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Mendelian randomization identifies proteins involved in neurodegenerative diseases.
Proteins are involved in multiple biological functions. High-throughput technologies have allowed the measurement of thousands of proteins in population biobanks. In this study, we aimed to identify proteins related to Alzheimer's disease, Parkinson's disease, multiple sclerosis and amyotrophic lateral sclerosis by leveraging large-scale genetic and proteomic data. We performed a two-sample cis Mendelian randomization study by selecting instrumental variables for the abundance of >2700 proteins measured by either Olink or SomaScan platforms in plasma from the UK Biobank and the deCODE Health Study. We also used the latest publicly available genome-wide association studies for the neurodegenerative diseases of interest. The potentially causal effect of proteins on neurodegenerative diseases was estimated based on the Wald ratio. We tested 13 377 protein-disease associations, identifying 169 associations that were statistically significant (5% false discovery rate). Evidence of co-localization between plasma protein abundance and disease risk (posterior probability > 0.80) was identified for 61 protein-disease pairs, leading to 50 unique protein-disease associations. Notably, 23 of 50 protein-disease associations corresponded to genetic loci not previously reported by genome-wide association studies. The two-sample Mendelian randomization and co-localization analysis also showed that APOE abundance in plasma was associated with three subcortical volumes (hippocampus, amygdala and nucleus accumbens) and white matter hyper-intensities, whereas PILRA and PILRB abundance in plasma was associated with caudate nucleus volume. Our study provided a comprehensive assessment of the effect of the human proteome that is currently measurable through two different platforms on neurodegenerative diseases. The newly associated proteins indicated the involvement of complement (C1S and C1R), microglia (SIRPA, SIGLEC9 and PRSS8) and lysosomes (CLN5) in Alzheimer's disease; the interleukin-6 pathway (CTF1) in Parkinson's disease; lysosomes (TPP1), blood-brain barrier integrity (MFAP2) and astrocytes (TNFSF13) in amyotrophic lateral sclerosis; and blood-brain barrier integrity (VEGFB), oligodendrocytes (PARP1), node of Ranvier and dorsal root ganglion (NCS1, FLRT3 and CDH15) and the innate immune system (CR1, AHSG and WARS) in multiple sclerosis. Our study demonstrates how harnessing large-scale genomic and proteomic data can yield new insights into the role of the plasma proteome in the pathogenesis of neurodegenerative diseases.
Data Interoperability for Ambulatory Monitoring of Cardiovascular Disease: A Scientific Statement From the American Heart Association.
Wearable devices are increasingly used by a growing portion of the population to track health and illnesses. The data emerging from these devices can potentially transform health care. This requires an interoperability framework that enables the deployment of platforms, sensors, devices, and software applications within diverse health systems, aiming to facilitate innovation in preventing and treating cardiovascular disease. However, the current data ecosystem includes several noninteroperable systems that inhibit such objectives. The design of clinically meaningful systems for accessing and incorporating these data into clinical workflows requires strategies to ensure the quality of data and clinical content and patient and caregiver accessibility. This scientific statement aims to address the best practices, gaps, and challenges pertaining to data interoperability in this area, with considerations for (1) data integration and the scope of measures, (2) application of these data into clinical approaches/strategies, and (3) regulatory/ethical/legal issues.
Use of Artificial Intelligence in Improving Outcomes in Heart Disease: A Scientific Statement From the American Heart Association.
A major focus of academia, industry, and global governmental agencies is to develop and apply artificial intelligence and other advanced analytical tools to transform health care delivery. The American Heart Association supports the creation of tools and services that would further the science and practice of precision medicine by enabling more precise approaches to cardiovascular and stroke research, prevention, and care of individuals and populations. Nevertheless, several challenges exist, and few artificial intelligence tools have been shown to improve cardiovascular and stroke care sufficiently to be widely adopted. This scientific statement outlines the current state of the art on the use of artificial intelligence algorithms and data science in the diagnosis, classification, and treatment of cardiovascular disease. It also sets out to advance this mission, focusing on how digital tools and, in particular, artificial intelligence may provide clinical and mechanistic insights, address bias in clinical studies, and facilitate education and implementation science to improve cardiovascular and stroke outcomes. Last, a key objective of this scientific statement is to further the field by identifying best practices, gaps, and challenges for interested stakeholders.
