The evolution and changing ecology of the African hominid oral microbiome.

The oral microbiome plays key roles in human biology, health, and disease, but little is known about the global diversity, variation, or evolution of this microbial community. To better understand the evolution and changing ecology of the human oral microbiome, we analyzed 124 dental biofilm metagenomes from humans, including Neanderthals and Late Pleistocene to present-day modern humans, chimpanzees, and gorillas, as well as New World howler monkeys for comparison. We find that a core microbiome of primarily biofilm structural taxa has been maintained throughout African hominid evolution, and these microbial groups are also shared with howler monkeys, suggesting that they have been important oral members since before the catarrhine-platyrrhine split ca. 40 Mya. However, community structure and individual microbial phylogenies do not closely reflect host relationships, and the dental biofilms of Homo and chimpanzees are distinguished by major taxonomic and functional differences. Reconstructing oral metagenomes from up to 100 thousand years ago, we show that the microbial profiles of both Neanderthals and modern humans are highly similar, sharing functional adaptations in nutrient metabolism. These include an apparent Homo-specific acquisition of salivary amylase-binding capability by oral streptococci, suggesting microbial coadaptation with host diet. We additionally find evidence of shared genetic diversity in the oral bacteria of Neanderthal and Upper Paleolithic modern humans that is not observed in later modern human populations. Differences in the oral microbiomes of African hominids provide insights into human evolution, the ancestral state of the human microbiome, and a temporal framework for understanding microbial health and disease.

Real-world experience with caplacizumab in the management of acute TTP.

The cornerstone of life-saving therapy in immune-mediated thrombotic thrombocytopenic purpura (iTTP) has been plasma exchange (PEX) combined with immunomodulatory strategies. Caplacizumab, a novel anti-von Willebrand factor nanobody trialed in 2 multicenter randomized controlled trials (RCTs) leading to European Union and US Food and Drug Administration approval, has been available in the United Kingdom (UK) through a patient access scheme. Data were collected retrospectively from 2018 to 2020 for 85 patients (4 children) receiving caplacizumab from 22 UK hospitals. Patient characteristics and outcomes in the real-world clinical setting were compared with caplacizumab trial end points and historical outcomes in the precaplacizumab era. Eighty-four of 85 patients received steroid and rituximab alongside PEX; 26% required intubation. Median time to platelet count normalization (3 days), duration of PEX (7 days), and hospital stay (12 days) were comparable with RCT data. Median duration of PEX and time from PEX initiation to platelet count normalization were favorable compared with historical outcomes (P < .05). Thrombotic thrombocytopenic purpura (TTP) recurred in 5 of 85 patients; all had persistent ADAMTS13 activity < 5 IU/dL. Of 31 adverse events in 26 patients, 17 of 31 (55%) were bleeding episodes, and 5 of 31 (16%) were thrombotic events (2 unrelated to caplacizumab); mortality was 6% (5/85), with no deaths attributed to caplacizumab. In 4 of 5 deaths, caplacizumab was introduced >48 hours after PEX initiation (3-21 days). This real-world evidence represents the first and largest series of TTP patients, including pediatric patients, receiving caplacizumab outside of clinical trials. Representative of true clinical practice, the findings provide valuable information for clinicians treating TTP globally.

The morphology of the Late Pleistocene hominin remains from the site of La Cotte de St Brelade, Jersey (Channel Islands).

Thirteen permanent fully erupted teeth were excavated at the Paleolithic site of La Cotte de St Brelade in Jersey in 1910 and 1911. These were all found in the same location, on a ledge behind a hearth in a Mousterian occupation level. They were originally identified as being Neanderthal. A fragment of occipital bone was found in a separate locality in a later season. Recent dating of adjacent sediments gives a probable age of <48 ka. The purpose of this article is to provide an updated description of the morphology of this material and consider its likely taxonomic assignment from comparison with Neanderthal and Homo sapiens samples. One of the original teeth has been lost, and we identify one as nonhominin. At least two adult individuals are represented. Cervix shape and the absence of common Neanderthal traits in several teeth suggest affinities with H. sapiens in both individuals, while crown and root dimensions and root morphology of all the teeth are entirely consistent with a Neanderthal attribution, pointing toward a possible shared Neanderthal and H. sapiens ancestry (the likely date of this material corresponds with the time in which both Neanderthals and H. sapiens were present in Europe). The occipital fragment is stratigraphically more recent and does not exhibit any diagnostic Neanderthal features.

Ontogenetic changes in femoral cross-sectional geometry during childhood locomotor development.

