An Ancient Harappan Genome Lacks Ancestry from Steppe Pastoralists or Iranian Farmers.

We report an ancient genome from the Indus Valley Civilization (IVC). The individual we sequenced fits as a mixture of people related to ancient Iranians (the largest component) and Southeast Asian hunter-gatherers, a unique profile that matches ancient DNA from 11 genetic outliers from sites in Iran and Turkmenistan in cultural communication with the IVC. These individuals had little if any Steppe pastoralist-derived ancestry, showing that it was not ubiquitous in northwest South Asia during the IVC as it is today. The Iranian-related ancestry in the IVC derives from a lineage leading to early Iranian farmers, herders, and hunter-gatherers before their ancestors separated, contradicting the hypothesis that the shared ancestry between early Iranians and South Asians reflects a large-scale spread of western Iranian farmers east. Instead, sampled ancient genomes from the Iranian plateau and IVC descend from different groups of hunter-gatherers who began farming without being connected by substantial movement of people.

Ancient DNA and deep population structure in sub-Saharan African foragers.

Multiple lines of genetic and archaeological evidence suggest that there were major demographic changes in the terminal Late Pleistocene epoch and early Holocene epoch of sub-Saharan Africa1-4. Inferences about this period are challenging to make because demographic shifts in the past 5,000 years have obscured the structures of more ancient populations3,5. Here we present genome-wide ancient DNA data for six individuals from eastern and south-central Africa spanning the past approximately 18,000 years (doubling the time depth of sub-Saharan African ancient DNA), increase the data quality for 15 previously published ancient individuals and analyse these alongside data from 13 other published ancient individuals. The ancestry of the individuals in our study area can be modelled as a geographically structured mixture of three highly divergent source populations, probably reflecting Pleistocene interactions around 80-20 thousand years ago, including deeply diverged eastern and southern African lineages, plus a previously unappreciated ubiquitous distribution of ancestry that occurs in highest proportion today in central African rainforest hunter-gatherers. Once established, this structure remained highly stable, with limited long-range gene flow. These results provide a new line of genetic evidence in support of hypotheses that have emerged from archaeological analyses but remain contested, suggesting increasing regionalization at the end of the Pleistocene epoch.

Ancient West African foragers in the context of African population history.

Our knowledge of ancient human population structure in sub-Saharan Africa, particularly prior to the advent of food production, remains limited. Here we report genome-wide DNA data from four children-two of whom were buried approximately 8,000 years ago and two 3,000 years ago-from Shum Laka (Cameroon), one of the earliest known archaeological sites within the probable homeland of the Bantu language group1-11. One individual carried the deeply divergent Y chromosome haplogroup A00, which today is found almost exclusively in the same region12,13. However, the genome-wide ancestry profiles of all four individuals are most similar to those of present-day hunter-gatherers from western Central Africa, which implies that populations in western Cameroon today-as well as speakers of Bantu languages from across the continent-are not descended substantially from the population represented by these four people. We infer an Africa-wide phylogeny that features widespread admixture and three prominent radiations, including one that gave rise to at least four major lineages deep in the history of modern humans.

The Beaker phenomenon and the genomic transformation of northwest Europe.

From around 2750 to 2500 bc, Bell Beaker pottery became widespread across western and central Europe, before it disappeared between 2200 and 1800 bc. The forces that propelled its expansion are a matter of long-standing debate, and there is support for both cultural diffusion and migration having a role in this process. Here we present genome-wide data from 400 Neolithic, Copper Age and Bronze Age Europeans, including 226 individuals associated with Beaker-complex artefacts. We detected limited genetic affinity between Beaker-complex-associated individuals from Iberia and central Europe, and thus exclude migration as an important mechanism of spread between these two regions. However, migration had a key role in the further dissemination of the Beaker complex. We document this phenomenon most clearly in Britain, where the spread of the Beaker complex introduced high levels of steppe-related ancestry and was associated with the replacement of approximately 90% of Britain's gene pool within a few hundred years, continuing the east-to-west expansion that had brought steppe-related ancestry into central and northern Europe over the previous centuries.

Erratum: The Beaker phenomenon and the genomic transformation of northwest Europe.

This corrects the article DOI: 10.1038/nature25738.

Improved Survival in a Cohort of Patients Aged 75 Years and Older With Fecal Immunochemical Testing-Detected Colorectal Cancer.