DAS28(3)CRP is a reliable measure of disease activity in pregnant women with rheumatoid arthritis.
OBJECTIVES: The disease activity of rheumatoid arthritis (RA) in pregnancy is most commonly assessed with the modified Disease Activity Score (DAS)-28, the DAS28(3)CRP. However, the performance of the DAS28(3)CRP in pregnancy has not been compared to musculoskeletal ultrasound (MSK-US) as a gold standard. We performed a prospective pilot study to test the hypothesis that pregnancy-related factors limit the reliability of the DAS28(3)CRP. METHODS: Pregnant women with RA were recruited from an Obstetric Rheumatology clinic and assessed during pregnancy (second (T2) and third (T3) trimesters) and postpartum with DAS28(3)CRP and MSK-US scores, with quantification of power Doppler (PD) signal in small joints (hands and feet). Age-matched non-pregnant women with RA underwent equivalent assessments. PD scores were calculated as mean scores of all joints scanned. RESULTS: We recruited 27 pregnant and 20 non-pregnant women with RA. DAS28(3)CRP was sensitive and specific for active RA in pregnancy and postpartum as defined by positive PD signal, but not in non-pregnancy. There were significant correlations between DAS28(3)CRP and PD scores throughout pregnancy (T2, r=0.82 (95% CI [0.42, 0.95], p<0.01); T3, r=0.68 (95% CI [0.38, 0.86], p<0.01)) and postpartum, r=0.84 (95% CI [0.60, 0.94], p<0.01), while this correlation in non-pregnancy was weaker (r=0.47 (95% CI [0, 0.77], p<0.05). CONCLUSIONS: This pilot study found that DAS28(3)CRP is a reliable measure of disease activity in pregnant women with RA. Based on these data, pregnancy does not appear to confound clinical evaluation of the tender and/or swollen joint counts.
Associations of polygenic risk scores with risks of stroke and its subtypes in Chinese.
BACKGROUND AND PURPOSE: Previous studies, mostly focusing on the European population, have reported polygenic risk scores (PRSs) might achieve risk stratification of stroke. We aimed to examine the association strengths of PRSs with risks of stroke and its subtypes in the Chinese population. METHODS: Participants with genome-wide genotypic data in China Kadoorie Biobank were split into a potential training set (n=22 191) and a population-based testing set (n=72 150). Four previously developed PRSs were included, and new PRSs for stroke and its subtypes were developed. The PRSs showing the strongest association with risks of stroke or its subtypes in the training set were further evaluated in the testing set. Cox proportional hazards regression models were used to estimate the association strengths of different PRSs with risks of stroke and its subtypes (ischaemic stroke (IS), intracerebral haemorrhage (ICH) and subarachnoid haemorrhage (SAH)). RESULTS: In the testing set, during 872 919 person-years of follow-up, 8514 incident stroke events were documented. The PRSs of any stroke (AS) and IS were both positively associated with risks of AS, IS and ICH (p<0.05). The HR for per SD increment (HRSD) of PRSAS was 1.10 (95% CI 1.07 to 1.12), 1.10 (95% CI 1.07 to 1.12) and 1.13 (95% CI 1.07 to 1.20) for AS, IS and ICH, respectively. The corresponding HRSD of PRSIS was 1.08 (95% CI 1.06 to 1.11), 1.08 (95% CI 1.06 to 1.11) and 1.09 (95% CI 1.03 to 1.15). PRSICH was positively associated with the risk of ICH (HRSD=1.07, 95% CI 1.01 to 1.14). PRSSAH was not associated with risks of stroke and its subtypes. The addition of current PRSs offered little to no improvement in stroke risk prediction and risk stratification. CONCLUSIONS: In this Chinese population, the association strengths of current PRSs with risks of stroke and its subtypes were moderate, suggesting a limited value for improving risk prediction over traditional risk factors in the context of current genome-wide association study under-representing the East Asian population.
Global age-sex-specific mortality, life expectancy, and population estimates in 204 countries and territories and 811 subnational locations, 1950-2021, and the impact of the COVID-19 pandemic: a comprehensive demographic analysis for the Global Burden of Disease Study 2021.
