A major topic of interest in human prehistory is how the large-scale genetic structure of modern populations outside of Africa was established. Demographic models have been developed that capture the ...relationships among small numbers of populations or within particular geographical regions, but constructing a phylogenetic tree with gene flow events for a wide diversity of non-Africans remains a difficult problem. Here, we report a model that provides a good statistical fit to allele-frequency correlation patterns among East Asians, Australasians, Native Americans, and ancient western and northern Eurasians, together with archaic human groups. The model features a primary eastern/western bifurcation dating to at least 45,000 years ago, with Australasians nested inside the eastern clade, and a parsimonious set of admixture events. While our results still represent a simplified picture, they provide a useful summary of deep Eurasian population history that can serve as a null model for future studies and a baseline for further discoveries.
Long-range migrations and the resulting admixtures between populations have been important forces shaping human genetic diversity. Most existing methods for detecting and reconstructing historical ...admixture events are based on allele frequency divergences or patterns of ancestry segments in chromosomes of admixed individuals. An emerging new approach harnesses the exponential decay of admixture-induced linkage disequilibrium (LD) as a function of genetic distance. Here, we comprehensively develop LD-based inference into a versatile tool for investigating admixture. We present a new weighted LD statistic that can be used to infer mixture proportions as well as dates with fewer constraints on reference populations than previous methods. We define an LD-based three-population test for admixture and identify scenarios in which it can detect admixture events that previous formal tests cannot. We further show that we can uncover phylogenetic relationships among populations by comparing weighted LD curves obtained using a suite of references. Finally, we describe several improvements to the computation and fitting of weighted LD curves that greatly increase the robustness and speed of the calculations. We implement all of these advances in a software package, ALDER, which we validate in simulations and apply to test for admixture among all populations from the Human Genome Diversity Project (HGDP), highlighting insights into the admixture history of Central African Pygmies, Sardinians, and Japanese.
The history of southern Africa involved interactions between indigenous hunter–gatherers and a range of populations that moved into the region. Here we use genome-wide genetic data to show that there ...are at least two admixture events in the history of Khoisan populations (southern African hunter–gatherers and pastoralists who speak non-Bantu languages with click consonants). One involved populations related to Niger–Congo-speaking African populations, and the other introduced ancestry most closely related to west Eurasian (European or Middle Eastern) populations. We date this latter admixture event to ∼900–1,800 y ago and show that it had the largest demographic impact in Khoisan populations that speak Khoe–Kwadi languages. A similar signal of west Eurasian ancestry is present throughout eastern Africa. In particular, we also find evidence for two admixture events in the history of Kenyan, Tanzanian, and Ethiopian populations, the earlier of which involved populations related to west Eurasians and which we date to ∼2,700–3,300 y ago. We reconstruct the allele frequencies of the putative west Eurasian population in eastern Africa and show that this population is a good proxy for the west Eurasian ancestry in southern Africa. The most parsimonious explanation for these findings is that west Eurasian ancestry entered southern Africa indirectly through eastern Africa.
A popular approach to learning about admixture from population genetic data is by computing the allele‐sharing summary statistics known as f‐statistics. Compared to some methods in population ...genetics, f‐statistics are relatively simple, but interpreting them can still be complicated at times. In addition, f‐statistics can be used to build admixture graphs (multi‐population trees allowing for admixture events), which provide more explicit and thorough modelling capabilities but are correspondingly more complex to work with. Here, I discuss some of these issues to provide users of these tools with a basic guide for protocols and procedures. My focus is on the kinds of conclusions that can or cannot be drawn from the results of f4‐statistics and admixture graphs, illustrated with real‐world examples involving human populations.
Austronesian languages are spread across half the globe, from Easter Island to Madagascar. Evidence from linguistics and archaeology indicates that the 'Austronesian expansion,' which began ...4,000-5,000 years ago, likely had roots in Taiwan, but the ancestry of present-day Austronesian-speaking populations remains controversial. Here, we analyse genome-wide data from 56 populations using new methods for tracing ancestral gene flow, focusing primarily on Island Southeast Asia. We show that all sampled Austronesian groups harbour ancestry that is more closely related to aboriginal Taiwanese than to any present-day mainland population. Surprisingly, western Island Southeast Asian populations have also inherited ancestry from a source nested within the variation of present-day populations speaking Austro-Asiatic languages, which have historically been nearly exclusive to the mainland. Thus, either there was once a substantial Austro-Asiatic presence in Island Southeast Asia, or Austronesian speakers migrated to and through the mainland, admixing there before continuing to western Indonesia.
Nonsteroidal anti-inflammatory drugs are commonly used analgesics in colorectal surgery. Controversy exists regarding the potential association between these drugs and anastomotic dehiscence.
