Absence of evidence for increase in risk for autism or attention-deficit hyperactivity disorder following antidepressant exposure during pregnancy: a replication study.

Multiple studies have examined the risk of prenatal antidepressant exposure and risk for autism spectrum disorder (ASD) or attention-deficit hyperactivity disorder (ADHD), with inconsistent results. Precisely estimating such risk, if any, is of great importance in light of the need to balance such risk with the benefit of depression and anxiety treatment. We developed a method to integrate data from multiple New England health systems, matching offspring and maternal health data in electronic health records to characterize diagnoses and medication exposure. Children with ASD or ADHD were matched 1:3 with children without neurodevelopmental disorders. Association between maternal antidepressant exposure and ASD or ADHD liability was examined using logistic regression, adjusting for potential sociodemographic and psychiatric confounding variables. In new cohorts of 1245 ASD cases and 1701 ADHD cases, along with age-, sex- and socioeconomic status matched controls, neither disorder was significantly associated with prenatal antidepressant exposure in crude or adjusted models (adjusted odds ratio 0.90, 95% confidence interval 0.50-1.54 for ASD; 0.97, 95% confidence interval 0.53-1.69 for ADHD). Pre-pregnancy antidepressant exposure significantly increased risk for both disorders. These results suggest that prior reports of association between prenatal antidepressant exposure and neurodevelopmental disease are likely to represent a false-positive finding, which may arise in part through confounding by indication. They further demonstrate the potential to integrate data across electronic health records studies spanning multiple health systems to enable efficient pharmacovigilance investigation.

The foot of Homo naledi.

Modern humans are characterized by a highly specialized foot that reflects our obligate bipedalism. Our understanding of hominin foot evolution is, although, hindered by a paucity of well-associated remains. Here we describe the foot of Homo naledi from Dinaledi Chamber, South Africa, using 107 pedal elements, including one nearly-complete adult foot. The H. naledi foot is predominantly modern human-like in morphology and inferred function, with an adducted hallux, an elongated tarsus, and derived ankle and calcaneocuboid joints. In combination, these features indicate a foot well adapted for striding bipedalism. However, the H. naledi foot differs from modern humans in having more curved proximal pedal phalanges, and features suggestive of a reduced medial longitudinal arch. Within the context of primitive features found elsewhere in the skeleton, these findings suggest a unique locomotor repertoire for H. naledi, thus providing further evidence of locomotor diversity within both the hominin clade and the genus Homo.

Prenatal antidepressant exposure is associated with risk for attention-deficit hyperactivity disorder but not autism spectrum disorder in a large health system.

Previous studies suggested that risk for Autism Spectrum Disorder (ASD) may be increased in children exposed to antidepressants during the prenatal period. The disease specificity of this risk has not been addressed and the possibility of confounding has not been excluded. Children with ASD or attention-deficit hyperactivity disorder (ADHD) delivered in a large New England health-care system were identified from electronic health records (EHR), and each diagnostic group was matched 1:3 with children without ASD or ADHD. All children were linked with maternal health data using birth certificates and EHRs to determine prenatal medication exposures. Multiple logistic regression was used to examine association between prenatal antidepressant exposures and ASD or ADHD risk. A total of 1377 children diagnosed with ASD and 2243 with ADHD were matched with healthy controls. In models adjusted for sociodemographic features, antidepressant exposure prior to and during pregnancy was associated with ASD risk, but risk associated with exposure during pregnancy was no longer significant after controlling for maternal major depression (odds ratio (OR) 1.10 (0.70-1.70)). Conversely, antidepressant exposure during but not prior to pregnancy was associated with ADHD risk, even after adjustment for maternal depression (OR 1.81 (1.22-2.70)). These results suggest that the risk of autism observed with prenatal antidepressant exposure is likely confounded by severity of maternal illness, but further indicate that such exposure may still be associated with ADHD risk. This risk, modest in absolute terms, may still be a result of residual confounding and must be balanced against the substantial consequences of untreated maternal depression.

Using electronic medical records to enable large-scale studies in psychiatry: treatment resistant depression as a model.