BACKGROUND: Estimates of demographic metrics are crucial to assess levels and trends of population health outcomes. The profound impact of the COVID-19 pandemic on populations worldwide has underscored the need for timely estimates to understand this unprecedented event within the context of long-term population health trends. The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2021 provides new demographic estimates for 204 countries and territories and 811 additional subnational locations from 1950 to 2021, with a particular emphasis on changes in mortality and life expectancy that occurred during the 2020-21 COVID-19 pandemic period. METHODS: 22 223 data sources from vital registration, sample registration, surveys, censuses, and other sources were used to estimate mortality, with a subset of these sources used exclusively to estimate excess mortality due to the COVID-19 pandemic. 2026 data sources were used for population estimation. Additional sources were used to estimate migration; the effects of the HIV epidemic; and demographic discontinuities due to conflicts, famines, natural disasters, and pandemics, which are used as inputs for estimating mortality and population. Spatiotemporal Gaussian process regression (ST-GPR) was used to generate under-5 mortality rates, which synthesised 30 763 location-years of vital registration and sample registration data, 1365 surveys and censuses, and 80 other sources. ST-GPR was also used to estimate adult mortality (between ages 15 and 59 years) based on information from 31 642 location-years of vital registration and sample registration data, 355 surveys and censuses, and 24 other sources. Estimates of child and adult mortality rates were then used to generate life tables with a relational model life table system. For countries with large HIV epidemics, life tables were adjusted using independent estimates of HIV-specific mortality generated via an epidemiological analysis of HIV prevalence surveys, antenatal clinic serosurveillance, and other data sources. Excess mortality due to the COVID-19 pandemic in 2020 and 2021 was determined by subtracting observed all-cause mortality (adjusted for late registration and mortality anomalies) from the mortality expected in the absence of the pandemic. Expected mortality was calculated based on historical trends using an ensemble of models. In location-years where all-cause mortality data were unavailable, we estimated excess mortality rates using a regression model with covariates pertaining to the pandemic. Population size was computed using a Bayesian hierarchical cohort component model. Life expectancy was calculated using age-specific mortality rates and standard demographic methods. Uncertainty intervals (UIs) were calculated for every metric using the 25th and 975th ordered values from a 1000-draw posterior distribution. FINDINGS: Global all-cause mortality followed two distinct patterns over the study period: age-standardised mortality rates declined between 1950 and 2019 (a 62·8% [95% UI 60·5-65·1] decline), and increased during the COVID-19 pandemic period (2020-21; 5·1% [0·9-9·6] increase). In contrast with the overall reverse in mortality trends during the pandemic period, child mortality continued to decline, with 4·66 million (3·98-5·50) global deaths in children younger than 5 years in 2021 compared with 5·21 million (4·50-6·01) in 2019. An estimated 131 million (126-137) people died globally from all causes in 2020 and 2021 combined, of which 15·9 million (14·7-17·2) were due to the COVID-19 pandemic (measured by excess mortality, which includes deaths directly due to SARS-CoV-2 infection and those indirectly due to other social, economic, or behavioural changes associated with the pandemic). Excess mortality rates exceeded 150 deaths per 100 000 population during at least one year of the pandemic in 80 countries and territories, whereas 20 nations had a negative excess mortality rate in 2020 or 2021, indicating that all-cause mortality in these countries was lower during the pandemic than expected based on historical trends. Between 1950 and 2021, global life expectancy at birth increased by 22·7 years (20·8-24·8), from 49·0 years (46·7-51·3) to 71·7 years (70·9-72·5). Global life expectancy at birth declined by 1·6 years (1·0-2·2) between 2019 and 2021, reversing historical trends. An increase in life expectancy was only observed in 32 (15·7%) of 204 countries and territories between 2019 and 2021. The global population reached 7·89 billion (7·67-8·13) people in 2021, by which time 56 of 204 countries and territories had peaked and subsequently populations have declined. The largest proportion of population growth between 2020 and 2021 was in sub-Saharan Africa (39·5% [28·4-52·7]) and south Asia (26·3% [9·0-44·7]). From 2000 to 2021, the ratio of the population aged 65 years and older to the population aged younger than 15 years increased in 188 (92·2%) of 204 nations. INTERPRETATION: Global adult mortality rates markedly increased during the COVID-19 pandemic in 2020 and 2021, reversing past decreasing trends, while child mortality rates continued to decline, albeit more slowly than in earlier years. Although COVID-19 had a substantial impact on many demographic indicators during the first 2 years of the pandemic, overall global health progress over the 72 years evaluated has been profound, with considerable improvements in mortality and life expectancy. Additionally, we observed a deceleration of global population growth since 2017, despite steady or increasing growth in lower-income countries, combined with a continued global shift of population age structures towards older ages. These demographic changes will likely present future challenges to health systems, economies, and societies. The comprehensive demographic estimates reported here will enable researchers, policy makers, health practitioners, and other key stakeholders to better understand and address the profound changes that have occurred in the global health landscape following the first 2 years of the COVID-19 pandemic, and longer-term trends beyond the pandemic. FUNDING: Bill & Melinda Gates Foundation.
