Weight gain is associated with shorter lifespan: a longitudinal study of New Zealand soldiers serving in both world wars.

Obesity is an increasing public health concern with important mortality consequences. Weight gain or maximum adult BMI, not BMI at one point in time, has been shown to be an important risk factor in cohorts studied recently during an era of rapid increase in population levels of overweight and obesity. However, there is limited evidence on individual weight trajectories from cohorts born before the mid-twentieth century. Archival world war military personnel files from New Zealand are freely available online, and identify service in both wars. A pilot study of 316 soldiers confirmed the files contain sufficient information to examine health trajectories and lifespan. Because this cohort are now entirely deceased, nearly the entire sample can be found in death records to estimate the impact of weight increases on lifespan. Weight change over 20-30 years and its relationship with lifespan is examined using ordinary least squares regression. The study demonstrates that military records are a feasible source for collecting data on adult weight and health trajectories in the first half of the twentieth century. Although this sample is likely to be composed of men fitter than average, there is a clear pattern of increasing weight from early to mid-adulthood. Weight gain from early adulthood to middle-age was found to be more strongly associated with mortality than weight in early adulthood. A one unit increase in BMI over the inter-war period was found to be associated with an 8 month decline in lifespan. These results confirm that weight gain in adulthood has an important impact on mortality in an earlier birth cohort than previously studied, and that data exist to measure any changes more precisely over time.

Breathing new life into death certificates: Extracting handwritten cause of death in the LIFE-M project.

The demographic and epidemiological transitions of the past 200 years are well documented at an aggregate level. Understanding differences in individual and group risks for mortality during these transitions requires linkage between demographic data and detailed individual cause of death information. This paper describes the digitization of almost 185,000 causes of death for Ohio to supplement demographic information in the Longitudinal, Intergenerational Family Electronic Micro-database (LIFE-M). To extract causes of death, our methodology combines handwriting recognition, extensive data cleaning algorithms, and the semi-automated classification of causes of death into International Classification of Diseases (ICD) codes. Our procedures are adaptable to other collections of handwritten data, which require both handwriting recognition and semi-automated coding of the information extracted.

Childhood Growth and Socioeconomic Outcomes in Early Adulthood Evidence from the Inter-War United States.

Childhood malnutrition and its later life effects were important concerns in European and North American social policy in the early twentieth century. However, there have been few studies of the long-term socioeconomic consequences of malnutrition in childhood. We use a unique longitudinal dataset to provide credible causal estimates of the effects of childhood nutrition on early-adult educational and employment outcomes. Our dataset includes 2,499 children in Saint Paul, Minnesota who were weighed and measured in a national children's health survey in 1918/1919 at 0-6 years of age. We observe those same people in the 1920, 1930 and 1940 U.S. censuses allowing us to measure childhood socioeconomic status (1920), adolescent school attendance (1930) and early-adult wages, and employment and educational attainment (1940). Examining variation between biological siblings, we are able to obtain credibly causal estimates of the relationship between childhood stature and weight and later life outcomes, largely canceling out the bias otherwise resulting from their joint correlation with genes and socioeconomic background. Because the initial survey located children within households, we identify the effect of differences in early childhood nutrition from differences between male siblings. Consistent with contemporary evidence from developing countries we find that being taller and heavier in early childhood is associated with better educational and labor market outcomes. Identifying all effects within families to control for socioeconomic background and family structure we find a standard deviation increase in BMI in early childhood was associated with a 3% increase in weekly earnings and that boys who were heavier for their age at the initial survey were 10% less likely to be unemployed in 1940. Taken together, these results confirm the importance of investments in early life health for later-life outcomes.

Mixtures of large-scale dynamic functional brain network modes.

