Paving the Path for Sustainable and Responsible Off-Label Use of Pharmaceutical Products in Europe.

Off-label use of pharmaceuticals involves a wide array of aspects ranging from legal and regulatory ones to clinical to safety considerations. Access to off-label therapies is particularly relevant question for patients in areas of unmet medical need. Simultaneously, off-label use also triggers wider considerations relating to social and economic sustainability of health care systems and access to health. National authorities have adapted different regulatory approaches to off-label use of pharmaceuticals, ranging from (1) "regulatory silence"; to (2) allowing off-label use at the discretion of the treating physician; and to (3) a more stringent approach in which off-label use is subject to third party approval. This article provides a brief overview of these different regulatory approaches from a helicopter perspective, and it discusses benefits and shortcomings these approaches. Finally, it presents ideas for preconditions for sustainable and responsible off-label use of pharmaceutical products to ensure patient safety whilst ensuring their timely access to health.

Comparison between Inbreeding Analyses Methodologies.

Surnames are widely used in inbreeding analysis, but the validity of results has often been questioned due to the failure to comply with the prerequisites of the method. Here we analyze inbreeding in Hallstatt (Austria) between the 17th and the 19th centuries both using genealogies and surnames. The high and significant correlation of the results obtained by both methods demonstrates the validity of the use of surnames in this kind of studies. On the other hand, the inbreeding values obtained (0.24 x 10⁻³ in the genealogies analysis and 2.66 x 10⁻³ in the surnames analysis) are lower than those observed in Europe for this period and for this kind of population, demonstrating the falseness of the apparent isolation of Hallstatt's population. The temporal trend of inbreeding in both analyses does not follow the European general pattern, but shows a maximum in 1850 with a later decrease along the second half of the 19th century. This is probably due to the high migration rate that is implied by the construction of transport infrastructures around the 1870's.

Craniometric evidence for Palaeoamerican survival in Baja California.

A current issue on the settlement of the Americas refers to the lack of morphological affinities between early Holocene human remains (Palaeoamericans) and modern Amerindian groups, as well as the degree of contribution of the former to the gene pool of the latter. A different origin for Palaeoamericans and Amerindians is invoked to explain such a phenomenon. Under this hypothesis, the origin of Palaeoamericans must be traced back to a common ancestor for Palaeoamericans and Australians, which departed from somewhere in southern Asia and arrived in the Australian continent and the Americas around 40,000 and 12,000 years before present, respectively. Most modern Amerindians are believed to be part of a second, morphologically differentiated migration. Here we present evidence of a modern Amerindian group from the Baja California Peninsula in Mexico, showing clearer affinities with Palaeoamerican remains than with modern Amerindians. Climatic changes during the Middle Holocene probably generated the conditions for isolation from the continent, restricting the gene flow of the original group with northern populations, which resulted in the temporal continuity of the Palaeoamerican morphological pattern to the present.

The influence of masticatory loading on craniofacial morphology: A test case across technological transitions in the Ohio valley.

Masticatory loading is one of the main environmental stimuli that generate craniofacial variation among recent humans. Experimental studies on a wide variety of mammals, including those with retrognathic postcanine teeth, predict that responses to masticatory loading will be greater in the occlusal plane, the inferior rostrum, and regions associated with the attachments of the temporalis and masseter muscles. Here we test these experimentally-derived predictions on an extinct human population from the middle and upper Ohio valley that underwent a marked shift from hunting-gathering to extensive farming during the last 3,000 years and for which we have good archaeological evidence about diet and food processing technology. Geometric morphometric methods were used to detect and measure the putative effect of diet changes on cranial shape independent of size. Our results partially confirm only some of the experimental predictions. The effect of softer and/or less tough diets on craniofacial shape seem to be concentrated in the relative reduction of the temporal fossa and in a displacement of the attachment of the temporal muscle. However, there were few differences in craniofacial shape in regions closer to the occlusal plane. These results highlight the utility of exploring specific localized morphological shifts using a hierarchical model of craniofacial integration.