Religion Welcome Here: A Pluriversal Approach to Religion and Global Bioethics.
This paper sets forth and defends a pluriversal approach to religion in the context of an increasingly global bioethics. Section I introduces a pluriversal view as a normative technique for engaging across difference. A normative pluriversal approach sets five constraints: civility, change from within, justice, non-domination, and tolerance. Section II applies a pluriversal approach to religion. It argues that this approach is epistemically just, recognizes diverse standpoints, and represents a productive, preferred, way to tackle global bioethics concerns. Section II also considers an opposing viewpoint, which holds that religious perspectives have no place in bioethics. We show that this viewpoint would have adverse effects on bioethics publishing, conferencing, and training programmes. The paper concludes (in Section III) that bioethicists should engage with people who hold different worldviews, including religious worldviews, and should do so in accordance with pluriversal ethical constraints.
What Is a Person?: Untapped Insights from Africa
What makes us 'persons' in the moral sense, beings with a certain dignity and worth? What Is a Person? Untapped Insights from Africa explores this question by bringing African and Western philosophies into conversation. Chapter 1 characterizes the contemporary scene in Africa and the West, noting striking differences. It proposes that these differences were not always present, are hardly inevitable, and can and should be bridged. Chapter 2 introduces Emergent Personhood, a new philosophy of personhood that combines insights from Africa and the West. It holds that beings with superlative worth emerge through social relational processes involving human beings, yet they are more than the sum of these relationships. Persons have an identity of their own and exhibit superlative moral worth, a remarkable feature not present at the base. Emergent Personhood justifies personhood for all human beings from birth to death, held equally by them, that cannot be lost or diminished. It also gives strong support to personhood for a wide range of animals, soils, rocks, and ecosystems. Focusing on human personhood, chapters 3 and 4 argue that high moral status emerges at birth, is stable across the lifespan, and reaches a terminus with death's declaration, which ends the human-human associations that enable personhood to arise. Chapters 5, 6, and 7 turn to non-human personhood, considering personhood for artificial intelligence, animals, non-living nature, and extraterrestrial life and lands.
Global, regional, and national burden of stroke and its risk factors, 1990-2021: a systematic analysis for the Global Burden of Disease Study 2021.
BACKGROUND: Up-to-date estimates of stroke burden and attributable risks and their trends at global, regional, and national levels are essential for evidence-based health care, prevention, and resource allocation planning. We aimed to provide such estimates for the period 1990-2021. METHODS: We estimated incidence, prevalence, death, and disability-adjusted life-year (DALY) counts and age-standardised rates per 100 000 people per year for overall stroke, ischaemic stroke, intracerebral haemorrhage, and subarachnoid haemorrhage, for 204 countries and territories from 1990 to 2021. We also calculated burden of stroke attributable to 23 risk factors and six risk clusters (air pollution, tobacco smoking, behavioural, dietary, environmental, and metabolic risks) at the global and regional levels (21 GBD regions and Socio-demographic Index [SDI] quintiles), using the standard GBD methodology. 