BACKGROUND: 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. OBJECTIVE: 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. DESIGN: This is a retrospective population-based cohort study. SETTINGS: Provincial data were collected from the Alberta Cancer Registry and the Alberta Colorectal Cancer Screening Program between November 2013 and 2019. PATIENTS: 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. MAIN OUTCOME MEASURES: The proportion of screen-detected colorectal cancers was calculated. Surgical intervention, hospital length of stay, postoperative mortality, and overall survival were analyzed. RESULTS: 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. LIMITATIONS: The retrospective study design prevents conclusions regarding causation. CONCLUSIONS: 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 . SOBREVIDA MEJORADA EN UNA COHORTE DE PACIENTES DE AOS O MS CON CNCER COLORRECTAL DETECTADOS POR RIF: 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 ).

Parallel palaeogenomic transects reveal complex genetic history of early European farmers.

Ancient DNA studies have established that Neolithic European populations were descended from Anatolian migrants who received a limited amount of admixture from resident hunter-gatherers. Many open questions remain, however, about the spatial and temporal dynamics of population interactions and admixture during the Neolithic period. Here we investigate the population dynamics of Neolithization across Europe using a high-resolution genome-wide ancient DNA dataset with a total of 180 samples, of which 130 are newly reported here, from the Neolithic and Chalcolithic periods of Hungary (6000-2900 bc, n = 100), Germany (5500-3000 bc, n = 42) and Spain (5500-2200 bc, n = 38). We find that genetic diversity was shaped predominantly by local processes, with varied sources and proportions of hunter-gatherer ancestry among the three regions and through time. Admixture between groups with different ancestry profiles was pervasive and resulted in observable population transformation across almost all cultural transitions. Our results shed new light on the ways in which gene flow reshaped European populations throughout the Neolithic period and demonstrate the potential of time-series-based sampling and modelling approaches to elucidate multiple dimensions of historical population interactions.

Genomic insights into the peopling of the Southwest Pacific.

The appearance of people associated with the Lapita culture in the South Pacific around 3,000 years ago 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. 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.

The Simons Genome Diversity Project: 300 genomes from 142 diverse populations.

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.

The genetic history of Ice Age Europe.

Modern humans arrived in Europe ~45,000 years ago, but little is known about their genetic composition before the start of farming ~8,500 years ago. Here we analyse genome-wide data from 51 Eurasians from ~45,000-7,000 years ago. Over this time, the proportion of Neanderthal DNA decreased from 3-6% to around 2%, consistent with natural selection against Neanderthal variants in modern humans. Whereas there is no evidence of the earliest modern humans in Europe contributing to the genetic composition of present-day Europeans, all individuals between ~37,000 and ~14,000 years ago descended from a single founder population which forms part of the ancestry of present-day Europeans. An ~35,000-year-old individual from northwest Europe represents an early branch of this founder population which was then displaced across a broad region, before reappearing in southwest Europe at the height of the last Ice Age ~19,000 years ago. During the major warming period after ~14,000 years ago, a genetic component related to present-day Near Easterners became widespread in Europe. These results document how population turnover and migration have been recurring themes of European prehistory.

Expanding the phenotype: Four new cases and hope for treatment in Bachmann-Bupp syndrome.

Bachmann-Bupp syndrome (BABS) is a rare syndrome caused by gain-of-function variants in the C-terminus of ornithine decarboxylase (ODC coded by the ODC1 gene). BABS is characterized by developmental delay, macrocephaly, macrosomia, and an unusual pattern of non-congenital alopecia. Recent diagnosis of four more BABS patients provides further characterization of the phenotype of this syndrome including late-onset seizures in the oldest reported patient at 23 years of age, representing the first report for this phenotype in BABS. Neuroimaging abnormalities continue to be an inconsistent feature of the syndrome. This may be related to the yet unknown impact of ODC/polyamine dysregulation on the developing brain in this syndrome. Variants continue to cluster, providing support to a universal biochemical mechanism related to elevated ODC protein, enzyme activity, and abnormalities in polyamine levels. Recommendations for medical management can now be suggested as well as the potential for targeted molecular or metabolic testing when encountering this unique phenotype. The natural history of this syndrome will evolve with difluoromethylornithine (DFMO) therapy and raise new questions for further study and understanding.

A comprehensive genomic history of extinct and living elephants.