Accurate temporal modelling of functional brain networks is essential in the quest for understanding how such networks facilitate cognition. Researchers are beginning to adopt time-varying analyses for electrophysiological data that capture highly dynamic processes on the order of milliseconds. Typically, these approaches, such as clustering of functional connectivity profiles and Hidden Markov Modelling (HMM), assume mutual exclusivity of networks over time. Whilst a powerful constraint, this assumption may be compromising the ability of these approaches to describe the data effectively. Here, we propose a new generative model for functional connectivity as a time-varying linear mixture of spatially distributed statistical "modes". The temporal evolution of this mixture is governed by a recurrent neural network, which enables the model to generate data with a rich temporal structure. We use a Bayesian framework known as amortised variational inference to learn model parameters from observed data. We call the approach DyNeMo (for Dynamic Network Modes), and show using simulations it outperforms the HMM when the assumption of mutual exclusivity is violated. In resting-state MEG, DyNeMo reveals a mixture of modes that activate on fast time scales of 100-150 ms, which is similar to state lifetimes found using an HMM. In task MEG data, DyNeMo finds modes with plausible, task-dependent evoked responses without any knowledge of the task timings. Overall, DyNeMo provides decompositions that are an approximate remapping of the HMM's while showing improvements in overall explanatory power. However, the magnitude of the improvements suggests that the HMM's assumption of mutual exclusivity can be reasonable in practice. Nonetheless, DyNeMo provides a flexible framework for implementing and assessing future modelling developments.

Long-Term Effects of Local-Area New Deal Work Relief in Childhood on Educational, Economic, and Health Outcomes Over the Life Course: Evidence From the Wisconsin Longitudinal Study.

The economic characteristics of one's childhood neighborhood have been found to determine long-term well-being. Policies enacted during childhood may change neighborhood trajectories and thus impact long-term outcomes for children. We use individual-level data from the Wisconsin Longitudinal Study to examine the enduring consequences of childhood exposure to local-area New Deal emergency employment work-relief activity. Our outcomes include adolescent cognition, educational attainment, midlife income, health behaviors, late-life cognition, and mortality. We find that children (ages 0-3) living in neighborhoods with moderate work-relief activity in 1940 had higher adolescent IQ scores, had higher class rank, and were more likely to obtain at least a bachelor's degree. We find enduring benefits for midlife income and late-life cognition for males who grew up in areas with a moderate amount of work relief. We find mixed results for males who grew up in the most disadvantaged areas with the highest levels of work-relief activity. These children had similar educational outcomes as those in the most advantaged districts with the lowest work-relief activity but had higher adult smoking rates. Our findings provide some of the first evidence of the long-term consequences of New Deal policies on children's long-term life course outcomes.

The mortality risk of being overweight in the twentieth century: Evidence from two cohorts of New Zealand men.

How have health and social mortality risks changed over time? Evidence from pre-1945 cohorts is sparse, mostly from the United States, and evidence is mixed on long-term changes in the risk of being overweight. We develop a dataset of men entering the NZ army in the two world wars, with objectively measured height and weight, and socioeconomic status in early adulthood. Our sample includes significant numbers of indigenous Maori, providing estimates of weight and mortality risk in an indigenous population. We follow men from war's end until death, with data on more than 12,000 men from each war. Overweight and obesity were important risk factors for mortality, and associated with shorter life expectancy. However, the reduction in life expectancy associated with being overweight declined from 5 to 3 years between the two cohorts, consistent with the hypothesis that being overweight became less risky during the twentieth century.

The Influence of Kin Proximity on the Reproductive Success of American Couples, 1900-1910.

Children require a large amount of time, effort, and resources to raise. Physical help, financial contributions, medical care, and other types of assistance from kin and social network members allow couples to space births closer together while maintaining or increasing child survival. We examine the impact of kin availability on couples' reproductive success in the early twentieth-century United States with a panel data set of over 3.1 million couples linked between the 1900 and 1910 U.S. censuses. Our results indicate that kin proximity outside the household was positively associated with fertility, child survival, and net reproduction, and suggest that declining kin availability was an important contributing factor to the fertility transition in the United States. We also find important differences between maternal and paternal kin inside the household-including higher fertility among women residing with their mother-in-law than among those residing with their mother-that support hypotheses related to the contrasting motivations and concerns of parents and parents-in-law.

Size-dependent intranasal administration of magnetoelectric nanoparticles for targeted brain localization.

