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Epidemiological trends during the past decade suggest that although incidence of nasopharyngeal carcinoma is gradually declining, even in endemic regions, mortality from the disease has fallen substantially. This finding is probably a result of a combination of lifestyle modification, population screening coupled with better imaging, advances in radiotherapy, and effective systemic agents. In particular, intensity-modulated radiotherapy has driven the improvement in tumour control and reduction in toxic effects in survivors. Clinical use of Epstein-Barr virus (EBV) as a surrogate biomarker in nasopharyngeal carcinoma continues to increase, with quantitative assessment of circulating EBV DNA used for population screening, prognostication, and disease surveillance. Randomised trials are investigating the role of EBV DNA in stratification of patients for treatment intensification and deintensification. Among the exciting developments in nasopharyngeal carcinoma, vascular endothelial growth factor inhibition and novel immunotherapies targeted at immune checkpoint and EBV-specific tumour antigens offer promising alternatives to patients with metastatic disease.

Analysis of ancient DNA from four individuals who lived in Vanuatu and Tonga between 2,300 and 3,100 years ago suggests that the Papuan ancestry seen in present-day occupants of this region was introduced at a later date. Waves of migration in the Southwest Pacific Pacific islanders today have been found to have ancestry from a mixture of lineages including Papuan, Australian and East Asian. David Reich and colleagues now report analysis of ancient genomic data from four individuals from Vanuatu and Tonga, South Pacific islands, representing the first ancient genomic data from Oceanian populations. Their analysis finds no evidence of Papuan ancestry in the early Remote Oceanians, suggesting that Papuan ancestry seen in contemporary Pacific islanders may reflect later migration. The appearance of people associated with the Lapita culture in the South Pacific around 3,000 years ago 1 marked the beginning of the last major human dispersal to unpopulated lands. However, the relationship of these pioneers to the long-established Papuan people of the New Guinea region is unclear. Here we present genome-wide ancient DNA data from three individuals from Vanuatu (about 3,100–2,700 years before present) and one from Tonga (about 2,700–2,300 years before present), and analyse them with data from 778 present-day East Asians and Oceanians. Today, indigenous people of the South Pacific harbour a mixture of ancestry from Papuans and a population of East Asian origin that no longer exists in unmixed form, but is a match to the ancient individuals. Most analyses have interpreted the minimum of twenty-five per cent Papuan ancestry in the region today as evidence that the first humans to reach Remote Oceania, including Polynesia, were derived from population mixtures near New Guinea, before their further expansion into Remote Oceania 2 , 3 , 4 , 5 . However, our finding that the ancient individuals had little to no Papuan ancestry implies that later human population movements spread Papuan ancestry through the South Pacific after the first peopling of the islands.

Duplications and deletions can lead to variation in copy number for genes and genomic loci among humans. Such variants can reveal evolutionary patterns and have implications for human health. Sudmant et al. examined copy-number variation across 236 individual genomes from 125 human populations. Deletions were under more selection, whereas duplications showed more population-specific structure. Interestingly, Oceanic populations retain large duplications postulated to have originated in an ancient Denisovan lineage. Science , this issue 10.1126/science.aab3761 Copy-number variation reveals how selection affects the human genome across the globe. In order to explore the diversity and selective signatures of duplication and deletion human copy-number variants (CNVs), we sequenced 236 individuals from 125 distinct human populations. We observed that duplications exhibit fundamentally different population genetic and selective signatures than deletions and are more likely to be stratified between human populations. Through reconstruction of the ancestral human genome, we identify megabases of DNA lost in different human lineages and pinpoint large duplications that introgressed from the extinct Denisova lineage now found at high frequency exclusively in Oceanic populations. We find that the proportion of CNV base pairs to single-nucleotide–variant base pairs is greater among non-Africans than it is among African populations, but we conclude that this difference is likely due to unique aspects of non-African population history as opposed to differences in CNV load.

