Relationship of sanitation, water boiling, and mosquito nets to health biomarkers in a rural subsistence population.

OBJECTIVES: Throughout human evolutionary history, parasites and pathogens were a major cause of mortality-modern urban life with public health infrastructure has changed disease exposure. We examine associations between boiling water, using latrines, mosquito net usage, and biomarkers among the Tsimane, a nonindustrial subsistence population with little public health infrastructure. METHODS: We conducted cross sectional surveys on water, latrines, and bed nets among 507 heads of households (aged 18-92 years, median age 41 years). Regression models estimated associations between behaviors and health biomarkers (ie, white blood cell count [WBC], hemoglobin, eosinophil count, and erythrocyte sedimentation rate) adjusting for age, sex, body mass index, wealth, schooling, and distance to the nearby market town. RESULTS: Latrine use is associated with 6.5% lower WBC count (ß = -679.6, P = .031, SE = 314.1), 17.4% lower eosinophil counts (ß = -244.7, P = .023, SE = 107.2), and reduced odds of eosinophilia (adjusted OR = 0.40, P < .019, 95% CI = 0.18-0.86). Boiling water and mosquito net use are not significantly associated with any biomarkers measured. CONCLUSIONS: In a subsistence population currently undergoing epidemiological transition, we find that latrine use was associated with several objective measures of health. This suggests that relatively low cost and low maintenance public health interventions may wish to focus on latrine use, as there is unmet need and potential health benefits for those who use latrines. Additionally, while the cost is higher, public health organizations aimed at improving sanitation may be able to use minimally invasive field-collected biomarkers as a diagnostic to objectively test the efficacy of interventions with greater specificity than anthropometric measurements.

Child nutritional status among births exceeding ideal family size in a high fertility population.

Ideal family size (IFS) is measured in social surveys to indicate unmet need for contraception and impending shifts in fertility behaviour. Whether exceeding IFS affects parental behaviour in ways that result in lower investments in child nutrition, well-being, and educational attainment is not known. This study examines parental IFS and the association between exceeding stated ideals and child nutritional status in a high-fertility, high-mortality population in the Bolivian Amazon. Height-for-age z-scores, weight-for-age z-scores, weight-for-height z-scores, stunting, haemoglobin, and anaemia status in 638 children aged 0-5 years are predicted as a function of birth order in relation to parental IFS, adjusting for household characteristics and mother and child random effects. Children of birth orders above paternal IFS experience higher weight-for-age z-scores when living further away from the market town of San Borja, consistent with underlying motivations for higher IFS and lower human capital investment in children in more remote areas (ß = .009, p = .027). Overall, we find no statistical evidence that birth orders in excess of parental ideals are associated with compromised child nutrition below age 2, a period of intensive breastfeeding in this population. Despite a vulnerability to nutritional deficiencies postweaning for children age 2-5, there was no association between birth order in excess of parental ideals and lower nutritional status. Further studies examining this association at various stages of the fertility transition will elucidate whether reported ideal or optimal family sizes are flexible as trade-offs between quality and quantity of children shift during the transition to lower fertility.

Rapid Implementation of a 3-Dimensional-Printed Patient-Specific Titanium Sacrum Implant for Severe Neuropathic Spinal Arthropathy and Guide to Compassionate US Regulatory Approval.

BACKGROUND AND OBJECTIVE: Rapid design and production of patient-specific 3-dimensional-printed implants (3DPIs) present a novel opportunity to restore the biomechanically demanding integrity of the lumbopelvic junction. We present a unique case of a 61-year-old patient with severe neuropathic spinal arthropathy (Charcot spine) who initially underwent a T4-to-sacrum spinal fusion. Massive bone destruction led to dissociation of his upper body from his pelvis and legs. Reconstruction of the spinopelvic continuity was planned with the aid of a personalized lumbosacral 3DPI. METHOD: Using high-resolution computed tomography scans, the custom 3DPI was made using additive titanium manufacturing. The unique 3DPI consisted of (1) a sacral platform with iliac screws, (2) modular corpectomy device with rigid connection to the sacral platform, and (3) anterior plate connection with screws for proximal fixation. The procedures to obtain compassionate use Food and Drug Administration approval were followed. The patient underwent debridement of a chronically open wound before undertaking the 3-stage reconstructive procedure. The custom 3DPI and additional instrumentation were inserted as part of a salvage rebuilding procedure. RESULTS: The chronology of the rapid implementation of the personalized sacral 3DPI from decision, design, manufacturing, Food and Drug Administration approval, and surgical execution lasted 28 days. The prosthesis was positioned in the defect according to the expected anatomic planes and secured using a screw-rod system and a vascularized fibular bone strut graft. The prosthesis provided an ideal repair of the lumbosacral junction and pelvic ring by merging spinal pelvic fixation, posterior pelvic ring fixation, and anterior spinal column fixation. CONCLUSION: To the best of our knowledge, this is the first case of a multilevel lumbar, sacral, and sacropelvic neuropathic (Charcot) spine reconstruction using a 3DPI sacral prosthesis. As the prevalence of severe spine deformities continues to increase, adoption of 3DPIs is becoming more relevant to offer personalized treatment for complex deformities.