The brain is a massive network of neurons which are interconnected through chemical and electrical field oscillations. It is hard to overestimate the significance of the ability to control chemical and physical properties of the network at both the collective and single-cell levels. Most psychiatric and neurodegenerative diseases are typically characterized by certain aberrations of these oscillations. Recently, magnetoelectric nanoparticles (MENs) have been introduced to achieve the desired control. MENs effectively enable wirelessly controlled nanoelectrodes deep in the brain. Although MENs have been shown to cross the blood-brain barrier via intravenous (IV) administration, achieving adequate efficacy of the delivery remains an open question. Herein, through in vivo studies on a mouse model, we demonstrate at least a 4-fold improved efficacy of the targeted delivery of MENs across BBB via intranasal administration compared to an equivalent IV administration.

The Effects of Education on Mortality: Evidence From Linked U.S. Census and Administrative Mortality Data.

Does education change people's lives in a way that delays mortality? Or is education primarily a proxy for unobserved endowments that promote longevity? Most scholars conclude that the former is true, but recent evidence based on Danish twin data calls this conclusion into question. Unfortunately, these potentially field-changing findings-that obtaining additional schooling has no independent effect on survival net of other hard-to-observe characteristics-have not yet been subject to replication outside Scandinavia. In this article, we produce the first U.S.-based estimates of the effects of education on mortality using a representative panel of male twin pairs drawn from linked complete-count census and death records. For comparison purposes, and to shed additional light on the roles that neighborhood, family, and genetic factors play in confounding associations between education and mortality, we also produce parallel estimates of the education-mortality relationship using data on (1) unrelated males who lived in different neighborhoods during childhood, (2) unrelated males who shared the same neighborhood growing up, and (3) non-twin siblings who shared the same family environment but whose genetic endowments vary to a greater degree. We find robust associations between education and mortality across all four samples, although estimates are modestly attenuated among twins and non-twin siblings. These findings-coupled with several robustness checks and sensitivity analyses-support a causal interpretation of the association between education and mortality for cohorts of boys born in the United States in the first part of the twentieth century.

Post-assembly α-helix to ß-sheet structural transformation within SAF-p1/p2a peptide nanofibers.

We report an unanticipated helix-to-sheet structural transformation within an assembly of SAF-p1 and SAF-p2a designer peptides. Solid-state NMR spectroscopic data support the assembled structure that was targeted by rational peptide design: an α-helical coiled-coil co-assembly of both peptides. Subsequent to assembly, however, the system converts to a ß-sheet structure that continues to exhibit nearest-neighbor interactions between the two peptide components. The structural transition occurs at pH 7.4 and exhibits strongly temperature-dependent kinetics between room temperature (weeks) and 40 °C (minutes). We further observed evidence of reversibility on the timescale of months at 4 °C. The structural conversion from the anticipated structure to an unexpected structure highlights an important aspect to the challenge of designing peptide assemblies. Furthermore, the conformational switching mechanism mediated by a prerequisite α-helical nanostructure represents a previously unknown route for ß-sheet designer peptide assembly.

Fracture Resistance of Titanium-Based Lithium Disilicate and Zirconia Implant Restorations.

PURPOSE: To evaluate the fracture resistance of a newer lithium disilicate abutment material. MATERIALS AND METHODS: A premolar-shaped implant crown was designed using CAD/CAM software, and four groups of implant and crown combinations were milled: (1) lithium-disilicate hybrid-abutment crown; (2) "screwmentable" lithium-disilicate hybrid abutment/lithium-disilicate crown with screw channel; (3) lithium-disilicate hybrid abutment/lithium-disilicate crown; and (4) zirconia hybrid abutment/lithium-disilicate crown (control). The specimens were cemented to a titanium-base implant system, subjected to thermocycling and cyclic loading, and fractured in a material testing device. RESULTS: The lithium-disilicate hybrid-abutment crown had significantly greater fracture load than all the other groups, which were not significantly different from each other. CONCLUSIONS: Based on fracture load, the new lithium-disilicate hybrid-abutment material may serve as a viable alternative to the use of zirconia as a hybrid-abutment material.

The impact of kin availability, parental religiosity, and nativity on fertility differentials in the late 19th-century United States.