Heritability of human cranial dimensions: comparing the evolvability of different cranial regions.

Quantitative craniometrical traits have been successfully incorporated into population genetic methods to provide insight into human population structure. However, little is known about the degree of genetic and non-genetic influences on the phenotypic expression of functionally based traits. Many studies have assessed the heritability of craniofacial traits, but complex patterns of correlation among traits have been disregarded. This is a pitfall as the human skull is strongly integrated. Here we reconsider the evolutionary potential of craniometric traits by assessing their heritability values as well as their patterns of genetic and phenotypic correlation using a large pedigree-structured skull series from Hallstatt (Austria). The sample includes 355 complete adult skulls that have been analysed using 3D geometric morphometric techniques. Heritability estimates for 58 cranial linear distances were computed using maximum likelihood methods. These distances were assigned to the main functional and developmental regions of the skull. Results showed that the human skull has substantial amounts of genetic variation, and a t-test showed that there are no statistically significant differences among the heritabilities of facial, neurocranial and basal dimensions. However, skull evolvability is limited by complex patterns of genetic correlation. Phenotypic and genetic patterns of correlation are consistent but do not support traditional hypotheses of integration of the human shape, showing that the classification between brachy- and dolicephalic skulls is not grounded on the genetic level. Here we support previous findings in the mouse cranium and provide empirical evidence that covariation between the maximum widths of the main developmental regions of the skull is the dominant factor of integration in the human skull.

Detection of a population replacement at the Classic-Postclassic transition in Mexico.

The Mexica Empire reached an outstanding social, economic and politic organization among Mesoamerican civilizations. Even though archaeology and history provide substantial information about their past, their biological origin and the demographic consequences of their settlement in the Central Valley of Mexico remain unsolved. Two main hypotheses compete to explain the Mexica origin: a social reorganization of the groups already present in the Central Valley after the fall of the Classic centres or a population replacement of the Mesoamerican groups by migrants from the north and the consequent setting up of the Mexica society. Here, we show that the main changes in the facial phenotype occur during the Classic-Postclassic transition, rather than in the rise of the Mexica. Furthermore, Mexica facial morphology seems to be already present in the early phases of the Postclassic epoch and is not related to the northern facial pattern. A combination of geometric morphometrics with Relethford-Blangero analyses of within- versus among-group variation indicates that Postclassic groups are more variable than expected. This result suggests that intense gene exchange was likely after the fall of the Classic and maybe responsible for the Postclassic facial phenotype. The source population for the Postclassic groups could be located somewhere in western Mesoamerica, since North Mexico and Central Mesoamerican Preclassic and Classic groups are clearly divergent from the Postclassic ones. Similarity among Preclassic and Classic groups and those from Aridoamerica could be reflecting the ancestral phenotypic pattern characteristic of the groups that first settled Mesoamerica.

Twin seasonality in a rural Catalonian population.

The seasonality of twinning in the Spanish populations has not been studied until now. Differences between seasonal distribution of the twin conceptions and those of the single births have been observed in other populations. The aim of this work is to explore the frequency of twinning in a rural population from Catalonia during the nineteenth century, as well as the seasonality patterns characterizing each of the twinning types. Data corresponding to all births recorded at Tortosa (South Catalonia) from 1801 to 1900 have been analyzed in order to study the twinning distribution. The distribution of the moving averages of the monthly rates of twins shows a peak in autumn. Twinning distribution differs from the total births' distribution in Tortosa. This fact is very clear in the case of unlike-sexed twins that have their greater incidence in the last quarter of the year, while the total maternities have their peak in the first one.

Pervasive genetic integration directs the evolution of human skull shape.