OBJECTIVES: The femur is a major weight-bearing bone that is variably loaded throughout growth as children transition through locomotory states prior to the attainment of a mature bipedal gait. Here, we document ontogenetic trends in femoral cross-sectional geometry (CSG) and explore how changes in loading regime may impact the structural arrangement of cortical bone along the length of the developing diaphysis. MATERIALS AND METHODS: Micro-CT scans of 110 immature femora were generated from a documented archaeological sample ranging in age from birth to 8.5 years old. CSG properties indicative of relative bone strength and bending rigidity were analyzed from cross-sections extracted at 35%, 50% and 65% of total intermetaphyseal length. RESULTS: Infants experience a marked redistribution of cortical bone between birth and 7 months facilitating a more advantageous mechanical structure for early load bearing behaviors as bone is displaced further from the section centroid. Early walkers are characterized by a mediolaterally reinforced cross-section that becomes more circular as gait continues to develop. DISCUSSION: During ontogeny the femur undergoes distinct morphological phases, which correspond with changes in loading regime. This study illustrates the importance of loading conditions in shaping immature bone morphology. Nonmechanical factors such as changes in hormonal environmental can also impact on this dynamic.

Sex differences in the patterning of age-related bone loss in the human hallucal metatarsal in rural and urban populations.

OBJECTIVES: Age-degenerative features of the metatarsals are poorly known despite the importance of metatarsal bone properties for investigating mobility patterns. We assessed the role of habitual activity in shaping the patterning and magnitude of sexual dimorphism in age-related bone loss in the hallucal metatarsal. MATERIALS AND METHODS: Cross-sections were extracted at midshaft from micro-computed tomography scan models of individuals from medieval rural (Abingdon Vineyard) and early industrial urban (Spitalfields) settings (n = 71). A suite of cross-sectional geometry dimensions and biomechanical properties were compared between populations. RESULTS: The rural group display generally stronger and larger metatarsals that show a greater capacity to resist torsion and that have comparatively greater bending strength along the medio-lateral plane. Men in both groups show greater values of cortical area than women, but only in the urban group do men show lower magnitudes of age-related decline compared to females. Women in rural and urban populations show different patterns of age-related decline in bone mass, particularly old women in the urban group show a marked decline in cortical area that is absent for women in the rural group. DISCUSSION: Lifetime exposure to hard, physical activity in an agricultural setting has contributed to the attainment of greater bone mass and stronger bones in young adults. Furthermore, over the life-course, less of this greater amount of bone is lost, such that sustained activity levels may have acted to buffer against age-related decline, and this is most pronounced for women, who are expected to experience greater bone loss later in life than men.

Effects of maternal, gestational, and perinatal variables on neonatal line width observed in a modern UK birth cohort.

OBJECTIVES: The objective of this study was to explore potential relationships between neonatal line (NNL) width and early life history variables such as maternal health, gestation, the birth process, and perinatal health. MATERIALS AND METHODS: Histological thin sections of deciduous canines were studied from 71 children from the Avon Longitudinal Study of Parents and Children (ALSPAC). The width of the NNL was measured in three locations on the tooth crown using spatial mapping techniques (ArcGIS) from digital images from an Olympus VS-120 microscope. Life history variables were collected prospectively through a combination of clinical observations and questionnaires. RESULTS: Infants born late term or post term had narrower neonatal lines than those born prematurely or at full term. Infants born in Autumn (September to November) had narrower NNLs than those born at other times of year. NNLs in infants born to mothers with hypertension were wider than those without. Infants resuscitated at birth or born to obese mothers had narrower NNLs than those that were not. There was no association between NNL width and either the type or duration of delivery. DISCUSSION: The NNL in enamel is an irregular accentuated line, but the factors underlying its formation and width remain unclear. In contrast to some previous studies, we found no association between wider NNLs and long or difficult births. Instead, we found that the width of the neonatal line NNL varied in relation to parameters that reflected the prenatal environment and length of gestation.

Infant funerary behavior and kinship in Pleistocene hunter-gatherers from Morocco.

Infant remains are relatively uncommon in the late Pleistocene (Upper Palaeolithic) archaeological record. Funerary treatment is considered indicative of social status and mirrors cultural attitudes toward the deceased or the group they represent. Here we report on the burials of six infants, including three who died at birth or shortly thereafter, from Later Stone Age (Iberomaurusian) levels at Grotte des Pigeons, Taforalt, in Morocco dating to ∼14,500 cal BP. Funerary treatment of the infants was equivalent to that of older individuals within the community, indicating an inclusive social status. The burials of two of the six infants, shown by previous aDNA analysis to be brother and sister, were overlain by ochre stained grinding stones that may have served as grave markers. In this case, a uniquely shared funerary treatment mirrored a close biological relationship, suggesting that kinship contributed to the patterning of funerary behavior within this Pleistocene burial assemblage.