METHODS: Most quantitative research on fertility decline in the United States ignores the potential impact of cultural and familial factors. We rely on new complete-count data from the 1880 U.S. census to construct couple-level measures of nativity/ethnicity, religiosity, and kin availability. We include these measures with a comprehensive set of demographic, economic, and contextual variables in Poisson regression models of net marital fertility to assess their relative importance. We construct models with and without area fixed effects to control for unobserved heterogeneity. CONTRIBUTION: All else being equal, we find a strong impact of nativity on recent net marital fertility. Fertility differentials among second generation couples relative to the native-born white population of native parentage were in most cases less than half of the differential observed among first generation immigrants, suggesting greater assimilation to native-born American childbearing norms. Our measures of parental religiosity and familial propinquity indicated a more modest impact on marital fertility. Couples who chose biblical names for their children had approximately 3% more children than couples relying on secular names while the presence of a potential mother-in-law in a nearby households was associated with 2% more children. Overall, our results demonstrate the need for more inclusive models of fertility behavior that include cultural and familial covariates.

Family structure and childhood anthropometry in Saint Paul, Minnesota in 1918.

Concern with childhood nutrition prompted numerous surveys of children's growth in the United States after 1870. The Children's Bureau's 1918 "Weighing and Measuring Test" measured two million children to produce the first official American growth norms. Individual data for 14,000 children survives from the Saint Paul, Minnesota survey whose stature closely approximated national norms. As well as anthropometry the survey recorded exact ages, street address and full name. These variables allow linkage to the 1920 census to obtain demographic and socioeconomic information. We matched 72% of children to census families creating a sample of nearly 10,000 children. Children in the entire survey (linked set) averaged 0.74 (0.72) standard deviations below modern WHO height-for-age standards, and 0.48 (0.46) standard deviations below modern weight-for-age norms. Sibship size strongly influenced height-for-age, and had weaker influence on weight-for-age. Each additional child six or underreduced height-for-age scores by 0.07 standard deviations (95% CI: -0.03, 0.11). Teenage siblings had little effect on height-forage. Social class effects were substantial. Children of laborers averaged half a standard deviation shorter than children of professionals. Family structure and socio-economic status had compounding impacts on children's stature.

Physical well-being and ethnic inequality in New Zealand prisons, 1840-1975.

The British colonization of New Zealand after 1840 was marked by an unusual concern compared to other settler colonies for incorporating the indigenous population Maori population into the new society. But despite a continuing political rhetoric of protection and sovereignty Maori have historically had lower living standards and, since the 1920s, higher rates of incarceration than European-descended New Zealanders (Pakeha). In this paper we examine differences between Maori and Pakeha over 130 years using prison records. Aggregate data from the Ministry of Justice show long-term change and differences in incarceration rates. Using a dataset of all extant registers of men entering New Zealand prisons we show change over time in convictions and in height. The adult statures of Maori and Pakeha were similar for men born before 1900 but marked differences emerged among cohorts born during the twentieth century. By World War II the gap in adult stature widened to around 3 cm, before narrowing for men born after World War II. Periods of divergence in stature are paralleled by divergence in fertility and indicators of family size, suggesting the possibility that increasing fertility stressed the economic situation of Maori families. The prison evidence suggests that inequalities in 'net nutrition' between Maori and Pakeha are long-standing but not unchanging, indeed they increased for cohorts born into the early 20th century. A subset of the data describing adolescents confirms that among those born after 1945 the ethnic differential was already visible by the age of 16 years.

osl-dynamics, a toolbox for modeling fast dynamic brain activity.

Neural activity contains rich spatiotemporal structure that corresponds to cognition. This includes oscillatory bursting and dynamic activity that span across networks of brain regions, all of which can occur on timescales of tens of milliseconds. While these processes can be accessed through brain recordings and imaging, modeling them presents methodological challenges due to their fast and transient nature. Furthermore, the exact timing and duration of interesting cognitive events are often a priori unknown. Here, we present the OHBA Software Library Dynamics Toolbox (osl-dynamics), a Python-based package that can identify and describe recurrent dynamics in functional neuroimaging data on timescales as fast as tens of milliseconds. At its core are machine learning generative models that are able to adapt to the data and learn the timing, as well as the spatial and spectral characteristics, of brain activity with few assumptions. osl-dynamics incorporates state-of-the-art approaches that can be, and have been, used to elucidate brain dynamics in a wide range of data types, including magneto/electroencephalography, functional magnetic resonance imaging, invasive local field potential recordings, and electrocorticography. It also provides novel summary measures of brain dynamics that can be used to inform our understanding of cognition, behavior, and disease. We hope osl-dynamics will further our understanding of brain function, through its ability to enhance the modeling of fast dynamic processes.