95% uncertainty intervals (UIs) for each individual future estimate were derived from the 2·5th and 97·5th percentiles of distributions generated from propagating 500 draws through the multistage computational pipeline. FINDINGS: In 2021, stroke was the third most common GBD level 3 cause of death (7·3 million [95% UI 6·6-7·8] deaths; 10·7% [9·8-11·3] of all deaths) after ischaemic heart disease and COVID-19, and the fourth most common cause of DALYs (160·5 million [147·8-171·6] DALYs; 5·6% [5·0-6·1] of all DALYs). In 2021, there were 93·8 million (89·0-99·3) prevalent and 11·9 million (10·7-13·2) incident strokes. We found disparities in stroke burden and risk factors by GBD region, country or territory, and SDI, as well as a stagnation in the reduction of incidence from 2015 onwards, and even some increases in the stroke incidence, death, prevalence, and DALY rates in southeast Asia, east Asia, and Oceania, countries with lower SDI, and people younger than 70 years. Globally, ischaemic stroke constituted 65·3% (62·4-67·7), intracerebral haemorrhage constituted 28·8% (28·3-28·8), and subarachnoid haemorrhage constituted 5·8% (5·7-6·0) of incident strokes. There were substantial increases in DALYs attributable to high BMI (88·2% [53·4-117·7]), high ambient temperature (72·4% [51·1 to 179·5]), high fasting plasma glucose (32·1% [26·7-38·1]), diet high in sugar-sweetened beverages (23·4% [12·7-35·7]), low physical activity (11·3% [1·8-34·9]), high systolic blood pressure (6·7% [2·5-11·6]), lead exposure (6·5% [4·5-11·2]), and diet low in omega-6 polyunsaturated fatty acids (5·3% [0·5-10·5]). INTERPRETATION: Stroke burden has increased from 1990 to 2021, and the contribution of several risk factors has also increased. Effective, accessible, and affordable measures to improve stroke surveillance, prevention (with the emphasis on blood pressure, lifestyle, and environmental factors), acute care, and rehabilitation need to be urgently implemented across all countries to reduce stroke burden. FUNDING: Bill & Melinda Gates Foundation.
Adverse perinatal outcomes associated with different classes of antiretroviral drugs in pregnant women with HIV.
OBJECTIVE: Women with HIV (WHIV) are at an increased risk of adverse perinatal outcomes compared to women without HIV, despite antiretroviral therapy (ART). There is evidence that the risk of adverse perinatal outcomes may differ according to ART regimen. We aimed to assess the risk of adverse perinatal outcomes among WHIV receiving different classes of ART, compared to women without HIV. DESIGN: A systematic review and meta-analysis. METHODS: We searched Medline, CINAHL, Global Health, and EMBASE for studies published between January 1, 1980, and July 14, 2023. We included studies which assessed the risk of 11 predefined adverse perinatal outcomes among WHIV receiving nonnucleoside reverse transcriptase inhibitor (NNRTI)-based ART, protease inhibitor based ART or integrase strand transfer inhibitor (INSTI)-based ART, compared to women without HIV. The perinatal outcomes assessed were preterm birth (PTB), very PTB (VPTB), spontaneous PTB (sPTB), low birthweight (LBW), very LBW (VLBW), term LBW, preterm LBW, small for gestational age (SGA), very SGA (VSGA), stillbirth and neonatal death (NND). Random effects meta-analyses examined the risk of each adverse outcome in WHIV receiving NNRTI-based, protease inhibitor based, or INSTI-based ART, compared with women without HIV. Subgroup and sensitivity analyses were conducted based on country income status, study quality, and timing of ART initiation. The protocol is registered with PROSPERO, CRD42021248987. RESULTS: Of 108 720 identified citations, 22 cohort studies including 191 857 women were eligible for analysis. We found that WHIV receiving NNRTI-based ART (mainly efavirenz or nevirapine) are at an increased risk of PTB (risk ratio 1.40, 95% confidence interval 1.27-1.56), VPTB (1.94, 1.25-3.01), LBW (1.63, 1.30-2.04), SGA (1.53, 1.17-1.99), and VSGA (1.48, 1.16-1.87), compared with women without HIV. WHIV receiving protease inhibitor based ART (mainly lopinavir/ritonavir or unspecified) are at an increased risk of PTB (1.88, 1.55-2.28), VPTB (2.06, 1.01-4.18), sPTB (16.96, 1.01-284.08), LBW (2.90, 2.41-3.50), VLBW (4.35, 2.67-7.09), and VSGA (2.37, 1.84-3.05), compared with women without HIV. WHIV receiving INSTI-based ART (mainly dolutegravir) are at an increased risk of PTB (1.17, 1.06-1.30) and SGA (1.20, 1.08-1.33), compared with women without HIV. CONCLUSION: The risks of adverse perinatal outcomes are higher among WHIV receiving ART compared with women without HIV, irrespective of the class of ART drugs. This underlines the need to further optimize ART in pregnancy and improve perinatal outcomes of WHIV.