It has long been unclear whether the different derived cranial traits of modern humans evolved independently in response to separate selection pressures or whether they resulted from the inherent morphological integration throughout the skull. In a novel approach to this issue, we combine evolutionary quantitative genetics and geometric morphometrics to analyze genetic and phenotypic integration in human skull shape. We measured human skulls in the ossuary of Hallstatt (Austria), which offer a unique opportunity because they are associated with genealogical data. Our results indicate pronounced covariation of traits throughout the skull. Separate simulations of selection for localized shape changes corresponding to some of the principal derived characters of modern human skulls produced outcomes that were similar to each other and involved a joint response in all of these traits. The data for both genetic and phenotypic shape variation were not consistent with the hypothesis that the face, cranial base, and cranial vault are completely independent modules but relatively strongly integrated structures. These results indicate pervasive integration in the human skull and suggest a reinterpretation of the selective scenario for human evolution where the origin of any one of the derived characters may have facilitated the evolution of the others.

Genetic relationships between parishes in the Ebro delta region (Spain) as estimated by migration matrix and surnames.

To determine whether there are preferential relationships among individuals from the different parishes of the Ebro River delta region, we analyzed the population relationships, taking into account both the birthplaces of the spouses and their surname frequencies. We used data from the 9,085 marriages recorded in the Ebro delta area between 1939 and 1995. Using each spouse's birthplace, we calculated the distances between the subject populations by means of the squared Euclidean distance. Also, from the surname frequencies in the marriages we obtained certain kinship measurements. In both analyses the results show a clear differentiation between the parish of Amposta and the rest of the parishes. This difference is mainly due to a greater number of marriages in which delta outsiders participated and can be related to the greater surname diversity and lesser endogamy observed in this population. On the other hand, if only endogamous marriages are taken into account, there is clearly a differentiation between the parishes from both banks of the river, with a strong homogeneity among the northside parishes. We compared the distances obtained from the birthplaces, the kinship parameters obtained from the surnames, and two geographic distance matrixes by means of a Mantel test, and the results show a strong and significant correlation between them when all marriages are considered. If, on the other hand, only endogamous marriages are taken into account, the barrier effect of the river on the interparish relationships can be appreciated.

Inbreeding from isonymy and repeated pairs of surnames in the Ebro Delta region (Tarragona, Spain).

The aim of the study was to evaluate the levels of inbreeding calculated from isonymy with its random (Fr) and nonrandom (Fn) components, and repeated pairs of surnames (RP2) and their random component (RP2r) in the Ebro River Delta region (Tarragona, Spain). This region is made up of four parishes, and data correspond to the period 1939-1995. The global results are on the same levels as observed in other studies, but the values obtained in 3 of 4 parishes are relatively high. The Fn global value is higher than Fr, as opposed to what happens in each parish, so there is a clear Wahlund effect of subdivision of the region into parishes. Among the parishes there is a clear differentiation for Amposta, with values much lower than for the rest, due to the behavior of this population, i.e., a high immigration rate.

Phenotypic evolution of human craniofacial morphology after admixture: a geometric morphometrics approach.

An evolutionary, diachronic approach to the phenotypic craniofacial pattern arisen in a human population after high levels of admixture and gene flow was achieved by means of geometric morphometrics. Admixture has long been studied after molecular data. Nevertheless, few efforts have been made to explain the morphological outcome in human craniofacial samples. The Spanish-Amerindian contact can be considered a good scenario for such an analysis. Here we present a comparative analysis of craniofacial shape changes observed between two putative ancestor groups, Spanish and precontact Aztecs, and two diachronic admixed groups, corresponding to early and late colonial periods from the Mexico's Central Valley. Quantitative shape comparisons of Amerindian, Spanish, and admixed groups were used to test the expectations of quantitative genetics for admixture events. In its simplest form, this prediction states that an admixed group will present phenotypic values falling between those of both parental groups. Results show that, in general terms, although the human skull is a complex, integrated structure, the craniofacial morphology observed fits the theoretical expectations of quantitative genetics. Thus, it is predictive of population structure and history. In fact, results obtained after the craniofacial analysis are in accordance with previous molecular and historical interpretations, providing evidence that admixture is a main microevolutionary agent influencing modern Mexican gene pool. However, expectations are not straightforward when moderate shape changes are considered. Deviations detected at localized structures, such as the upper and lower face, highlight the evolution of a craniofacial pattern exclusively inherent to the admixed groups, indicating that quantitative characters might respond to admixture in a complicated, nondirectional way.

