Cost-effectiveness of antenatal multiple micronutrients and balanced energy protein supplementation compared to iron and folic acid supplementation in India, Pakistan, Mali, and Tanzania: A dynamic microsimulation study.

BACKGROUND: Malnutrition among women of childbearing age is especially prevalent in Asia and sub-Saharan Africa and can be harmful to the fetus during pregnancy. In the most recently available Demographic and Health Survey (DHS), approximately 10% to 20% of pregnant women in India, Pakistan, Mali, and Tanzania were undernourished (body mass index [BMI] <18.5 kg/m2), and according to the Global Burden of Disease (GBD) 2017 study, approximately 20% of babies were born with low birth weight (LBW; <2,500 g) in India, Pakistan, and Mali and 8% in Tanzania. Supplementing pregnant women with micro and macronutrients during the antenatal period can improve birth outcomes. Recently, the World Health Organization (WHO) recommended antenatal multiple micronutrient supplementation (MMS) that includes iron and folic acid (IFA) in the context of rigorous research. Additionally, WHO recommends balanced energy protein (BEP) for undernourished populations. However, few studies have compared the cost-effectiveness of different supplementation regimens. We compared the cost-effectiveness of MMS and BEP with IFA to quantify their benefits in 4 countries with considerable prevalence of maternal undernutrition. METHODS AND FINDINGS: Using nationally representative estimates from the 2017 GBD study, we conducted an individual-based dynamic microsimulation of population cohorts from birth to 2 years of age in India, Pakistan, Mali, and Tanzania. We modeled the effect of maternal nutritional supplementation on infant birth weight, stunting and wasting using effect sizes from Cochrane systematic reviews and published literature. We used a payer's perspective and obtained costs of supplementation per pregnancy from the published literature. We compared disability-adjusted life years (DALYs) and incremental cost-effectiveness ratios (ICERs) in a baseline scenario with existing antenatal IFA coverage with scenarios where 90% of antenatal care (ANC) attendees receive either universal MMS, universal BEP, or MMS + targeted BEP (women with prepregnancy BMI <18.5 kg/m2 receive BEP containing MMS while women with BMI ≥18.5 kg/m2 receive MMS). We obtained 95% uncertainty intervals (UIs) for all outputs to represent parameter and stochastic uncertainty across 100 iterations of model runs. ICERs for all scenarios were lowest in Pakistan and greatest in Tanzania, in line with the baseline trend in prevalence of and attributable burden to LBW. MMS + targeted BEP averts more DALYs than universal MMS alone while remaining cost-effective. ICERs for universal MMS compared to baseline IFA were $52 (95% UI: $28 to $78) for Pakistan, $72 (95% UI: $37 to $118) for Mali, $70 (95% UI: $43 to $104) for India, and $253 (95% UI: $112 to $481) for Tanzania. ICERs for MMS + targeted BEP compared to baseline IFA were $54 (95% UI: $32 to $77) for Pakistan, $73 (95% UI: $40 to $104) for Mali, $83 (95% UI: $58 to $111) for India, and $245 (95% UI: $127 to $405) for Tanzania. Study limitations include generalizing experimental findings from the literature to our populations of interest and using population-level input parameters that may not reflect the heterogeneity of subpopulations. Additionally, our microsimulation fuses multiple sources of data and may be limited by data quality and availability. CONCLUSIONS: In this study, we observed that MMS + targeted BEP averts more DALYs and remains cost-effective compared to universal MMS. As countries consider using MMS in alignment with recent WHO guidelines, offering targeted BEP is a cost-effective strategy that can be considered concurrently to maximize benefits and synergize program implementation.

Junior medical doctors' decision making when using advance care directives to guide treatment for people with dementia: a cross-sectional vignette study.