Whole-genome sequencing of individuals from 125 populations provides insight into patterns of genetic diversity, natural selection and human demographic history during the peopling of Eurasia and finds evidence for genetic vestiges of an early expansion of modern humans out of Africa in Papuans. The DNA of early human migrations Three international collaborations reporting in this issue of Nature describe 787 high-quality genomes from individuals from geographically diverse populations. David Reich and colleagues analysed whole-genome sequences of 300 individuals from 142 populations. Their findings include an accelerated estimated rate of accumulation of mutations in non-Africans compared to Africans since divergence, and that indigenous Australians, New Guineans and Andamanese do not derive substantial ancestry from an early dispersal of modern humans but from the same source as that of other non-Africans. Eske Willerlsev and colleagues obtained whole-genome data for 83 Aboriginal Australians and 25 Papuans from the New Guinea Highlands. They estimate that Aboriginal Australians and Papuans diverged from Eurasian populations 51,000–72,000 years ago, following a single out-of-Africa dispersal. Luca Pagani et al . report on a dataset of 483 high-coverage human genomes from 148 populations worldwide, including 379 new genomes from 125 populations. Their analyses support the model by which all non-African populations derive most of their genetic ancestry from a single recent migration out of Africa, although a Papuan contribution suggests a trace of an earlier human expansion. High-coverage whole-genome sequence studies have so far focused on a limited number 1 of geographically restricted populations 2 , 3 , 4 , 5 , or been targeted at specific diseases, such as cancer 6 . Nevertheless, the availability of high-resolution genomic data has led to the development of new methodologies for inferring population history 7 , 8 , 9 and refuelled the debate on the mutation rate in humans 10 . Here we present the Estonian Biocentre Human Genome Diversity Panel (EGDP), a dataset of 483 high-coverage human genomes from 148 populations worldwide, including 379 new genomes from 125 populations, which we group into diversity and selection sets. We analyse this dataset to refine estimates of continent-wide patterns of heterozygosity, long- and short-distance gene flow, archaic admixture, and changes in effective population size through time as well as for signals of positive or balancing selection. We find a genetic signature in present-day Papuans that suggests that at least 2% of their genome originates from an early and largely extinct expansion of anatomically modern humans (AMHs) out of Africa. Together with evidence from the western Asian fossil record 11 , and admixture between AMHs and Neanderthals predating the main Eurasian expansion 12 , our results contribute to the mounting evidence for the presence of AMHs out of Africa earlier than 75,000 years ago.

Here we report the Simons Genome Diversity Project data set: high quality genomes from 300 individuals from 142 diverse populations. These genomes include at least 5.8 million base pairs that are not present in the human reference genome. Our analysis reveals key features of the landscape of human genome variation, including that the rate of accumulation of mutations has accelerated by about 5% in non-Africans compared to Africans since divergence. We show that the ancestors of some pairs of present-day human populations were substantially separated by 100,000 years ago, well before the archaeologically attested onset of behavioural modernity. We also demonstrate that indigenous Australians, New Guineans and Andamanese do not derive substantial ancestry from an early dispersal of modern humans; instead, their modern human ancestry is consistent with coming from the same source as that of other non-Africans. Deep whole-genome sequencing of 300 individuals from 142 diverse populations provides insights into key population genetic parameters, shows that all modern human ancestry outside of Africa including in Australasians is consistent with descending from a single founding population, and suggests a higher rate of accumulation of mutations in non-Africans compared to Africans since divergence. The DNA of early human migrations Three international collaborations reporting in this issue of Nature describe 787 high-quality genomes from individuals from geographically diverse populations. David Reich and colleagues analysed whole-genome sequences of 300 individuals from 142 populations. Their findings include an accelerated estimated rate of accumulation of mutations in non-Africans compared to Africans since divergence, and that indigenous Australians, New Guineans and Andamanese do not derive substantial ancestry from an early dispersal of modern humans but from the same source as that of other non-Africans. Eske Willerlsev and colleagues obtained whole-genome data for 83 Aboriginal Australians and 25 Papuans from the New Guinea Highlands. They estimate that Aboriginal Australians and Papuans diverged from Eurasian populations 51,000–72,000 years ago, following a single out-of-Africa dispersal. Luca Pagani et al . report on a dataset of 483 high-coverage human genomes from 148 populations worldwide, including 379 new genomes from 125 populations. Their analyses support the model by which all non-African populations derive most of their genetic ancestry from a single recent migration out of Africa, although a Papuan contribution suggests a trace of an earlier human expansion.

In the introduction to this special issue, the editors introduce the reader to research methodologies and analyses not commonly presented in mainstream health policy literature. Intersectional analysis, for example, is a means of drilling down into how the multiple social categories a person occupies (e.g., gender, class, ethnicity) may influence their experience of inequality. When an intersectional framework was applied to US Behavioral Risk Factor Surveillance System data in 2018 and 2019, for example, gender minority Blacks were identified as having distinctly poor health experiences compared with cisgender Black and other non-Black gender minority populations.1 Consequently, health policies and monitoring programs that purport to advance health equity must account for multiply marginalized populations such as these.Looking at drug policy through an intersectional lens reinforces the importance of macrolevel social determinants as they interact with meso and microlevel factors to influence drug harms and mediate policy and intervention effectiveness2 as well as the role of power in excluding certain perspectives, framings, forms of knowledge, and experience.3 Ethnographic, social-scientific, and community-based research methodologies challenge power imbalances by favoring the embodied knowledge of those with lived experience, knowledge gained by direct observation and study of the particular history and economic and political systems in a given location,2 as opposed to forms of professional expertise favored by public authorities seeking to govern society at a distance.