Functional-cranial approach to the influence of economic strategy on skull morphology.

Environmental factors are assumed to play an important role in the shaping of craniofacial morphology. Here we propose a statistical approach which can be of utility in estimating the magnitude and localization of a particular nongenetic factor upon the specific functional components of the skull. Our analysis is a combination of previous attempts of apportionment of variance and the application of craniofunctional theory. The effect of subsistence strategy on craniofacial functional components was studied on 18 populations of hunter-gatherers and farmers from South America. Results demonstrate that the environmental factors studied likely influenced the masticatory component's size and shape. Even when this effect is not large enough to clearly differentiate among subsistence strategies (since whole craniofacial variation among populations remains greater), the method used here provides interesting clues to localize plastic or adaptive responses to external stimuli.

Origin of Fueguian-Patagonians: an approach to population history and structure using R matrix and matrix permutation methods.

A complicated history of isolation between Fueguian and Patagonian groups (originated by the appearance of the Straits of Magellan) as much as differences in population structure and life strategies constitute important factors in the clustering pattern of those groups. The aim of this work was to test several hypotheses about population structure and history of Fueguian-Patagonians to propose a model that incorporates predictions for future studies. R matrix methods and matrix permutation analyses were performed upon a data matrix of craniofacial measurements of 441 skulls divided into nine samples pertaining to six Patagonian and three Fueguian populations. Association of biological distances with three matrices representing several settlement patterns was tested using matrix permutation tests. Results of R matrix study show that the minimum genetic distance obtained confirms separation between Fueguians and Patagonians. Moreover, an analysis of residual variances from the expected regression line confirms admixture between Andean and Pampean populations and Araucanian groups, consistent with ethnohistorical observations. A model representing a long history of isolation between Fueguian and Patagonians, rather than a model emphasizing differences in life-strategies, presented the best correlation with the biological distance matrix. Because similar results were already obtained in archaeological, molecular, and morphological studies, a model for the settlement of Tierra del Fuego is proposed. It is summarized by four main hypotheses that can be tested independently by different disciplines in the future.

Patterns of phenotypic covariation and correlation in modern humans as viewed from morphological integration.

Proportionality of phenotypic and genetic distance is of crucial importance to adequately focus on population history and structure, and it depends on the proportionality of genetic and phenotypic covariance. Constancy of phenotypic covariances is unlikely without constancy of genetic covariation if the latter is a substantial component of the former. If phenotypic patterns are found to be relatively stable, the most probable explanation is that genetic covariance matrices are also stable. Factors like morphological integration account for such stability. Morphological integration can be studied by analyzing the relationships among morphological traits. We present here a comparison of phenotypic correlation and covariance structure among worldwide human populations. Correlation and covariance matrices between 47 cranial traits were obtained for 28 populations, and compared with design matrices representing functional and developmental constraints. Among-population differences in patterns of correlation and covariation were tested for association with matrices of genetic distances (obtained after an examination of 10 Alu-insertions) and with Mahalanobis distances (computed after craniometrical traits). All matrix correlations were estimated by means of Mantel tests. Results indicate that correlation and covariance structure in our species is stable, and that among-group correlation/covariance similarity is not related to genetic or phenotypic distance. Conversely, genetic and morphological distance matrices were highly correlated. Correlation and covariation patterns were largely associated with functional and developmental factors, which probably account for the stability of covariance patterns.