Endochondral growth disruption during vitamin D deficiency rickets in a mid-19th century series from Bethnal Green, London, UK.

OBJECTIVES: Vitamin D affects many aspects of cartilage and skeletal development. Inconsistent findings currently exist regarding the impact of vitamin D deficiency on childhood growth. This study aims to evaluate the impact of vitamin D deficiency on childhood skeletal development by exploring long bone growth in children with healed and active rickets. MATERIALS AND METHODS: Forty-four known-age children (2 months to 12 years) with rickets and 99 without rickets were compared with modern reference data from North America. Diaphyseal lengths of children with active rickets (34.1%, 15/44), healed rickets (65.9%, 29/44), and without rickets (99/143, 69.2%) were expressed as a percentage of expected length and an average percentage value was calculated across all available long bones. RESULTS: Combined data for all six long bones revealed that children with active rickets had achieved only 75.3% of their expected size whereas, on average, children with healed rickets had achieved 81.6% of their expected size. On average, children without skeletal evidence of rickets had achieved 83.7% of their expected size. Children with severe skeletal manifestations of active rickets had a lower average percentage of expected size (70.4%) than the remainder of children affected by the condition. DISCUSSION: Pronounced growth faltering existed in children with active rickets and affected the upper and lower limb, indicating systemic growth failures during the deficiency. Poor maternal health, early weaning and inadequate infant feeding, and lack of sunlight exposure likely contributed to the development of rickets. Complex interactions between pathological conditions, nutritional deficiencies and vitamin D deficiency may have exacerbated growth impacts.

Patterns of long bone growth in a mid-19th century documented sample of the urban poor from Bethnal Green, London, UK.

OBJECTIVES: Studies of male and female long bone growth in past populations are limited and usually constrained by the lack of personal identification. This article aimed to evaluate long bone growth in a series of mid-19th century documented burials associated with the urban poor from Bethnal Green, London, UK. MATERIALS AND METHODS: Maximum diaphyseal lengths from 74 males and 70 females (2 months to 12 years) were compared to modern reference data from North America. Diaphyseal lengths were expressed as a percentage of expected length and an average percentage value was calculated across all available long bones. An index of growth progression was introduced to explore differences in the progress of males and females towards their projected adult size. RESULTS: Deviation from the expected growth attainment was evident in both sexes in the archaeological series by 2-4 months of age. Only 19.4% (28/144) of the children had attained an average long bone length >90% of the predicted mean in the reference series. The percentage of expected growth attainment decreased steadily in both sexes during infancy and early childhood. Overall, females deviated further from their expected growth progression than males. DISCUSSION: Growth faltering in both males and females was established during infancy (<1 year) with no evidence for recovery in older age groups. Early weaning and inadequate artificial feeding, together with impoverished living conditions and limited sanitary provision, most likely impacted on childhood growth.

Age estimation of immature human skeletal remains from the dimensions of the girdle bones in the postnatal period.

OBJECTIVES: This study provides classical calibration regression formulae for age estimation from the dimensions of unfused shoulder and pelvic girdle bones. MATERIALS AND METHODS: Age estimation models were derived from a sample of 160 known age and sex individuals (63 females and 97 males) aged birth to 12 years, selected from Portuguese and English skeletal collections. The sample was divided into two age groups at the age of 2 years, and formulae were obtained for the sexes separately and combined. RESULTS: Measurements of the pelvis provide more precise age estimates than the shoulder. In the younger age group, the height and width of the ilium, and the height of the glenoid yield the most precise age estimates. In the older age group, the length of the clavicle provides the most precise estimates, followed by measurements of the pubis and ischium. DISCUSSION: In the younger individuals (<2 years), age estimates based on measurements of the pelvic girdle seem to be as or more precise than those based on the length of long bones. In older individuals (≥2 years), estimates based on the measurements of the girdles are less precise than those based on the length of long bones. These age estimation formulae may be useful for fragmentary and incomplete material in archaeological and forensic contexts. The formulae are suitable for a variety of archeological populations living under adverse conditions. These conditions are similar to some "developing" countries, and hence the formulae may also be applicable to modern forensic remains from such environments.

Age estimation of immature human skeletal remains from the metaphyseal and epiphyseal widths of the long bones in the post-natal period.