Developing evidence-based patient-focused learning materials to support health behaviour change for people living with psoriatic arthritis.
OBJECTIVES: In psoriatic arthritis (PsA), self-management is important for patient function and quality of life. Behaviour change can be difficult, patients could benefit from high-quality support to initiate change. Our aim was to codesign the project as theory-informed, evidence-based, patient-focused, materials supporting healthy lifestyle changes for patients diagnosed with PsA. METHODS: Development of the materials was overseen by a steering group of patients with PsA, psychologists, rheumatologists, a design team and researchers. First, a literature review was performed to establish the evidence base for behaviours and potential interventions in PsA, including diet, weight, alcohol, smoking, exercise, anxiety, depression and stress. An initial roundtable of patients with PsA prioritised areas and content ideas. Draft materials including a website and downloadable materials were produced. A second roundtable of patients with PsA collected feedback on the draft content and design. A third roundtable was held with patients with PsA and a fourth with clinicians to refine the materials and ensuring that they were evidence based, accessible, interesting, and helpful to initiate and maintain change. A final evaluation survey was performed to review the draft website before launching the final materials. RESULTS: 15 candidate topics were prioritised. A website and set of postcards summarising the topics were developed by the design team and refined following feedback from the roundtable groups. CONCLUSION: This project created patient-focused resources to support behaviour change. It addresses common concerns of patients with PsA about how they may optimise their health by providing practical and brief interventions to challenge and support them to make changes.
Evaluation of the psychometric properties of the UBACC questionnaire in a multi-country psychiatric study in Africa.
BACKGROUND: The University of California, San Diego Brief Assessment of Capacity to Consent (UBACC) is a tool to assess the capacity of participants to consent in psychiatric research. However, little is known about the psychometric properties in low and middle-income countries. This study aimed to examine the psychometric properties of the UBACC. METHODS: We examined the reliability, latent factor structure, and item response of the first attempt of the UBACC items in a sample of 32,208 adults (16,467 individuals with psychosis and 15,741 controls) in Ethiopia, Kenya, South Africa, and Uganda; exploring these properties in the full sample and stratified by country, diagnostic status, sex, and ethnolinguistic language groups. RESULTS: Exploratory factor analysis (EFA) suggested a two-factor model for the overall sample. However, a three-factor model was more appropriate when examining the latent structure across country, language, and sex. Confirmatory factor analyses (CFA) revealed an adequately fitting three-factor model for the full sample and across country, sex, and language. A two-factor model, however, was more appropriate for English and Amharic languages. Across all groups, the internal consistency of the UBACC was low, indicating below-threshold reliability (Cronbach's α (95 % CI = 0.58 (0.57-0.59). Using a multidimensional item-response theory framework for the full sample revealed that UBACC item 8, measuring understanding of the benefits of study participation, was the most discriminating item. Many of the other items had below-threshold discriminating characteristics. CONCLUSION: EFA and CFA converged towards a two and three-dimensional structure for the UBACC, in line with the developers of the original scale. The differences in properties between populations and language groups, low internal consistency, and below-threshold item functioning suggest that investigations into the cultural and linguistic nuances are still warranted. Understanding the utility of consent tools, such as the UBACC, in underrepresented populations will be a part of the larger process which ensures that research participants are adequately protected.
Coming to terms with climate change: a glossary for climate change impacts on mental health and well-being.
Climate change is a major threat to global health. Its effects on physical health are increasingly recognised, but mental health impacts have received less attention. The mental health effects of climate change can be direct (resulting from personal exposure to acute and chronic climatic changes), indirect (via the impact on various socioeconomic, political and environmental determinants of mental health) and overarching (via knowledge, education and awareness of climate change). These impacts are unequally distributed according to long-standing structural inequities which are exacerbated by climate change. We outline key concepts and pathways through which climate change may affect mental health and explore the responses to climate change at different levels, from emotions to politics, to highlight the need for multilevel action. We provide a broad reference to help guide researchers, practitioners and policy-makers in the use and understanding of different terms in this rapidly growing interdisciplinary field.