BACKGROUND: Electronic medical records (EMR) provide a unique opportunity for efficient, large-scale clinical investigation in psychiatry. However, such studies will require development of tools to define treatment outcome. METHOD: Natural language processing (NLP) was applied to classify notes from 127 504 patients with a billing diagnosis of major depressive disorder, drawn from out-patient psychiatry practices affiliated with multiple, large New England hospitals. Classifications were compared with results using billing data (ICD-9 codes) alone and to a clinical gold standard based on chart review by a panel of senior clinicians. These cross-sectional classifications were then used to define longitudinal treatment outcomes, which were compared with a clinician-rated gold standard. RESULTS: Models incorporating NLP were superior to those relying on billing data alone for classifying current mood state (area under receiver operating characteristic curve of 0.85-0.88 v. 0.54-0.55). When these cross-sectional visits were integrated to define longitudinal outcomes and incorporate treatment data, 15% of the cohort remitted with a single antidepressant treatment, while 13% were identified as failing to remit despite at least two antidepressant trials. Non-remitting patients were more likely to be non-Caucasian (p<0.001). CONCLUSIONS: The application of bioinformatics tools such as NLP should enable accurate and efficient determination of longitudinal outcomes, enabling existing EMR data to be applied to clinical research, including biomarker investigations. Continued development will be required to better address moderators of outcome such as adherence and co-morbidity.

Makers of the early Aurignacian of Europe.

Despite intensive study and a number of remarkable discoveries in the last two decades of the 20th century, our understanding of the cultural and biological processes that resulted in the emergence of the Upper Paleolithic and the establishment of modern humans in Interpleniglacial Europe remains far from complete. There is active debate concerning the timing and location of the origins of the Aurignacian, the nature of the origins of Initial Upper Paleolithic industries (whether by autochthonous development or through acculturation by Aurignacian peoples), the timing of the appearance of early modern humans and the disappearance of the Neandertals, and the relationship of archeologically defined cultures to these different types of hominids. Frustrating our attempts to address these latter two questions is a general paucity of taxonomically diagnostic human fossil material from early Upper Paleolithic contexts. We undertake here a review of the human fossil record of Interpleniglacial Europe, and its archeological and chronological context, to clarify to the extent possible the nature of the relationship between hominid groups and the earliest Upper Paleolithic artifact industries, particularly the early Aurignacian. Although substantial difficulties involved in interpreting the fossil, archeological, and geochronological records of this time period prohibit making any definitive statements, a number of observations are suggested by the current data: 1) the Middle Paleolithic of Europe appears to have been made exclusively by Neandertals; 2) Initial Upper Paleolithic industries (with the exception of the Bachokirian) appear to have their roots in the late Middle Paleolithic industries of their respective regions; 3) all of the human fossils yet recovered from Initial Upper Paleolithic (except the Bachokirian) contexts for which any diagnostic morphology is present have their greatest morphological affinities with Neandertals and not early modern humans; 4) modern humans were almost certainly established in Europe by ca. 32 ky BP, with a strong possibility that they were there by ca. 36 ky BP. Claims for an appearance before 36 ky BP cannot be substantiated with currently available evidence; 5) the hypothesis that modern humans are uniquely associated with the Aurignacian cannot yet be refuted. Aurignacian-associated human fossils (including those from the Bachokirian) for which any diagnostic morphology is present have their greatest affinities with early modern Europeans and not Neandertals; and 6) Neandertals and modern humans coexisted in Europe for at least 2,000-4,000 years, and perhaps for 8,000-10,000 years or longer. The overall picture is one of an extended period of cultural contact, involving some degree of genetic exchange, between Neandertals and early modern Europeans.

A modern human humerus from the early aurignacian of Vogelherdhöhle (Stetten, Germany).

