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 ).

Ancient DNA reveals five streams of migration into Micronesia and matrilocality in early Pacific seafarers.

Micronesia began to be peopled earlier than other parts of Remote Oceania, but the origins of its inhabitants remain unclear. We generated genome-wide data from 164 ancient and 112 modern individuals. Analysis reveals five migratory streams into Micronesia. Three are East Asian related, one is Polynesian, and a fifth is a Papuan source related to mainland New Guineans that is different from the New Britain-related Papuan source for southwest Pacific populations but is similarly derived from male migrants ~2500 to 2000 years ago. People of the Mariana Archipelago may derive all of their precolonial ancestry from East Asian sources, making them the only Remote Oceanians without Papuan ancestry. Female-inherited mitochondrial DNA was highly differentiated across early Remote Oceanian communities but homogeneous within, implying matrilocal practices whereby women almost never raised their children in communities different from the ones in which they grew up.

South-to-north migration preceded the advent of intensive farming in the Maya region.

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.

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.

Social stratification without genetic differentiation at the site of Kulubnarti in Christian Period Nubia.

Relatively little is known about Nubia's genetic landscape prior to the influence of the Islamic migrations that began in the late 1st millennium CE. Here, we increase the number of ancient individuals with genome-level data from the Nile Valley from three to 69, reporting data for 66 individuals from two cemeteries at the Christian Period (~650-1000 CE) site of Kulubnarti, where multiple lines of evidence suggest social stratification. The Kulubnarti Nubians had ~43% Nilotic-related ancestry (individual variation between ~36-54%) with the remaining ancestry consistent with being  introduced through Egypt and ultimately deriving from an ancestry pool like that found in the Bronze and Iron Age Levant. The Kulubnarti gene pool - shaped over a millennium - harbors disproportionately female-associated West Eurasian-related ancestry. Genetic similarity among individuals from the two cemeteries supports a hypothesis of social division without genetic distinction. Seven pairs of inter-cemetery relatives suggest fluidity between cemetery groups. Present-day Nubians are not directly descended from the Kulubnarti Nubians, attesting to additional genetic input since the Christian Period.

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.

Three Phases of Ancient Migration Shaped the Ancestry of Human Populations in Vanuatu.

The archipelago of Vanuatu has been at the crossroads of human population movements in the Pacific for the past three millennia. To help address several open questions regarding the history of these movements, we generated genome-wide data for 11 ancient individuals from the island of Efate dating from its earliest settlement to the recent past, including five associated with the Chief Roi Mata's Domain World Heritage Area, and analyzed them in conjunction with 34 published ancient individuals from Vanuatu and elsewhere in Oceania, as well as present-day populations. Our results outline three distinct periods of population transformations. First, the four earliest individuals, from the Lapita-period site of Teouma, are concordant with eight previously described Lapita-associated individuals from Vanuatu and Tonga in having almost all of their ancestry from a "First Remote Oceanian" source related to East and Southeast Asians. Second, both the Papuan ancestry predominating in Vanuatu for the past 2,500 years and the smaller component of Papuan ancestry found in Polynesians can be modeled as deriving from a single source most likely originating in New Britain, suggesting that the movement of people carrying this ancestry to Remote Oceania closely followed that of the First Remote Oceanians in time and space. Third, the Chief Roi Mata's Domain individuals descend from a mixture of Vanuatu- and Polynesian-derived ancestry and are related to Polynesian-influenced communities today in central, but not southern, Vanuatu, demonstrating Polynesian genetic input in multiple groups with independent histories.

Applying f4 -statistics and admixture graphs: Theory and examples.

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.

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.

Interactions between earliest Linearbandkeramik farmers and central European hunter gatherers at the dawn of European Neolithization.

Archaeogenetic research over the last decade has demonstrated that European Neolithic farmers (ENFs) were descended primarily from Anatolian Neolithic farmers (ANFs). ENFs, including early Neolithic central European Linearbandkeramik (LBK) farming communities, also harbored ancestry from European Mesolithic hunter gatherers (WHGs) to varying extents, reflecting admixture between ENFs and WHGs. However, the timing and other details of this process are still imperfectly understood. In this report, we provide a bioarchaeological analysis of three individuals interred at the Brunn 2 site of the Brunn am Gebirge-Wolfholz archeological complex, one of the oldest LBK sites in central Europe. Two of the individuals had a mixture of WHG-related and ANF-related ancestry, one of them with approximately 50% of each, while the third individual had approximately all ANF-related ancestry. Stable carbon and nitrogen isotope ratios for all three individuals were within the range of variation reflecting diets of other Neolithic agrarian populations. Strontium isotope analysis revealed that the ~50% WHG-ANF individual was non-local to the Brunn 2 area. Overall, our data indicate interbreeding between incoming farmers, whose ancestors ultimately came from western Anatolia, and local HGs, starting within the first few generations of the arrival of the former in central Europe, as well as highlighting the integrative nature and composition of the early LBK communities.