Live-Cell Imaging Shows Uneven Segregation of Extrachromosomal DNA Elements and Transcriptionally Active Extrachromosomal DNA Hubs in Cancer.

Oncogenic extrachromosomal DNA elements (ecDNA) play an important role in tumor evolution, but our understanding of ecDNA biology is limited. We determined the distribution of single-cell ecDNA copy number across patient tissues and cell line models and observed how cell-to-cell ecDNA frequency varies greatly. The exceptional intratumoral heterogeneity of ecDNA suggested ecDNA-specific replication and propagation mechanisms. To evaluate the transfer of ecDNA genetic material from parental to offspring cells during mitosis, we established the CRISPR-based ecTag method. ecTag leverages ecDNA-specific breakpoint sequences to tag ecDNA with fluorescent markers in living cells. Applying ecTag during mitosis revealed disjointed ecDNA inheritance patterns, enabling rapid ecDNA accumulation in individual cells. After mitosis, ecDNAs clustered into ecDNA hubs, and ecDNA hubs colocalized with RNA polymerase II, promoting transcription of cargo oncogenes. Our observations provide direct evidence for uneven segregation of ecDNA and shed new light on mechanisms through which ecDNAs contribute to oncogenesis. SIGNIFICANCE: ecDNAs are vehicles for oncogene amplification. The circular nature of ecDNA affords unique properties, such as mobility and ecDNA-specific replication and segregation behavior. We uncovered fundamental ecDNA properties by tracking ecDNAs in live cells, highlighting uneven and random segregation and ecDNA hubs that drive cargo gene transcription.See related commentary by Henssen, p. 293.This article is highlighted in the In This Issue feature, p. 275.

Neonatal, postneonatal, childhood, and under-5 mortality for 187 countries, 1970-2010: a systematic analysis of progress towards Millennium Development Goal 4.

BACKGROUND: Previous assessments have highlighted that less than a quarter of countries are on track to achieve Millennium Development Goal 4 (MDG 4), which calls for a two-thirds reduction in mortality in children younger than 5 years between 1990 and 2015. In view of policy initiatives and investments made since 2000, it is important to see if there is acceleration towards the MDG 4 target. We assessed levels and trends in child mortality for 187 countries from 1970 to 2010. METHODS: We compiled a database of 16 174 measurements of mortality in children younger than 5 years for 187 countries from 1970 to 2009, by use of data from all available sources, including vital registration systems, summary birth histories in censuses and surveys, and complete birth histories. We used Gaussian process regression to generate estimates of the probability of death between birth and age 5 years. This is the first study that uses Gaussian process regression to estimate child mortality, and this technique has better out-of-sample predictive validity than do previous methods and captures uncertainty caused by sampling and non-sampling error across data types. Neonatal, postneonatal, and childhood mortality was estimated from mortality in children younger than 5 years by use of the 1760 measurements from vital registration systems and complete birth histories that contained specific information about neonatal and postneonatal mortality. FINDINGS: Worldwide mortality in children younger than 5 years has dropped from 11.9 million deaths in 1990 to 7.7 million deaths in 2010, consisting of 3.1 million neonatal deaths, 2.3 million postneonatal deaths, and 2.3 million childhood deaths (deaths in children aged 1-4 years). 33.0% of deaths in children younger than 5 years occur in south Asia and 49.6% occur in sub-Saharan Africa, with less than 1% of deaths occurring in high-income countries. Across 21 regions of the world, rates of neonatal, postneonatal, and childhood mortality are declining. The global decline from 1990 to 2010 is 2.1% per year for neonatal mortality, 2.3% for postneonatal mortality, and 2.2% for childhood mortality. In 13 regions of the world, including all regions in sub-Saharan Africa, there is evidence of accelerating declines from 2000 to 2010 compared with 1990 to 2000. Within sub-Saharan Africa, rates of decline have increased by more than 1% in Angola, Botswana, Cameroon, Congo, Democratic Republic of the Congo, Kenya, Lesotho, Liberia, Rwanda, Senegal, Sierra Leone, Swaziland, and The Gambia. INTERPRETATION: Robust measurement of mortality in children younger than 5 years shows that accelerating declines are occurring in several low-income countries. These positive developments deserve attention and might need enhanced policy attention and resources. FUNDING: Bill & Melinda Gates Foundation.

Worldwide mortality in men and women aged 15-59 years from 1970 to 2010: a systematic analysis.