Implicit in much of the discussion of the cultural and population biological dynamics of modern human origins in Europe is the assumption that the Aurignacian, from its very start, was made by fully modern humans. The veracity of this assumption has been challenged in recent years by the association of Neandertal skeletal remains with a possibly Aurignacian assemblage at Vindija Cave (Croatia) and the association of Neandertals with distinctly Upper Paleolithic (but non-Aurignacian) assemblages at Arcy-sur-Cure and St. C¿esaire (France). Ideally we need human fossil material that can be confidently assigned to the early Aurignacian to resolve this issue, yet in reality there is a paucity of well-provenanced human fossils from early Upper Paleolithic contexts. One specimen, a right humerus from the site of Vogelherd (Germany), has been argued, based on its size, robusticity, and muscularity, to possibly represent a Neandertal in an Aurignacian context. The morphological affinities of the Vogelherd humerus were explored by univariate and multivariate comparisons of humeral epiphyseal and diaphyseal shape and strength measures relative to humeri of Neandertals and Early Upper Paleolithic (later Aurignacian and Gravettian) modern humans. On the basis of diaphyseal cross-sectional geometry, deltoid tuberosity morphology, and distal epiphyseal morphology, the specimen falls clearly and consistently with European early modern humans and not with Neandertals. Along with the other Vogelherd human remains, the Vogelherd humerus represents an unequivocal association between the Aurignacian and modern human morphology in Europe.

Locomotion and body proportions of the Saint-Césaire 1 Châtelperronian Neandertal.

The initial Upper Paleolithic (Châtelperronian) of western Europe was associated with late European Neandertals, best known through the Saint-Césaire 1 partial skeleton. Biomechanical cross-sectional analysis of the Saint-Césaire 1 femoral diaphysis at the subtrochanteric and midshaft levels, given the plasticity of mammalian diaphyseal cortical bone, provides insights into the habitual levels and patterns of loading on the lower limbs from body mass, proportions, and locomotion. The overall robustnesses of the femoral diaphyses of European Neandertals and early modern humans are similar once contrasts in body proportions are incorporated into the body size scaling. Saint-Césaire 1 matches these samples only if it is provided with Neandertal-like hyperarctic body proportions. And the rounded proximal femoral diaphysis of Saint-Césaire 1 is similar to those of earlier Neandertals, likely also reflecting similar cold-adapted broad pelvic regions. However, although morphologically similar to those of archaic Homo, the Saint-Césaire 1 femoral midshaft exhibits the anteroposterior reinforcement characteristic of early modern humans. Consequently, Saint-Césaire 1 appears as a morphological Neandertal with hyperarctic body proportions who nonetheless had shifted locomotor patterns to more closely resemble those of other Upper Paleolithic humans.

EMG of the human flexor pollicis longus muscle: implications for the evolution of hominid tool use.

Modern humans possess a distinct and well-developed flexor pollicis longus muscle, an extrinsic thumb flexor which is "either rudimentary or absent" in great apes (Straus, 1942, p. 228). Previous workers (e.g., Napier, 1962; Susman, 1988) have related the origin of a well-developed flexor pollicis longus muscle to the acquisition of precision grasping and stone tool making capabilities in early hominids. The proposed functional association between flexor pollicis longus activity, precision grasping, and stone tool manufacture has, however, never been tested experimentally. This study uses electromyographic techniques (EMG) to investigate the role of flexor pollicis longus during a variety of tool making, tool using, and manipulatory behaviors in order to determine the functional and evolutionary significance of the human flexor pollicis longus muscle. Our results indicate that flexor pollicis longus is recruited during forceful tool using and stone tool making behaviors, regardless of the power or precision grip used to hold the tool. In particular, both stone tool use and stone tool making employing three- and four-jaw chuck precision grips elicit consistently high levels of FPL activity. Flexor pollicis longus activity increases most when resistance is increased to the thumb's volar pad during these hammering, cutting, and knapping behaviors. In contrast, we observed relatively low levels of flexor pollicis longus activity during the fine manipulation of food items, the making of slender wooden probes, and the use of these probes as tools. The paleontological, archaeological, and experimental data suggest that a well-developed flexor pollicis longus muscle functioned initially in the hominid lineage to stabilize the terminal pollical phalanx against loads applied to the thumb's apical pad during the frequent and forceful use of unmodified stones as tools.

Identification of Euro-Americans, Afro-Americans, and Amerindians from palatal dimensions.