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.

The formation of human populations in South and Central Asia.

By sequencing 523 ancient humans, we show that the primary source of ancestry in modern South Asians is a prehistoric genetic gradient between people related to early hunter-gatherers of Iran and Southeast Asia. After the Indus Valley Civilization's decline, its people mixed with individuals in the southeast to form one of the two main ancestral populations of South Asia, whose direct descendants live in southern India. Simultaneously, they mixed with descendants of Steppe pastoralists who, starting around 4000 years ago, spread via Central Asia to form the other main ancestral population. The Steppe ancestry in South Asia has the same profile as that in Bronze Age Eastern Europe, tracking a movement of people that affected both regions and that likely spread the distinctive features shared between Indo-Iranian and Balto-Slavic languages.

Ancient DNA reveals a multistep spread of the first herders into sub-Saharan Africa.

How food production first entered eastern Africa ~5000 years ago and the extent to which people moved with livestock is unclear. We present genome-wide data from 41 individuals associated with Later Stone Age, Pastoral Neolithic (PN), and Iron Age contexts in what are now Kenya and Tanzania to examine the genetic impacts of the spreads of herding and farming. Our results support a multiphase model in which admixture between northeastern African-related peoples and eastern African foragers formed multiple pastoralist groups, including a genetically homogeneous PN cluster. Additional admixture with northeastern and western African-related groups occurred by the Iron Age. These findings support several movements of food producers while rejecting models of minimal admixture with foragers and of genetic differentiation between makers of distinct PN artifacts.

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.

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 genomes document multiple waves of migration in Southeast Asian prehistory.

Southeast Asia is home to rich human genetic and linguistic diversity, but the details of past population movements in the region are not well known. Here, we report genome-wide ancient DNA data from 18 Southeast Asian individuals spanning from the Neolithic period through the Iron Age (4100 to 1700 years ago). Early farmers from Man Bac in Vietnam exhibit a mixture of East Asian (southern Chinese agriculturalist) and deeply diverged eastern Eurasian (hunter-gatherer) ancestry characteristic of Austroasiatic speakers, with similar ancestry as far south as Indonesia providing evidence for an expansive initial spread of Austroasiatic languages. By the Bronze Age, in a parallel pattern to Europe, sites in Vietnam and Myanmar show close connections to present-day majority groups, reflecting substantial additional influxes of migrants.

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

This corrects the article DOI: 10.1038/nature25738.

Population Turnover in Remote Oceania Shortly after Initial Settlement.

Ancient DNA from Vanuatu and Tonga dating to about 2,900-2,600 years ago (before present, BP) has revealed that the "First Remote Oceanians" associated with the Lapita archaeological culture were directly descended from the population that, beginning around 5000 BP, spread Austronesian languages from Taiwan to the Philippines, western Melanesia, and eventually Remote Oceania. Thus, ancestors of the First Remote Oceanians must have passed by the Papuan-ancestry populations they encountered in New Guinea, the Bismarck Archipelago, and the Solomon Islands with minimal admixture [1]. However, all present-day populations in Near and Remote Oceania harbor >25% Papuan ancestry, implying that additional eastward migration must have occurred. We generated genome-wide data for 14 ancient individuals from Efate and Epi Islands in Vanuatu from 2900-150 BP, as well as 185 present-day individuals from 18 islands. We find that people of almost entirely Papuan ancestry arrived in Vanuatu by around 2300 BP, most likely reflecting migrations a few hundred years earlier at the end of the Lapita period, when there is also evidence of changes in skeletal morphology and cessation of long-distance trade between Near and Remote Oceania [2, 3]. Papuan ancestry was subsequently diluted through admixture but remains at least 80%-90% in most islands. Through a fine-grained analysis of ancestry profiles, we show that the Papuan ancestry in Vanuatu derives from the Bismarck Archipelago rather than the geographically closer Solomon Islands. However, the Papuan ancestry in Polynesia-the most remote Pacific islands-derives from different sources, documenting a third stream of migration from Near to Remote Oceania.

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.