access to structurally complex amines. We conducted DFT calculations to inform mechanistic understanding and rationalize unexpected selectivity trends. Furthermore, we developed a practical, scalable desymmetrization to deliver enantioenriched dearomatized products and enable downstream synthetic applications. We ultimately used this dearomative strategy to efficiently synthesize a collection of densely functionalized small molecules.

Breast Milk Retinol Concentrations Reflect Total Liver Vitamin A Reserves and Dietary Exposure in Thai Lactating Women from Urban and Rural Areas.

BACKGROUND: Measuring vitamin A (VA) status during lactation is required to inform dietary recommendations. Limited data exist on VA stores in women. OBJECTIVES: Our objective was to assess VA status in lactating Thai women by measuring total body VA stores (TBSs), serum and breast milk retinol concentrations, and dietary intake. METHODS: Lactating women (n = 94), 6-8 wk postpartum, were enrolled from rural (Ayutthaya) and urban (Bangkok) areas. TBSs were measured by the 13C-retinol isotope dilution (RID) technique using 2.0 µmol 13C-retinyl acetate and a single blood sample 14 d post-dose. Natural 13C-enrichment was determined in nonenrolled women (n = 11). Estimated total liver VA reserves (TLRs) were determined using assumptions for lactation. Serum, foremilk, and hindmilk samples were analyzed for retinol by HPLC. Dietary VA intake was assessed by FFQ and 24-h dietary recalls for 3 d. Multiple regression and Pearson correlation were used to evaluate relations. RESULTS: Median VA intakes were 51.8% of 2003 Thai daily recommendations for lactating women, with the majority from animal-source foods. Many women in Ayutthaya consumed liver weekly. Considering TLRs as 50% TBS, 20% and 11% of mothers in Ayutthaya and Bangkok, respectively, showed deficient reserves (≤0.10 µmol retinol/g). Median (quartile 1, quartile 3) serum [1.58 (1.34, 1.91) and 1.52 (1.30, 1.70) µmol/L] and milk [1.88 (1.29, 2.95) and 1.74 (0.96, 2.26) µmol/L] retinol in Ayutthaya and Bangkok, respectively, were normal. Women with deficient TLRs showed low milk retinol concentrations (≤1.0 µmol/L) and consumed less dietary VA, especially from animal-source foods. Breast milk retinol concentrations, especially hindmilk, demonstrated strong correlation with TBSs and TLRs estimated from the RID test. CONCLUSIONS: Approximately 15% of Thai lactating women had deficient TLRs. Breast milk retinol concentrations in conjunction with dietary intake records show potential to screen mothers at risk of VA deficiency to guide interventions.The Thai Clinical Trials Registry number is TCTR20160824001 for the work in Thailand.

Anthocyanin and Lycopene Contents Do Not Affect ß-Carotene Bioefficacy from Multicolored Carrots (Daucus carota L.) in Male Mongolian Gerbils.

BACKGROUND: Anthocyanins and carotenoids are phytochemicals that may benefit health through provitamin A carotenoid (PAC), antioxidant, and anti-inflammatory activities. These bioactives may mitigate chronic diseases. Consumption of multiple phytochemicals may impact bioactivity in synergistic or antagonistic manners. OBJECTIVES: Two studies in weanling male Mongolian gerbils assessed the relative bioefficacy of ß-carotene equivalents (BCEs) to vitamin A (VA) with simultaneous consumption of the non-PAC lycopene or anthocyanins from multicolored carrots. METHODS: After 3-wk VA depletion, 5-6 gerbils were killed as baseline groups. The remaining gerbils were divided into 4 carrot treatment groups; the positive control group received retinyl acetate and the negative control group was given vehicle soybean oil (n = 10/group; n = 60/study). In the lycopene study, gerbils consumed feed varying in lycopene sourced from red carrots. In the anthocyanin study, gerbils consumed feed varying in anthocyanin content sourced from purple-red carrots, and positive controls received lycopene. Treatment feeds had equalized BCEs: 5.59 ± 0.96 µg/g (lycopene study) and 7.02 ± 0.39 µg/g (anthocyanin study). Controls consumed feeds without pigments. Serum, liver, and lung samples were analyzed for retinol and carotenoid concentrations using HPLC. Data were analyzed by ANOVA and Tukey's studentized range test. RESULTS: In the lycopene study, liver VA did not differ between groups (0.11 ± 0.07 µmol/g) indicating no effect of varying lycopene content. In the anthocyanin study, liver VA concentrations in the medium-to-high (0.22 ± 0.14 µmol/g) and medium-to-low anthocyanin (0.25 ± 0.07 µmol/g) groups were higher than the negative control (0.11 ± 0.07 µmol/g) (P < 0.05). All treatment groups maintained baseline VA concentrations (0.23 ± 0.06 µmol/g). Combining studies, serum retinol had 12% sensitivity to predict VA deficiency, defined as 0.7 µmol/L. CONCLUSIONS: These gerbil studies suggested that simultaneous consumption of carotenoids and anthocyanins does not impact relative BCE bioefficacy. Breeding carrots for enhanced pigments to improve dietary intake should continue.