Seven measurements were taken on 414 Euro-American, Afro-American, and Amerindian palates in an attempt to evaluate differences in dental arcade shape among these three groups. Width measurements across the palate at the first incisor, canine, second premolar, and second molar were taken directly on the dental arcade. The distances along the sagittal plane from the front of the palate to the level of these teeth were calculated from measurements taken between the right central incisor and the canine, second premolar and second molar. Discriminant functions computed from the measurements properly classified palates by group 66.0% of the time if sex is unknown. If sex is known to be male, other functions properly classified 65.7% of the sample; for sex known to be female 72.0% correct classification was achieved. Because these percentage are more than twice that expected from probability theory alone, it is concluded that the seven measurements are useful in determining ethnic group.

Particulate versus integrated evolution of the upper body in late pleistocene humans: a test of two models.

Evolutionary biologists are largely polarized in their approaches to integrating microevolutionary and macroevolutionary processes. Neo-Darwinians typically seek to identify population-level selective and genetic processes that culminate in macroevolutionary events. Epigeneticists and structuralists, on the other hand, emphasize developmental constraints on the action of natural selection, and highlight the role of epigenetic shifts in producing evolutionary change in morphology. Accordingly, the ways in which these paradigms view and address morphological contrasts between classes of related organisms differ. These paradigms, although seldomly explicitly stated, emerge in paleoanthropology as well. Considerations of postcranial morphological contrasts between archaic and modern humans typically fall into one of two broad interpretive models. The first derives from the neo-Darwinian perspective and holds that evolution in the postcranial skeleton was largely mosaic (operating in a particulate manner), and that temporal change in specific traits informs us about behavioral shifts or genetic evolution affecting isolated anatomical regions (i.e., adaptive behavioral inferences can be made from comparative studies of individual trait complexes). The alternative model follows from the epigeneticist paradigm and sees change in specific postcranial traits as correlated responses to change in overall body form (involving shifts in regulation of skeletal growth, or selective and developmental responses to broad adaptive shifts). By this view, integration of functional systems both constrains and directs evolution of various traits, and morphological contrasts inform us about overall change in body form related to change in such things as overall growth patterns, climatic adaptation, and technological dependency. These models were tested by confirmatory factor analysis using measures of upper body form and upper limb morphological traits in Eurasian Neandertal and early modern fossils and recent human samples. Results indicate (1) a model of morphological integration fits the data better than a model of no integration, but (2) this integration accounts for less than half of the variance in upper limb traits, suggesting a high degree of tolerance for particulate evolution in the context of an integrated upper body plan. Significant relationships were detected between joint shapes and body size, between humeral shaft shape and body size and chest shape, and between measures of biomechanical efficiency and robusticity. The observed morphological differences between late archaic and early modern humans reflect particulate evolution in the context of constraints imposed by genetic and morphological integration. While particulate approaches to interpreting the fossil record appear to be justified, attention must also be paid to delineating the nature and extent of morphological integration and its role in both constraining and producing observed patterns of variation between groups. Confirmatory factor analysis provides a means of examining trait covariance matrices, and serves as a useful method of identifying patterns of integration in morphology.

Postcranial robusticity in Homo. II: Humeral bilateral asymmetry and bone plasticity.

The analysis of humeral asymmetry in Recent human skeletal samples and an extant tennis-player sample documents minimal asymmetry in bone length, little asymmetry in distal humeral articular breadth, but pronounced and variable asymmetry in mid- and distal diaphyseal cross-sectional geometric parameters. More specifically, skeletal samples of normal modern Euroamericans, prehistoric and early historic Amerindians, and prehistoric Japanese show moderate (ca. 5-14%) median asymmetry in diaphyseal cross-sectional areas and polar second moments of area, whereas the tennis-player sample, with pronounced unilateral physical activity, exhibits median asymmetries of 28-57% in the same parameters. A sample of Neandertals with nonpathological upper limbs exhibits similarly low articular asymmetry but pronounced diaphyseal asymmetries, averaging 24-57%. In addition, three Neandertals with actual or possible post-traumatic upper limb alterations have the same low articular asymmetry but extremely high diaphyseal asymmetries, averaging 112-215%. These data support those from experimental work on animals, exercise programs of humans, and human clinical contexts in establishing the high degree of diaphyseal plasticity possible for humans, past and present, under changing biomechanical loading conditions. This lends support to activity-related functional interpretations of changing human diaphyseal morphology and robusticity during the Pleistocene.

Renal response to 7 days of lower body positive pressure in squirrel monkeys.