Survival of men with metastatic hormone-sensitive prostate cancer and adrenal-permissive HSD3B1 inheritance.

BACKGROUNDMetastatic hormone-sensitive prostate cancer (mHSPC) is androgen dependent, and its treatment includes androgen deprivation therapy (ADT) with gonadal testosterone suppression. Since 2014, overall survival (OS) has been prolonged with addition of other systemic therapies, such as adrenal androgen synthesis blockers, potent androgen receptor blockers, or docetaxel, to ADT. HSD3B1 encodes the rate-limiting enzyme for nongonadal androgen synthesis, 3ß-hydroxysteroid dehydrogenase-1, and has a common adrenal-permissive missense-encoding variant that confers increased synthesis of potent androgens from nongonadal precursor steroids and poorer prostate cancer outcomes.METHODSOur prespecified hypothesis was that poor outcome associated with inheritance of the adrenal-permissive HSD3B1 allele with ADT alone is reversed in patients with low-volume (LV) mHSPC with up-front ADT plus addition of androgen receptor (AR) antagonists to inhibit the effect of adrenal androgens. HSD3B1 genotype was obtained in 287 patients with LV disease treated with ADT + AR antagonist only in the phase III Enzalutamide in First Line Androgen Deprivation Therapy for Metastatic Prostate Cancer (ENZAMET) trial and was associated with clinical outcomes.RESULTSPatients who inherited the adrenal-permissive HSD3B1 allele had more favorable 5-year clinical progression-free survival and OS when treated with ADT plus enzalutamide or ADT plus nonsteroidal antiandrogen compared with their counterparts who did not have adrenal-permissive HSD3B1 inheritance. HSD3B1 was also associated with OS after accounting for known clinical variables. Patients with both genotypes benefited from early enzalutamide.CONCLUSIONThese data demonstrated an inherited physiologic driver of prostate cancer mortality is associated with clinical outcomes and is potentially pharmacologically reversible.FUNDINGNational Cancer Institute, NIH; Department of Defense; Prostate Cancer Foundation, Australian National Health and Medical Research Council.

Targeted Bioluminescent Imaging of Pancreatic Ductal Adenocarcinoma Using Nanocarrier-Complexed EGFR-Binding Affibody-Gaussia Luciferase Fusion Protein.

In vivo imaging has enabled impressive advances in biological research, both preclinical and clinical, and researchers have an arsenal of imaging methods available. Bioluminescence imaging is an advantageous method for in vivo studies that allows for the simple acquisition of images with low background signals. Researchers have increasingly been looking for ways to improve bioluminescent imaging for in vivo applications, which we sought to achieve by developing a bioluminescent probe that could specifically target cells of interest. We chose pancreatic ductal adenocarcinoma (PDAC) as the disease model because it is the most common type of pancreatic cancer and has an extremely low survival rate. We targeted the epidermal growth factor receptor (EGFR), which is frequently overexpressed in pancreatic cancer cells, using an EGFR-specific affibody to selectively identify PDAC cells and delivered a Gaussia luciferase (GLuc) bioluminescent protein for imaging by engineering a fusion protein with both the affibody and the bioluminescent protein. This fusion protein was then complexed with a G5-PAMAM dendrimer nanocarrier. The dendrimer was used to improve the protein stability in vivo and increase signal strength. Our targeted bioluminescent complex had an enhanced uptake into PDAC cells in vitro and localized to PDAC tumors in vivo in pancreatic cancer xenograft mice. The bioluminescent complexes could delineate the tumor shape, identify multiple masses, and locate metastases. Through this work, an EGFR-targeted bioluminescent-dendrimer complex enabled the straightforward identification and imaging of pancreatic cancer cells in vivo in preclinical models. This argues for the targeted nanocarrier-mediated delivery of bioluminescent proteins as a way to improve in vivo bioluminescent imaging.