This ...study aimed to determine whether postoperative nonsteroidal anti-inflammatory drug use is associated with intestinal anastomotic dehiscence.
PubMed, EMBASE, CENTRAL, and references of included articles were searched without date or language restriction.
Randomized controlled trials and observational studies that compared postoperative nonsteroidal anti-inflammatory drug use with nonuse and reported on intestinal anastomotic dehiscence were selected.
The use of postoperative nonsteroidal anti-inflammatory drugs relative to placebo or nonuse was investigated.
Risk ratios and adjusted or unadjusted odds ratios for anastomotic dehiscence were pooled across randomized controlled trials and observational studies using DerSimonian and Laird random-effects models.
Among 4395 citations identified, 6 randomized controlled trials (n = 473 patients) and 11 observational studies (n > 20,184 patients) were included. Pooled analyses revealed that nonsteroidal anti-inflammatory drug use was nonsignificantly associated with anastomotic dehiscence in randomized controlled trials (risk ratio, 1.96; 95% CI, 0.74-5.16; I = 0%) and significantly associated with anastomotic dehiscence in observational studies (OR, 1.46; 95% CI, 1.14-1.86; I = 54%). In stratified analyses of observational study data, the pooled OR for anastomotic dehiscence was statistically significant for studies of nonselective nonsteroidal anti-inflammatory drug use (6 studies; > 4900 patients; OR, 2.09; 95% CI, 1.65-2.64; I = 0%), but was not statistically significant for studies of cyclooxygenase-2 selective nonsteroidal anti-inflammatory drug use (3 studies; >697 patients; OR, 1.34; 95% CI, 0.78-2.31; I = 0%).
Studies varied by patient selection criteria, drug exposures, and definitions of anastomotic dehiscence. Analyses of randomized controlled trials and cyclooxygenase-2 selective nonsteroidal anti-inflammatory drugs were potentially underpowered.
Pooled observational data suggest an association between postoperative nonsteroidal anti-inflammatory drug use and intestinal anastomotic dehiscence. Caution may be warranted in using these medications in patients at risk for this complication.
Fecal immunochemical testing is an accepted form of colorectal cancer screening and is recommended for adults up to the age of 75 years in Canadian guidelines. However, many individuals 75 years and ...older continue to receive fecal immunochemical testing despite being outside accepted guidelines.
This study aimed to determine whether patients aged 75 years and older with screen-detected cancer demonstrated improved outcomes and survival compared with patients with non-screen-detected cancer.
This is a retrospective population-based cohort study.
Provincial data were collected from the Alberta Cancer Registry and the Alberta Colorectal Cancer Screening Program between November 2013 and 2019.
We identified an aggregated patient cohort aged 75 years and older with a diagnosis of colorectal cancer from November 2013 to November 2019, as well as patients 75 years and older who underwent fecal immunochemical testing within these dates.
The proportion of screen-detected colorectal cancers was calculated. Surgical intervention, hospital length of stay, postoperative mortality, and overall survival were analyzed.
Between November 2013 and 2019, 3586 patients 75 years and older were diagnosed with colorectal cancer; 690 (19%) were "screen-detected." Screen-detected patients were almost 3 times more likely to undergo surgery (OR, 2.83) and had a 36% overall survival benefit (HR, 0.64) compared with non-screen-detected patients, adjusted for other variables such as age, Charlson Comorbidity Index, and stage.
The retrospective study design prevents conclusions regarding causation.
Screen detection of colorectal cancer in patients aged 75 years and older is associated with improved overall survival when controlling for other potential confounders. When compared with their non-screen-detected counterparts, these patients have an earlier stage of disease and are more likely to undergo surgical intervention with improved outcomes, irrespective of age. These data may support screening for appropriately selected patients who would otherwise fall outside of current guidelines. See Video Abstract at http://links.lww.com/DCR/B986 .