OBJECTIVES: This study provides regression and classical calibration models for the estimation of age from the dimensions of the metaphyses and epiphyses of the six long bones. METHODS: A sample of 148 known sex and age individuals (56 females and 92 males), aged between birth and 12 years of age, selected from Portuguese and English skeletal collections. Age estimation models were obtained separately for each sex and for the sexes combined, for the entire sample and for the sample divided into two subsamples at the age of 2 years. RESULTS: The best performing epiphysis is the proximal epiphysis of the tibia. For the metaphyses, the distal metaphysis of the tibia and the proximal metaphysis of the femur are best for individuals below and above 2 years of age, respectively. Growth of the metaphyses is similar to that of the diaphysis. Results suggest that age can be as accurately estimated from the width of the metaphyses and epiphyses as from the length of the diaphyses, or as from the length of the deciduous and permanent teeth. CONCLUSIONS: These models may be useful for fragmentary material in both archaeological and forensic contexts. However, due to the background of the samples, the models would be most applicable to individuals exposed to adverse environmental conditions during growth and development. Metaphyseal and epiphyseal widths may be less affected by ecological conditions than diaphyseal length.

Quantification of 3D curvature in the iliac crest: Ontogeny and implications for sex determination in juveniles.

OBJECTIVES: Sex-specific differences in the shape of the iliac crest have been reported based on quantification of simplified curvature using two-dimensional variables or qualitative identification of faint/marked S-shaped curvature. An objective and quantitative approach for the evaluation of iliac crest curvature in juveniles was developed. Using three-dimensional data, ontogenetic variation in iliac curvature was investigated in relation to size and chronological age and its accuracy for sex estimation among juveniles was evaluated. MATERIALS AND METHODS: Three-dimensional geometric morphometric landmarks were collected from virtual models of 53 surface-scanned ilia and used to: (1) quantify differences between male and female shape, and (2) to calculate a measure of sinuosity by extracting linear measurements relative to a plane constructed in virtual space. RESULTS: Males were found to exhibit on average more pronounced curvature of the iliac crest than females in equivalent age groups, and the difference between sexes was more marked on the posterior section of the bone than on the anterior section. Classification accuracy was higher for measurements of sinuosity relative to a three-dimensional plane (62-87%) than for landmarks describing crest shape (64-74%). CONCLUSIONS: An increased likelihood of correct male identification (reduced rate of false positive identification) was observed in older children (>5 years). This reflects divergence of male and female iliac crest shape with size (or age), and the development of a unique, more curved iliac crest shape in males. The results suggest more conspicuous male trait expression than female trait expression.

Earliest evidence for caries and exploitation of starchy plant foods in Pleistocene hunter-gatherers from Morocco.

Dental caries is an infectious disease that causes tooth decay. The high prevalence of dental caries in recent humans is attributed to more frequent consumption of plant foods rich in fermentable carbohydrates in food-producing societies. The transition from hunting and gathering to food production is associated with a change in the composition of the oral microbiota and broadly coincides with the estimated timing of a demographic expansion in Streptococcus mutans, a causative agent of human dental caries. Here we present evidence linking a high prevalence of caries to reliance on highly cariogenic wild plant foods in Pleistocene hunter-gatherers from North Africa, predating other high caries populations and the first signs of food production by several thousand years. Archaeological deposits at Grotte des Pigeons in Morocco document extensive evidence for human occupation during the Middle Stone Age and Later Stone Age (Iberomaurusian), and incorporate numerous human burials representing the earliest known cemetery in the Maghreb. Macrobotanical remains from occupational deposits dated between 15,000 and 13,700 cal B.P. provide evidence for systematic harvesting and processing of edible wild plants, including acorns and pine nuts. Analysis of oral pathology reveals an exceptionally high prevalence of caries (51.2% of teeth in adult dentitions), comparable to modern industrialized populations with a diet high in refined sugars and processed cereals. We infer that increased reliance on wild plants rich in fermentable carbohydrates and changes in food processing caused an early shift toward a disease-associated oral microbiota in this population.

A qualitative study to develop a patient-reported outcome for dysmenorrhea.

PURPOSE: Dysmenorrhea refers to the experience of pelvic pain/cramps experienced by women around or during menstruation. A literature review indicated that no existing patient-reported outcome measure was adequate to support labeling claims in dysmenorrhea. Therefore, this study aimed to develop a new measure that could be used as a primary end point in dysmenorrhea clinical trials. METHODS: Open-ended interviews were conducted with 52 dysmenorrhea patients, including a subset of 12 women with a comorbid pelvic pain condition (PPC). Verbatim transcripts were analyzed thematically. The findings were used to generate draft items for an electronic diary (eDiary). A further 24 dysmenorrhea patients pilot-tested the eDiary for 1-5 weeks and completed cognitive interviews to assess content validity. Revisions to the eDiary were implemented based on the findings. RESULTS: In the first set of interviews, 51 women (98 %) spontaneously reported pain/cramps in or around the pelvic region (abdomen, lower back, legs/upper thighs, and vaginal area). Pain experiences reported were similar across dysmenorrhea and dysmenorrhea plus PPC subgroups, except that the pelvic pain among PPC patients occurred throughout the month, not only during menstruation. All participants described the detrimental impact of dysmenorrhea on health-related quality of life. CONCLUSIONS: The eDiary was conceptually comprehensive and easy to complete/understand during cognitive debriefing. The resulting nine-item diary included assessment of: menstrual bleeding severity; pain severity; use of analgesics; impact on work/school, physical activities, social and leisure activities, and sleep. Psychometric validation is ongoing and will assess the reliability, validity, and responsiveness of the eDiary as a comprehensive dysmenorrhea assessment.