BACKGROUND: Junior medical doctors have a key role in discussions and decisions about treatment and end-of-life care for people with dementia in hospital. Little is known about junior doctors' decision-making processes when treating people with dementia who have advance care directives (ACDs), or the factors that influence their decisions. To describe among junior doctors in relation to two hypothetical vignettes involving patients with dementia: (1) their legal compliance and decision-making process related to treatment decisions; (2) the factors influencing their clinical decision-making; and (3) the factors associated with accurate responses to one hypothetical vignette. METHOD: A cross-sectional survey of junior doctors, including trainees, interns, registrars and residents, on clinical rotation in five public hospitals located in one Australian state. The anonymous, investigator-developed survey was conducted between August 2018 and June 2019. Two hypothetical vignettes describing patients with dementia presenting to hospital with an ACD and either: (1) bacterial pneumonia; or (2) suspected stroke were presented in the survey. Participants were asked to indicate whether they would commence treatment, given the ACD instructions described in each vignette. RESULTS: Overall, 116 junior doctors responded (35% consent rate). In Vignette 1, 58% of respondents (n = 67/116) selected the legally compliant option (i.e. not commence treatment). Participants who chose the legally compliant option perceived 'following patient wishes' (n = 32/67; 48%) and 'legal requirements to follow ACDs' (n = 32/67; 48%) as equally important reasons for complying with the ACD. The most common reason for not selecting the legally compliant option in Vignette 1 was the 'ACD is relevant in my decision-making process, but other factors are more relevant' (n = 14/37; 38%). In Vignette 2, 72% of respondents (n = 83/116) indicated they would commence treatment (i.e. not follow the ACD) and 18% (n = 21/116) selected they would not commence treatment. (i.e. follow the ACD). Similar reasons influenced participant decision-making in Vignette 2, a less legally certain scenario. CONCLUSIONS: There are critical gaps in junior doctors' compliance with the law as it relates to the implementation of ACDs. Despite there being differences in relation to the legal answer and its certainty, clinical and ethical factors guided decision-making over and above the law in both vignettes. More education and training to guide junior doctors' clinical decision-making and ensure compliance with the law is required.

Junior Medical Officers' knowledge of advance care directives and substitute decision making for people without decision making capacity: a cross sectional survey.

BACKGROUND: For the benefits of advance care planning to be realised during a hospital admission, the treating team must have accurate knowledge of the law pertaining to implementation of advance care directives (ACDs) and substitute decision making. AIMS: To determine in a sample of Junior Medical Officers (JMOs): (1) knowledge of the correct order to approach people as substitute decision makers if a patient does not have capacity to consent to treatment; (2) knowledge of the legal validity of ACDs when making healthcare decisions for persons without capacity to consent to treatment, including the characteristics associated with higher knowledge; and (3) barriers to enacting ACDs. METHODS: A cross-sectional survey was conducted at five public hospitals in New South Wales, Australia. Interns, residents, registrars, and trainees on clinical rotation during the recruitment period were eligible to participate. Consenting participants completed an anonymous pen-and-paper survey. RESULTS: A total of 118 JMOs completed a survey (36% return rate). Fifty-five percent of participants were female and 56.8% were aged 20-29 years. Seventy-five percent of JMOs correctly identified a Guardian as the first person to approach if a patient did not have decision-making capacity, and 74% correctly identified a person's spouse or partner as the next person to approach. Only 16.5% identified all four persons in the correct order, and 13.5% did not identify any in the correct order. The mean number of correct responses to the questions assessing knowledge of the legal validity of ACDs was 2.6 (SD = 1.1) out of a possible score of 6. Only 28 participants (23.7%) correctly answered four or more knowledge statements correctly. None of the explored variables were significantly associated with higher knowledge of the legal validity of ACDs. Uncertainty about the currency of ACDs and uncertainty about the legal implications of relying on an ACD when a patient's family or substitute decision maker disagree with it were the main barriers to enacting ACDs. CONCLUSION: JMOs knowledge of the legal validity of ACDs for persons without decision making capacity and the substitute decision making hierarchy is limited. There is a clear need for targeted education and training to improve knowledge in this area for this cohort.

Knowledge and confidence of junior medical doctors in discussing and documenting resuscitation plans: a cross-sectional survey.

BACKGROUND: A resuscitation plan is a medically authorised order to use or withhold resuscitation interventions. Absence of appropriate resuscitation orders exposes patients to the risk of invasive medical interventions that may be of questionable benefit depending on individual circumstances. AIMS: To describe among junior doctors: (i) self-reported confidence discussing and completing resuscitation plans; (ii) knowledge of resuscitation policy including whether resuscitation plans are legally enforceable and key triggers for completion; and (iii) the factors associated with higher knowledge of triggers for completing resuscitation plans. METHODS: A cross-sectional survey was conducted at five hospitals. Junior doctors on clinical rotation were approached at scheduled training sessions, before or after ward rounds or at change of rotation orientation days and provided with a pen-and-paper survey. RESULTS: A total of 118 junior doctors participated. Most felt confident discussing (79%; n = 92) and documenting (87%; n = 102) resuscitation plans with patients. However, only 45% (n = 52) of doctors correctly identified that resuscitation plans are legally enforceable medical orders. On average, doctors correctly identified 6.8 (standard deviation = 1.8) out of 10 triggers for completing a resuscitation plan. Doctors aged >30 years were four times more likely to have high knowledge of triggers for completing resuscitation plans (odds ratio 4.28 (95% confidence interval 1.54-11.89); P = 0.0053). CONCLUSION: Most junior doctors feel confident discussing and documenting resuscitation plans. There is a need to improve knowledge about legal obligations to follow completed resuscitation plans, and about when resuscitation plans should be completed to ensure they are completed with patients who are most at risk.