ANTECEDENTES:La prueba basada en una Reacción Inmunoquímica Fecal - RIF, es una forma aceptada de detección de cáncer colorrectal y esta recomendada en adultos a partir de los 75 años en las guías canadienses. Sin embargo, muchas personas de 75 años o más continúan realizándose pruebas inmunoquímicas fecales a pesar de estar fuera de las guías aceptadas.OBJETIVO:Poder determinar si los pacientes de 75 años o más con detección RIF positiva a un cáncer demuestran mejores resultados y sobrevida comparados con los pacientes sin detección.DISEÑO:Estudio de cohortes retrospectivo basado en una población definida.CONFIGURACIÓN:Se recopilaron los datos provinciales del Registro de cánceres y del Programa de detección de cáncer colorrectal de Alberta, Canada, entre 2013 y 2019.PACIENTES:Identificamos una cohorte agregada de pacientes de 75 años o más con diagnóstico de cáncer colorrectal desde noviembre de 2013 hasta noviembre de 2019, así como pacientes de 75 años o más que se sometieron a pruebas inmunoquímicas fecales dentro de las fechas mencionadas.PRINCIPALES MEDIDAS DE RESULTADO:Se calculó la proporción de cánceres colorrectales detectados mediante un cribado. Se analizaron la intervención quirúrgica, la duración de la estadía hospitalaria, la mortalidad post-operatoria y la sobrevida global.RESULTADOS:Entre noviembre de 2013 y noviembre 2019, 3586 pacientes de 75 años o más, fueron diagnosticados con cáncer colorrectal; 690 (19%) fueron detectados por cribado. Los pacientes detectados mediante el cribado, tenían casi tres veces más probabilidades de someterse a una cirugía (Razón de Probabilidad de 2,83) y beneficiaron de una sobrevida general del 36 % (HR 0,64) comparados con los pacientes sin detectación por cribado, corregidos por otras variables como la edad, el índice de comorbilidad de Charlson y el estadío del tumor.LIMITACIONES:El diseño retrospective del presente estudio impide obtener conclusiones con respecto a la causalidad.CONCLUSIONES:La detección por cribado de cáncer colorrectal en pacientes de 75 años o más se asocia con una mejor sobrevida general cuando se controlan los otros posibles factores de confusión. Comparando con las contrapartes no detectadas por cribado, estos pacientes se encuentran en una etapa más temprana de la enfermedad y es más probable que se sometan a una intervención quirúrgica con mejores resultados, independientemente a la edad. Estos datos pueden respaldar la detección de pacientes adecuadamente seleccionados que, de otro modo, quedarían fuera de las pautas actuales. Consulte Video Resumen en http://links.lww.com/DCR/B986 . (Traducción-Dr. Xavier Delgadillo ).
The genetic prehistory of human populations in Central America is largely unexplored leaving an important gap in our knowledge of the global expansion of humans. We report genome-wide ancient DNA ...data for a transect of twenty individuals from two Belize rock-shelters dating between 9,600-3,700 calibrated radiocarbon years before present (cal. BP). The oldest individuals (9,600-7,300 cal. BP) descend from an Early Holocene Native American lineage with only distant relatedness to present-day Mesoamericans, including Mayan-speaking populations. After ~5,600 cal. BP a previously unknown human dispersal from the south made a major demographic impact on the region, contributing more than 50% of the ancestry of all later individuals. This new ancestry derived from a source related to present-day Chibchan speakers living from Costa Rica to Colombia. Its arrival corresponds to the first clear evidence for forest clearing and maize horticulture in what later became the Maya region.
Objective To evaluate the ability of sapropterin dihydrochloride (pharmaceutical preparation of tetrahydrobiopterin) to increase phenylalanine (Phe) tolerance while maintaining adequate blood Phe ...control in 4- to 12-year-old children with phenylketonuria (PKU). Study design This international, double-blind, randomized, placebo-controlled study screened for sapropterin response among 90 enrolled subjects in Part 1. In Part 2, 46 responsive subjects with PKU were randomized (3:1) to sapropterin, 20 mg/kg/d, or placebo for 10 weeks while continuing on a Phe-restricted diet. After 3 weeks, a dietary Phe supplement was added every 2 weeks if Phe control was adequate. Results The mean (±SD) Phe supplement tolerated by the sapropterin group had increased significantly from the pretreatment amount (0 mg/kg/d) to 20.9 (±15.4) mg/kg/d ( P < .001) at the last visit at which subjects had adequate blood Phe control (<360 μmol/L), up to week 10. Over the 10-week period, the placebo group tolerated only an additional 2.9 (±4.0) mg/kg/d Phe supplement; the mean difference from the sapropterin group (±SE) was 17.7 ± 4.5 mg/kg/d ( P < .001). No severe or serious related adverse events were observed. Conclusions Sapropterin is effective in increasing Phe tolerance while maintaining blood Phe control and has an acceptable safety profile in this population of children with PKU.
Abstract
A popular approach to learning about admixture from population genetic data is by computing the allele‐sharing summary statistics known as
f
‐statistics. Compared to some methods in ...population genetics,
f
‐statistics are relatively simple, but interpreting them can still be complicated at times. In addition,
f
‐statistics can be used to build admixture graphs (multi‐population trees allowing for admixture events), which provide more explicit and thorough modelling capabilities but are correspondingly more complex to work with. Here, I discuss some of these issues to provide users of these tools with a basic guide for protocols and procedures. My focus is on the kinds of conclusions that can or cannot be drawn from the results of
f
4
‐statistics and admixture graphs, illustrated with real‐world examples involving human populations.
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