Comparison of Total Body Vitamin A Stores Using Individual versus Population 13C-Natural Abundance of Serum Retinol in Preschool Children and Women Residing in 6 Diverse African Countries.

BACKGROUND: Stable isotope techniques using 13C to assess vitamin A (VA) dietary sources, absorption, and total body VA stores (TBSs) require determination of baseline 13C abundance. 13C-natural abundance is approximately 1.1% total carbon, but varies with foods consumed, supplements taken, and food fortification with synthetic retinyl palmitate. OBJECTIVES: We determined 13C variation from purified serum retinol and the resulting impact on TBSs using pooled data from preschool children in Burkina Faso, Cameroon, Ethiopia, South Africa, Tanzania, and Zambia and Zambian women. METHODS: Seven studies included children (n = 639; 56 ± 25 mo; 48% female) and one in women (n = 138; 29 ± 8.5 y). Serum retinol 13C-natural abundance was determined using GC-C-IRMS. TBSs were available in 7 studies that employed retinol isotope dilution (RID). Serum CRP and α1-acid-glycoprotein (AGP) were available from 6 studies in children. Multivariate mixed models assessed the impact of covariates on retinol 13C. Spearman correlations and Bland-Altman analysis compared serum and milk retinol 13C and evaluated the impact of using study- or global-retinol 13C estimates on calculated TBSs. RESULTS: 13C-natural abundance (%, median [Q1, Q3]) differed among countries (low: Zambia, 1.0744 [1.0736, 1.0753]; high: South Africa, 1.0773 [1.0769, 1.0779]) and was associated with TBSs, CRP, and AGP in children and with TBSs in women. 13C-enrichment from serum and milk retinol were correlated (r = 0.52; P = 0.0001). RID in children and women using study and global estimates had low mean bias (range, -3.7% to 2.2%), but larger 95% limits of agreement (range, -23% to 37%). CONCLUSIONS: 13C-natural abundance is different among human cohorts in Africa. Collecting this information in subgroups is recommended for surveys using RID. When TBSs are needed on individuals in clinical applications, baseline 13C measures are important and should be measured in all enrolled subjects.

Association between Biomarkers of Inflammation and Total Liver Vitamin A Reserves Estimated by 13C-Retinol Isotope Dilution among Preschool Children in 5 African Countries.

BACKGROUND: Vitamin A (VA) assessment is important for targeting public health programs. Retinol isotope dilution (RID) is a sensitive method to estimate total body VA stores (TBSs) and total liver reserves (TLRs), but the impact of subclinical inflammation on RID is unclear. OBJECTIVE: We determined the association between TBSs and TLRs, estimated by RID, and inflammation among preschool children without clinical infection in Burkina Faso, Cameroon, Ethiopia, South Africa, and Tanzania. METHODS: Five studies (n = 532; 47.9 ± 8.3 mo; 49.0% male) included 13C-RID and measurement of inflammation markers, CRP, and α1-acid glycoprotein (AGP). Spearman correlations were used to evaluate TBSs and TLRs with inflammation biomarkers. Wilcoxon and Kruskal-Wallis tests were used to compare TBSs and TLRs by inflammation categories [normal vs. elevated CRP (>5 mg/L) or AGP (>1 g/L)] and inflammation stage [reference, incubation (elevated CRP), early convalescence (elevated CRP and AGP), and late convalescence (elevated AGP)]. RESULTS: Complete data were available for 439 children. Median (Q1, Q3) TLRs ranged from 0.12 (0.07, 0.18) µmol/g in Ethiopia to 1.10 (0.88, 1.38) µmol/g in South Africa. Elevated CRP ranged from 4% in Burkina Faso to 42% in Cameroon, and elevated AGP from 20% in Tanzania to 58% in Cameroon. Pooled analysis (excluding Cameroon) showed a negative correlation between TBSs and AGP (ρ = -0.131, P = 0.01). Children with elevated AGP had higher probability of having lower TBSs (probability = 0.61, P = 0.002). TBSs differed among infection stages (P = 0.020). Correlations between TLRs and CRP or AGP were not significant. CONCLUSIONS: No indication of systematic bias in RID-estimated TLRs was found due to subclinical inflammation among preschool children. The inverse relationship between TBSs and AGP may reflect decreased stores after infection or an effect of inflammation on isotope partitioning. Further research should investigate potential confounding variables to improve TBS-estimate validity.