Micronutrient status and leukocyte telomere length in school-age Colombian children.

PURPOSE: Leukocyte telomere length (LTL) is a biomarker of inflammation and oxidative stress that predicts chronic disease risk. Nutritional factors are related to LTL in adulthood, but these associations are not well characterized in children. We examined whether micronutrient status biomarkers were associated with LTL in school-age children. METHODS: We conducted a cross-sectional study of 330 boys and 393 girls aged 5-12 years from Bogotá, Colombia. We quantified blood concentrations of hemoglobin, ferritin, zinc, vitamin A, folate, and vitamin B-12; and measured LTL using qPCR in DNA extracted from buffy coat. We estimated mean differences in LTL by quartiles of micronutrient status biomarkers and categories of relevant sociodemographic and anthropometric covariates with the use of linear regression. RESULTS: In girls, plasma vitamin B-12 was positively associated with LTL (adjusted LTL difference between extreme vitamin B-12 quartiles = 0.11; P, trend = 0.02). LTL was also positively associated with birth order in girls (P, trend = 0.02). In boys, LTL was not related to the micronutrient status biomarkers but, unexpectedly, it was positively associated with birth weight (P = 0.02), height-for-age Z score (P, trend = 0.01), and serum C-reactive protein (P, trend = 0.01). CONCLUSIONS: LTL is associated with vitamin B-12 status among girls. LTL is also associated with birth weight, height, and C-reactive protein in boys.

Simulated data for census-scale entity resolution research without privacy restrictions: a large-scale dataset generated by individual-based modeling.

Background: Entity resolution (ER) is the process of identifying and linking records that refer to the same real-world entity. ER is a fundamental challenge in data science, and a common barrier to ER research and development is that the data fields used for this fuzzy matching are personally identifiable information, such as name, address, and date of birth. The necessary restrictions on accessing and sharing these authentic data have slowed the work in developing, testing, and adopting new methods and software for ER. We recently released pseudopeople, a Python package that allows users to generate simulated datasets with configurable noise approaching the scale and complexity of the data on which large organizations and federal agencies, like the US Census Bureau regularly perform ER. With pseudopeople, researchers can develop new algorithms and software for ER of US population data without needing access to personal and confidential information. Methods: We created the simulated population data available for noising with pseudopeople using our Vivarium simulation platform. Our model simulates individuals and their families, households, and employment dynamics over time, which we observe through simulated censuses, surveys, and administrative data collection systems. Results: Our simulation process produced over 900 gigabytes of simulated censuses, surveys, and administrative data for pseudopeople, representing hundreds of millions of simulants. A sample simulated population of thousands of simulants is now openly available to all users of the pseudopeople package, and large-scale simulated populations of millions and hundreds of millions of simulants are also available by online request through GitHub. These simulated population data are structured for use by the pseudopeople package, which includes additional affordances to add various kinds of noise to the data to provide realistic, sharable challenges for ER researchers.

Children's event reports: factors affecting responses to repeated questions in vignette scenarios and event recall interviews.

When adults repeat questions, children often give inconsistent answers. This study aimed to test the claim that these inconsistencies occur because children infer that their first answer was unsatisfactory, and that the adult expects them to change their answer. Children aged 4, 6, and 8 years (N= 134) were asked about vignettes in which an adult repeated a question, with manipulation of the adult's overt dissatisfaction (high vs. low pressure) and knowledge about the information sought. On a separate occasion, the children were given an unrelated event recall interview containing repeated questions. All age groups showed sensitivity to adult dissatisfaction, interpreting question repetition as an implicit request for answer change more frequently in the high than in the low-pressure vignettes. Overall, however, these 'change-expected' interpretations were least frequent in the younger children, who were the most prone to shifting. Also there was no evidence that these interpretations were associated with more frequent shifting in the recall interview. The results do not provide clear support for a simple conversational inference account of shifting, especially in younger children.

Phthalate Exposures, DNA Methylation and Adiposity in Mexican Children Through Adolescence.