The purpose of this study was to characterize the renal response to central volume expansion using lower body positive pressure (LBPP) in the adult male squirrel monkey (Saimiri sciureus). Urinary excretion of sodium, potassium, and water and plasma aldosterone concentrations were measured during a control day, 7 days of LBPP, and a recovery day. Time control experiments in the same animals included chair sitting without exposure to LBPP. Seven monkeys (600-1,000 g) were trained to sit in a specially designed metabolism chair before chronic implantation of arterial and venous catheters to facilitate maintenance infusion of saline, monitoring of vascular pressures, and blood sampling; urine was collected via a condomlike tube. A cephalad shift in body fluid was induced by applying 20 mmHg of air pressure from the waist down. Urine volume and sodium excretion were increased significantly (28 to 52 ml/day and 0.4 to 3.5 meq/day, respectively) during the initial 24 h of LBPP with most of this response occurring in the first 6-12 h. From the 2nd to the 7th day of LBPP, urinary excretion rates for sodium and water were not different from chair-sitting controls. Water and sodium balance significantly decreased from +15 to -12 ml/day and from +1.1 to -2.2 meq/day, respectively, from the control to the first day of LBPP. This change in balance was not observed in the time-control group. Removal of the stimulus resulted in a modest conservation of sodium and water. The renal responses were not associated with any changes in plasma aldosterone levels.(ABSTRACT TRUNCATED AT 250 WORDS)

Neandertal scapular glenoid morphology.

Analysis of Neandertal and recent human scapular glenoid fossae reveals that the former had long, narrow, and flat glenoid articular surfaces relative to those of modern humans. Comparison of glenoid length, breadth, and curvature to humeral articular dimensions demonstrates that Neandertal glenoid length and curvature scale to proximal and distal humeral articular dimensions in the same manner as those of modern humans. The remaining contrast is in the relatively greater glenoid fossa width seen in modern humans. This difference in morphology implies differences in the habitual degree of dorsoventral glenohumeral movement between Neandertals and modern humans. This in turn may be related to contrasts in tool use, especially with respect to throwing and projectile use.

Neandertal radial tuberosity orientation.

Examination of adult and immature Neandertal radii demonstrates that the medial versus anterior orientations of their radial tuberosities fall within recent human ranges of variation, but on the average their radial tuberosities are significantly more medially, as opposed to anteromedially, oriented. This more posterior positioning of their radial tuberosities implies a maintenance of an effective moment arm for M. biceps brachii through the full range of supination, an interpretation which fits with the hypertrophy of and increased moment arms for their forearm pronator muscles. It is an additional indication of the muscular hypertrophy evident elsewhere in Neandertal upper limbs.

Renal function in the term pregnant rat: a micropuncture study.

The purpose of this study was to define individual nephron function and salt and fluid reabsorption in the term pregnant rat utilizing standard micropuncture techniques. The studies were performed at the time of maximal sodium retention and when extracellular fluid volume was significantly increased. During micropuncture in 7 pregnant and 9 non-pregnant rats, we found no difference, respectively, in GFR 1.04 +/- 0.06 vs. 1.13 +/- 0.06 ml/min/kidney or nephron GFR 35 +/- 0.9 vs. 33 +/- 1 ml/min. Fractional and absolute Na reabsorption was also not significantly different in the proximal tubule or the loop of Henle. Along the distal tubule, fractional reabsorption was higher in pregnancy, 71 +/- 3 vs. 62 +/- 4 but not statistically different, 0.05 less than p less than 0.10. Beyond the late distal tubule absolute delivery and reabsorption were greater in the nonpregnant rats. Distal nephron potassium secretion was similar in both groups. In anesthetized rats during clearance studies but without surgery for micropuncture, GFR in the pregnant group was significantly higher than the nonpregnant rats, 1.65 +/- 0.06 vs. 1.28 +/- 1.10 ml/min/kidneys as was tubular reabsorption of sodium. We conclude that pregnant rats exhibit glomerular tubular balance and that potassium handling along the superficial nephron is unaffected by pregnancy. The sodium retention of pregnancy appears to occur because of the failure of inhibition of tubular sodium reabsorption, a response which is normally expected when extracellular volume is expanded.