Elephantids are the world's most iconic megafaunal family, yet there is no comprehensive genomic assessment of their relationships. We report a total of 14 genomes, including 2 from the American mastodon, which is an extinct elephantid relative, and 12 spanning all three extant and three extinct elephantid species including an ∼120,000-y-old straight-tusked elephant, a Columbian mammoth, and woolly mammoths. Earlier genetic studies modeled elephantid evolution via simple bifurcating trees, but here we show that interspecies hybridization has been a recurrent feature of elephantid evolution. We found that the genetic makeup of the straight-tusked elephant, previously placed as a sister group to African forest elephants based on lower coverage data, in fact comprises three major components. Most of the straight-tusked elephant's ancestry derives from a lineage related to the ancestor of African elephants while its remaining ancestry consists of a large contribution from a lineage related to forest elephants and another related to mammoths. Columbian and woolly mammoths also showed evidence of interbreeding, likely following a latitudinal cline across North America. While hybridization events have shaped elephantid history in profound ways, isolation also appears to have played an important role. Our data reveal nearly complete isolation between the ancestors of the African forest and savanna elephants for ∼500,000 y, providing compelling justification for the conservation of forest and savanna elephants as separate species.

Ancient human genomes suggest three ancestral populations for present-day Europeans.

We sequenced the genomes of a ∼7,000-year-old farmer from Germany and eight ∼8,000-year-old hunter-gatherers from Luxembourg and Sweden. We analysed these and other ancient genomes with 2,345 contemporary humans to show that most present-day Europeans derive from at least three highly differentiated populations: west European hunter-gatherers, who contributed ancestry to all Europeans but not to Near Easterners; ancient north Eurasians related to Upper Palaeolithic Siberians, who contributed to both Europeans and Near Easterners; and early European farmers, who were mainly of Near Eastern origin but also harboured west European hunter-gatherer related ancestry. We model these populations' deep relationships and show that early European farmers had ∼44% ancestry from a 'basal Eurasian' population that split before the diversification of other non-African lineages.

Mutation update for the SATB2 gene.

SATB2-associated syndrome (SAS) is an autosomal dominant neurodevelopmental disorder caused by alterations in the SATB2 gene. Here we present a review of published pathogenic variants in the SATB2 gene to date and report 38 novel alterations found in 57 additional previously unreported individuals. Overall, we present a compilation of 120 unique variants identified in 155 unrelated families ranging from single nucleotide coding variants to genomic rearrangements distributed throughout the entire coding region of SATB2. Single nucleotide variants predicted to result in the occurrence of a premature stop codon were the most commonly seen (51/120 = 42.5%) followed by missense variants (31/120 = 25.8%). We review the rather limited functional characterization of pathogenic variants and discuss current understanding of the consequences of the different molecular alterations. We present an expansive phenotypic review along with novel genotype-phenotype correlations. Lastly, we discuss current knowledge of animal models and present future prospects. This review should help provide better guidance for the care of individuals diagnosed with SAS.

A Working Model of the Deep Relationships of Diverse Modern Human Genetic Lineages Outside of Africa.

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.

Calibrating the Human Mutation Rate via Ancestral Recombination Density in Diploid Genomes.

The human mutation rate is an essential parameter for studying the evolution of our species, interpreting present-day genetic variation, and understanding the incidence of genetic disease. Nevertheless, our current estimates of the rate are uncertain. Most notably, recent approaches based on counting de novo mutations in family pedigrees have yielded significantly smaller values than classical methods based on sequence divergence. Here, we propose a new method that uses the fine-scale human recombination map to calibrate the rate of accumulation of mutations. By comparing local heterozygosity levels in diploid genomes to the genetic distance scale over which these levels change, we are able to estimate a long-term mutation rate averaged over hundreds or thousands of generations. We infer a rate of 1.61 ± 0.13 × 10-8 mutations per base per generation, which falls in between phylogenetic and pedigree-based estimates, and we suggest possible mechanisms to reconcile our estimate with previous studies. Our results support intermediate-age divergences among human populations and between humans and other great apes.

Practice and attitudes regarding double gloving among staff surgeons and surgical trainees.

BACKGROUND: Despite supporting evidence, many staff surgeons and surgical trainees do not routinely double glove. We performed a study to assess rates of and attitudes toward double gloving and the use of eye protection in the operating room. METHODS: We conducted an electronic survey among all staff surgeons and surgical trainees at 2 tertiary care centres in Alberta between September and November 2015.We analyzed the data using log-binomial regression for binary outcomes to account for multiple independent variables and interactions. For 2-group comparisons, we used a 2-group test of proportions. RESULTS: The response rate was 34.3% (361/1051); 205/698 staff surgeons (29.4%) and 156/353 surgical trainees (44.2%) responded. Trainees were more likely than staff surgeons to ever double glove in the operating room (p = 0.01) and to do so routinely (p = 0.01). Staff surgeons were more likely than trainees to never double glove (p = 0.01). A total of 300/353 respondents (85.0%) reported using eye protection routinely in the operating room. Needle-stick injury was common (184 staff surgeons [92.5%], 115 trainees [74.7%]). Reduced tactile feedback, decreased manual dexterity and discomfort/poor fit were perceived barriers to double gloving. CONCLUSION: Rates of double gloving leave room for improvement. Surgical trainees were more likely than staff surgeons to double glove. Barriers remain to routine double gloving among staff surgeons and trainees. Increased education on the benefits of double gloving and early introduction of this practice may increase uptake.