Phthalates are a class of endocrine disrupting chemicals with near ubiquitous exposure to populations around the world. Phthalates have been associated with children's adiposity in previous studies, though discrepancies exist across studies that may be due to timing of exposure or outcome assessment and population differences (i.e., genetics, other confounders). DNA methylation, an epigenetic modification involved in gene regulation, may mediate the effects of early life phthalate exposures on health outcomes. This study aims to evaluate the mediating effect of DNA methylation at growth-related genes on the association between phthalate exposure and repeat measures of adiposity (BMI-for-age z-score, waist circumference, and skinfolds thickness) in Mexican children. Urinary phthalate metabolite concentrations were quantified in mothers at each of the three trimesters of pregnancy and in children at the first peri-adolescent study visit. Blood leukocyte DNA methylation at H19 and HSD11B2 was quantified during the first peri-adolescent visit, and adiposity was measured at the first visit and again ~3 years later among participants (n = 109 boys, 114 girls) from the Early Life Exposure in Mexico to Environmental Toxicants (ELEMENT) project. Associations between phthalates or DNA methylation and repeat outcome measures were assessed separately in boys and girls using generalized estimating equation models including covariates (urinary specific gravity, maternal education, and child's age). Sobel tests were used to assess DNA methylation as a mediator in models adjusting for the same covariates. Associations between phthalates and adiposity varied by phthalate and timing of exposure. Early gestation MBP, MIBP, and MBzP were associated with adiposity among girls. For example, among girls first trimester maternal urine concentrations of MIBP were associated with increases in skinfold thickness, BMI-for-age, and waist circumference (p < 0.01). Second trimester and adolescent MBzP were associated with adiposity among boys in opposite directions. In girls, H19 methylation was positively associated with skinfold thickness. No significant mediation of phthalate exposure on adiposity by DNA methylation of H19 or HSD11B2 was observed (Sobel p > 0.05). However, the mediation analysis was underpowered to detect small to medium effect sizes, and the role of DNA methylation as a mediator between phthalates and outcomes merits further study.

Antibiotic-Induced Alterations of the Gut Microbiota Alter Secondary Bile Acid Production and Allow for Clostridium difficile Spore Germination and Outgrowth in the Large Intestine.

It is hypothesized that the depletion of microbial members responsible for converting primary bile acids into secondary bile acids reduces resistance to Clostridium difficile colonization. To date, inhibition of C. difficile growth by secondary bile acids has only been shown in vitro. Using targeted bile acid metabolomics, we sought to define the physiologically relevant concentrations of primary and secondary bile acids present in the murine small and large intestinal tracts and how these impact C. difficile dynamics. We treated mice with a variety of antibiotics to create distinct microbial and metabolic (bile acid) environments and directly tested their ability to support or inhibit C. difficile spore germination and outgrowth ex vivo. Susceptibility to C. difficile in the large intestine was observed only after specific broad-spectrum antibiotic treatment (cefoperazone, clindamycin, and vancomycin) and was accompanied by a significant loss of secondary bile acids (deoxycholate, lithocholate, ursodeoxycholate, hyodeoxycholate, and ω-muricholate). These changes were correlated to the loss of specific microbiota community members, the Lachnospiraceae and Ruminococcaceae families. Additionally, physiological concentrations of secondary bile acids present during C. difficile resistance were able to inhibit spore germination and outgrowth in vitro. Interestingly, we observed that C. difficile spore germination and outgrowth were supported constantly in murine small intestinal content regardless of antibiotic perturbation, suggesting that targeting growth of C. difficile will prove most important for future therapeutics and that antibiotic-related changes are organ specific. Understanding how the gut microbiota regulates bile acids throughout the intestine will aid the development of future therapies for C. difficile infection and other metabolically relevant disorders such as obesity and diabetes. IMPORTANCE Antibiotics alter the gastrointestinal microbiota, allowing for Clostridium difficile infection, which is a significant public health problem. Changes in the structure of the gut microbiota alter the metabolome, specifically the production of secondary bile acids. Specific bile acids are able to initiate C. difficile spore germination and also inhibit C. difficile growth in vitro, although no study to date has defined physiologically relevant bile acids in the gastrointestinal tract. In this study, we define the bile acids C. difficile spores encounter in the small and large intestines before and after various antibiotic treatments. Antibiotics that alter the gut microbiota and deplete secondary bile acid production allow C. difficile colonization, representing a mechanism of colonization resistance. Multiple secondary bile acids in the large intestine were able to inhibit C. difficile spore germination and growth at physiological concentrations and represent new targets to combat C. difficile in the large intestine.