Gonadal tumors in a contemporary cohort of patients with differences in sex development undergoing surgery - A multi-site study from the Pediatric Urologic Oncology Working Group of the societies for pediatric urology.

BACKGROUND: Disturbances in gonadal development lead to increased risk of gonadal malignancy in some but not all patients with differences in sex development (DSD). However, the natural history of these tumors is poorly described, and the literature remains sparse. OBJECTIVE: The objective of this study was to describe the incidence of germ cell neoplasia in situ (GCNIS) and germ cell tumor (GCT) in a contemporary cohort of patients with DSD undergoing surgery and to provide long-term oncologic outcomes for these patients. STUDY DESIGN: Patients with DSD who have undergone gonadectomy or gonadal biopsy were identified at four institutions. Clinical characteristics, pathology, and treatment details were obtained retrospectively. Patients were stratified into risk categories based on DSD diagnosis. Oncologic treatment and outcomes were recorded. Descriptive statistics are reported using parametric methods. RESULTS: 83 patients were identified. Distribution of diagnoses is summarized in the summary table. 14 (16.9%) patients underwent gonadal biopsy, and 71 (85.5%) patients underwent gonadectomy (50/71 gonadectomies were bilateral). 8/83 (9.6%) patients had GCNIS or GCT (7 GCNIS, 1 GCT). Median age at surgery was 2.95 years (y) (interquartile range [IQR] 0.6-12.2) and 14y (IQR 0.85-16.9) in patients without and with GCNIS/GCT, respectively. All 8 patients with GCNIS/GCT had high or intermediate risk DSD diagnoses (4 mixed gonadal dysgenesis, 3 Turner with Y, 1 partial gonadal dysgenesis). Of the patients with high-risk diagnoses, 8/54 (15%) had GCNIS/GCT. No patient received adjuvant therapy, no patient had a recurrence, and all patients were living with mean follow up 6.4y. DISCUSSION: The risk of gonadal malignancy is heterogeneous in the DSD population and can vary based on DSD diagnosis as well as maturation, testicularization, and location of the gonads. The most recent consensus recommendations on gonadal management emphasize risk stratification and consideration of gonadal surveillance based on gender of rearing, but supporting literature remains sparse. In this contemporary cohort of DSD patients who underwent gonadal surgery, most patients did not have evidence of adverse pathology, all patients with malignant or premalignant pathology had a high/intermediate risk DSD diagnosis, and all patients with GCNIS/GCT were treated with surgery alone without recurrence. CONCLUSIONS: The distribution of patients with premalignant and malignant gonadal pathology and DSD in this cohort aligns with prior literature, and oncologic outcomes were excellent. These data add valuable information to the current literature and highlight the necessity to develop appropriate screening regimens for retained gonads.

Oxidized mC modulates synthetic lethality to PARP inhibitors for the treatment of leukemia.

TET2 haploinsufficiency is a driving event in myeloid cancers and is associated with a worse prognosis in patients with acute myeloid leukemia (AML). Enhancing residual TET2 activity using vitamin C increases oxidized 5-methylcytosine (mC) formation and promotes active DNA demethylation via base excision repair (BER), which slows leukemia progression. We utilize genetic and compound library screening approaches to identify rational combination treatment strategies to improve use of vitamin C as an adjuvant therapy for AML. In addition to increasing the efficacy of several US Food and Drug Administration (FDA)-approved drugs, vitamin C treatment with poly-ADP-ribosyl polymerase inhibitors (PARPis) elicits a strong synergistic effect to block AML self-renewal in murine and human AML models. Vitamin-C-mediated TET activation combined with PARPis causes enrichment of chromatin-bound PARP1 at oxidized mCs and γH2AX accumulation during mid-S phase, leading to cell cycle stalling and differentiation. Given that most AML subtypes maintain residual TET2 expression, vitamin C could elicit broad efficacy as a PARPi therapeutic adjuvant.