BACKGROUND: Adult deaths are a crucial priority for global health. Causes of adult death are important components of Millennium Development Goals 5 and 6. However, adult mortality has received little policy attention, resources, or monitoring efforts. This study aimed to estimate worldwide mortality in men and women aged 15-59 years. METHODS: We compiled a database of 3889 measurements of adult mortality for 187 countries from 1970 to 2010 using vital registration data and census and survey data for deaths in the household corrected for completeness, and sibling history data from surveys corrected for survival bias. We used Gaussian process regression to generate yearly estimates of the probability of death between the ages of 15 years and 60 years (45q15) for men and women for every country with uncertainty intervals that indicate sampling and non-sampling error. We showed that these analytical methods have good predictive validity for countries with missing data. FINDINGS: Adult mortality varied substantially across countries and over time. In 2010, the countries with the lowest risk of mortality for men and women are Iceland and Cyprus, respectively. In Iceland, male 45q15 is 65 (uncertainty interval 61-69) per 1000; in Cyprus, female 45q15 is 38 (36-41) per 1000. Highest risk of mortality in 2010 is seen in Swaziland for men (45q15 of 765 [692-845] per 1000) and Zambia for women (606 [518-708] per 1000). Between 1970 and 2010, substantial increases in adult mortality occurred in sub-Saharan Africa because of the HIV epidemic and in countries in or related to the former Soviet Union. Other regional trends were also seen, such as stagnation in the decline of adult mortality for large countries in southeast Asia and a striking decline in female mortality in south Asia. INTERPRETATION: The prevention of premature adult death is just as important for global health policy as the improvement of child survival. Routine monitoring of adult mortality should be given much greater emphasis. FUNDING: Bill & Melinda Gates Foundation.

Predictors of Contemporary under-5 Child Mortality in Low- and Middle-Income Countries: A Machine Learning Approach.

Child Mortality (CM) is a worldwide concern, annually affecting as many as 6.81% children in low- and middle-income countries (LMIC). We used data of the Multiple Indicators Cluster Survey (MICS) (N = 275,160) from 27 LMIC and a machine-learning approach to rank 37 distal causes of CM and identify the top 10 causes in terms of predictive potency. Based on the top 10 causes, we identified households with improved conditions. We retrospectively validated the results by investigating the association between variations of CM and variations of the percentage of households with improved conditions at country-level, between the 2005-2007 and the 2013-2017 administrations of the MICS. A unique contribution of our approach is to identify lesser-known distal causes which likely account for better-known proximal causes: notably, the identified distal causes and preventable and treatable through social, educational, and physical interventions. We demonstrate how machine learning can be used to obtain operational information from big dataset to guide interventions and policy makers.

Men's and women's views on acceptability of husband-to-wife violence and use of corporal punishment with children in 21 low- and middle-income countries.

BACKGROUND: Monitoring violence against women and children, and understanding risk factors and consequences of such violence, are key parts of the action plan for the Sustainable Development Goals (SDGs) set by the United Nations General Assembly in 2015. OBJECTIVE: We examined how men's and women's views about the acceptability of husband-to-wife violence are related within households and how views about the acceptability of husband-to-wife violence are related to beliefs in the necessity of using corporal punishment to rear children and to reported use of corporal punishment with children. PARTICIPANTS AND SETTING: We used nationally representative samples of men and women in 37,641 households in 21 low- and middle-income countries that participated in UNICEF's Multiple Indicator Cluster Survey. METHODS: We conducted a series of logistic regression models, controlling for clustering within country, with outcomes of whether participants believe corporal punishment is necessary in childrearing, and whether a child in their household experienced corporal punishment in the last month. RESULTS: In 46 % of households, men, women, or both men and women believed husbands are justified in hitting their wives. Children in households in which both men and women believe husbands are justified in hitting their wives had 1.83 times the odds of experiencing corporal punishment as children in households in which neither men nor women believe husbands are justified in hitting their wives (95 % CI: 1.12, 2.97). CONCLUSIONS: Working toward the realization of SDG 5 and SDG 16 involving prevention of violence against women and children, respectively, should be complementary undertakings.

Health costs of reproduction are minimal despite high fertility, mortality and subsistence lifestyle.

Women exhibit greater morbidity than men despite higher life expectancy. An evolutionary life history framework predicts that energy invested in reproduction trades-off against investments in maintenance and survival. Direct costs of reproduction may therefore contribute to higher morbidity, especially for women given their greater direct energetic contributions to reproduction. We explore multiple indicators of somatic condition among Tsimane forager-horticulturalist women (Total Fertility Rate = 9.1; n = 592 aged 15-44 years, n = 277 aged 45+). We test whether cumulative live births and the pace of reproduction are associated with nutritional status and immune function using longitudinal data spanning 10 years. Higher parity and faster reproductive pace are associated with lower nutritional status (indicated by weight, body mass index, body fat) in a cross-section, but longitudinal analyses show improvements in women's nutritional status with age. Biomarkers of immune function and anemia vary little with parity or pace of reproduction. Our findings demonstrate that even under energy-limited and infectious conditions, women are buffered from the potential depleting effects of rapid reproduction and compound offspring dependency characteristic of human life histories.