In this viewpoint, we explore the use of big data analytics and artificial intelligence (AI) and discuss important challenges to their ethical, effective, and equitable use within opioid use disorder (OUD) treatment settings. Applying our collective experiences as OUD policy and treatment experts, we discuss 8 key challenges that OUD treatment services must contend with to make the most of these rapidly evolving technologies: data and algorithmic transparency, clinical validation, new practitioner-technology interfaces, capturing data relevant to improving patient care, understanding and responding to algorithmic outputs, obtaining informed patient consent, navigating mistrust, and addressing digital exclusion and bias. Through this paper, we hope to critically engage clinicians and policy makers on important ethical considerations, clinical implications, and implementation challenges involved in big data analytics and AI deployment in OUD treatment settings.

Current proposed mechanisms implicate both early and latent Epstein–Barr virus (EBV) infection in the carcinogenic cascade, whereas epidemiological studies have always associated nasopharyngeal carcinoma (NPC) with early childhood EBV infection and with chronic ear, nose, and sinus conditions. Moreover, most patients with NPC present with IgA antibody titers to EBV capsid antigen (VCA‐IgA), which can precede actual tumor presentation by several years. If early childhood EBV infection indeed constitutes a key event in NPC carcinogenesis, one would have to explain the inability to detect the virus in normal nasopharyngeal epithelium of patients at a high risk for EBV infection. It is perhaps possible that EBV resides within the salivary glands, instead of the epithelium, during latency. This claim is indirectly supported by observations that the East Asian phenotype shares the characteristics of an increased susceptibility to NPC and immature salivary gland morphogenesis, the latter of which is influenced by the association of salivary gland morphogenesis with an evolutionary variant of the human ectodysplasin receptor gene (EDAR), EDARV370A. Whether the immature salivary gland represents a more favorable nidus for EBV is uncertain, but in patients with infectious mononucleosis, EBV has been isolated in this anatomical organ. The presence of EBV‐induced lymphoepitheliomas in the salivary glands and lungs further addresses the possibility of submucosal spread of the virus. Adding to the fact that the fossa of Rosen Müller contains a transformative zone active only in the first decade of life, one might be tempted to speculate the possibility of an alternative carcinogenic cascade for NPC that is perhaps not dissimilar to the model of human papillomavirus and cervical cancer.

Organisms adapt to environmental changes in order to survive. Mothers exposed to nutritional stresses can induce an adaptive response in their offspring. However, the molecular mechanisms behind such inheritable links are not clear. Here we report that in Drosophila , starvation of mothers primes the progeny against subsequent nutritional stress. We found that RpL10Ab represses TOR pathway activity by genetically interacting with TOR pathway components TSC2 and Rheb. In addition, starved mothers produce offspring with lower levels of RpL10Ab in the germline, which results in higher TOR pathway activity, conferring greater resistance to starvation-induced oocyte loss. The RpL10Ab locus encodes for the RpL10Ab mRNA and a stable intronic sequence RNA ( sisR-8 ), which collectively repress RpL10Ab pre-mRNA splicing in a negative feedback mechanism. During starvation, an increase in maternally deposited RpL10Ab and sisR-8 transcripts leads to the reduction of RpL10Ab expression in the offspring. Our study suggests that the maternally deposited RpL10Ab and sisR-8 transcripts trigger a negative feedback loop that mediates intergenerational adaptation to nutritional stress as a starvation response.

Background Although the Cox time-varying coefficient (TVC) model has been developed to address non-proportional hazard (PH), its use remains underexplored. Instead, the restricted mean survival time (RMST) has been widely used in non-PH settings to quantify treatment effects using life expectancy ratio (LER) and life expectancy difference (LED). Methods This study explores a novel extension of the Cox TVC model under non-PH to generate LER and LED to enable a direct comparison with RMST based on flexible parametric survival model (FPM). An intensive simulation study was conducted to compare the performance of FPM to the Cox TVC model under PH and non-PH assumptions. The survival time t was assumed to follow the Piecewise Exponential distribution with various censoring patterns generated from the Uniform distribution. Both methods were evaluated via a randomised clinical trial of nasopharyngeal cancer exhibiting increasing treatment benefit. Results Intensive simulations showed Cox TVC outperformed FPM under non-PH in terms of bias and coverage, with generally higher power observed in scenarios of crossing or diverging curves under low censoring. In real-world data, the FPM produced slightly larger LER and LED estimates than Cox TVC. Cox TVC has the advantage of assessing treatment effect at different milestones and detecting earlier difference when estimating using hazard ratio (HR). Conclusion Overall, Cox TVC is a viable option for summarising treatment effect using LER and LED under non-PH conditions. It would be beneficial to complement the reporting by providing estimates of HR at specific milestone to detect early differences.