CONTEXTE: Malgré les preuves à l'appui, plusieurs chirurgiens en poste et chirurgiens en formation n'utilisent pas d'emblée le double gantage. Nous avons procédé à une étude pour évaluer le taux d'utilisation du double gantage, les opinions à son endroit et l'utilisation de la protection oculaire au bloc opératoire. MÉTHODES: Nous avons envoyé un sondage électronique à tous les chirurgiens en poste et chirurgiens en formation de 2 centres de soins tertiaires de l'Alberta entre septembre et novembre 2015. Nous avons analysé les données à l'aide d'un modèle de régression logarithmique binomiale pour les résultats binaires afin de tenir compte des variables indépendantes et des interactions. Pour les comparaisons à 2 groupes, nous avons utilisé le test de comparaison de 2 proportions. RÉSULTATS: Le taux de réponse a été de 34,3 % (361/1051); 205 chirurgiens en poste sur 698 (29,4 %) et 156 chirurgiens en formation sur 353 (44,2 %) ont répondu. Au bloc opératoire, les stagiaires étaient plus susceptibles de doubler leurs gants que les chirurgiens en poste (p = 0,01) et de le faire d'emblée (p = 0,01); et les chirurgiens en poste étaient plus susceptibles de ne jamais doubler leurs gants que les stagiaires (p = 0,01). En tout 300 répondeurs sur 353 (85,0 %) ont dit utiliser d'emblée une protection oculaire au bloc opératoire. Les piqûres d'aiguille accidentelles ont été fréquentes (184 chez les chirurgiens en poste [92,5 %], 115 chez les stagiaires [74,7 %]). Une réduction de la sensibilité tactile et de la dextérité manuelle et l'inconfort ou le piètre ajustement ont été les obstacles perçus au double gantage. CONCLUSION: Les taux de double gantage laissent à désirer. Les chirurgiens en formation sont plus susceptibles d'adopter le double gantage que les chirurgiens en poste. Des obstacles continuent de nuire à l'utilisation du double gantage d'emblée, tant chez les chirurgiens en poste que chez les chirurgiens en formation. Une meilleure sensibilisation aux avantages du double gantage et l'introduction de cette pratique dès le début de la formation pourrait faciliter son adoption.

Ancient west Eurasian ancestry in southern and eastern Africa.

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.

Genetic evidence for recent population mixture in India.

Most Indian groups descend from a mixture of two genetically divergent populations: Ancestral North Indians (ANI) related to Central Asians, Middle Easterners, Caucasians, and Europeans; and Ancestral South Indians (ASI) not closely related to groups outside the subcontinent. The date of mixture is unknown but has implications for understanding Indian history. We report genome-wide data from 73 groups from the Indian subcontinent and analyze linkage disequilibrium to estimate ANI-ASI mixture dates ranging from about 1,900 to 4,200 years ago. In a subset of groups, 100% of the mixture is consistent with having occurred during this period. These results show that India experienced a demographic transformation several thousand years ago, from a region in which major population mixture was common to one in which mixture even between closely related groups became rare because of a shift to endogamy.

Postoperative Nonsteroidal Anti-inflammatory Drug Use and Intestinal Anastomotic Dehiscence: A Systematic Review and Meta-Analysis.

BACKGROUND: Nonsteroidal anti-inflammatory drugs are commonly used analgesics in colorectal surgery. Controversy exists regarding the potential association between these drugs and anastomotic dehiscence. OBJECTIVE: This study aimed to determine whether postoperative nonsteroidal anti-inflammatory drug use is associated with intestinal anastomotic dehiscence. DATA SOURCES: PubMed, EMBASE, CENTRAL, and references of included articles were searched without date or language restriction. STUDY SELECTION: Randomized controlled trials and observational studies that compared postoperative nonsteroidal anti-inflammatory drug use with nonuse and reported on intestinal anastomotic dehiscence were selected. INTERVENTION: The use of postoperative nonsteroidal anti-inflammatory drugs relative to placebo or nonuse was investigated. MAIN OUTCOME MEASURES: 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. RESULTS: 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%). LIMITATIONS: 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. CONCLUSIONS: 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.