A virtual geometric morphometric approach to the quantification of long bone bilateral asymmetry and cross-sectional shape.

OBJECTIVE: The widespread use of three-dimensional digitization means that models of whole bone geometry are routinely captured for many applications in virtual anthropology. In this article, we test whether a geometric morphometric (GMM) approach can be used to accurately quantify directional bilateral asymmetry in cross-sectional shape using virtual bone models. METHODS: We introduce a method to (1) orient virtual long bone models and extract cross sections and (2) collect GMM landmarks to analyze cross-sectional shape. Landmark data, captured using polar radii, were analyzed for an example study set of paired humeri from Andaman Islanders sampled at 35%, 50%, and 65% locations. RESULTS: The GMM method can (1) detect significant differences in left and right cross-sectional shape and (2) allow the directionality of shape change (distribution of bone from centroid) to be evaluated in the context of whole outline shape and in relation to the axis of maximum bending rigidity. The protocol may be used with models created from laser (surface) scan or computed tomography (CT) scan data, and applied to cross-sectional images that were collected using periosteal molding techniques. CONCLUSIONS: The results demonstrate directional bilateral asymmetry in shape, but do not recover the same signal for size measurements. Our method offers a pathway to quantify both the pattern of variation in shape and the relationship between size and shape variation, opening new questions about how those patterns manifest over ontogeny, change temporally or differ in relation to the nature and intensity of the activity, and bone loading conditions.

Shape, size, and maturity trajectories of the human ilium.

Morphological traits of the ilium have consistently been more successful for juvenile sex determination than have techniques applied to other skeletal elements, however relatively little is known about the ontogeny and maturation of size and shape dimorphism in the ilium. We use a geometric morphometric approach to quantitatively separate the ontogeny of size and shape of the ilium, and analyze interpopulation differences in the onset, rate and patterning of sexual dimorphism. We captured the shape of three traits for a total of 191 ilia from Lisbon (Portugal) and London (UK) samples of known age and sex (0-17 years). Our results indicate that a) there is a clear dissociation between the ontogeny of size and shape in males and females, b) the ontogeny of size and shape are each defined by non-linear trajectories that differ between the sexes, c) there are interpopulation differences in ontogenetic shape trajectories, which point to population-specific patterning in the attainment of sexual dimorphism, and d) the rate of shape maturation and size maturation is typically higher for females than males. Male and female shape differences in the ilium are brought about by trajectory divergence. Differences in size and shape maturation between the sexes suggest that maturity may confound our ability to discriminate between the sexes by introducing variation not accounted for in age-based groupings. The accuracy of sex determination methods using the ilium may be improved by the use of different traits for particular age groups, to capture the ontogenetic development of shape in both sexes.

Age estimation of immature human skeletal remains from the diaphyseal length of the long bones in the postnatal period.

Age at death in immature human skeletal remains has been estimated from the diaphyseal length of the long bones, but few studies have actually been designed specifically for the purpose of age estimation and those which have, show important caveats. This study uses regression and classical calibration to model the relationship between age and diaphyseal length of the six long bones, in a sample of 184 known sex and age individuals (72 females and 112 males), younger than 13 years of age, selected from Portuguese and English skeletal collections. Age estimation models based on classical calibration were obtained for each of the six long bones, and separately for each sex and for the sexes combined, and also for the entire sample and when it is subdivided into two subsamples at the age of 2 years. Comparisons between inverse and classical calibration show there is a systematic bias in age estimations obtained from inverse calibration. In the classical calibration models, the length of the femur provides the most accurate estimates of age. Age estimates are more accurate for the male subsample and for individuals under the age of 2 years. These results and a test of previously published methods caution against inverse calibration as a technique for developing age estimation methods even from the immature skeleton. Age estimation methods developed using cemetery collections of identified human skeletons should not be uncritically applied to present-day populations from the same region since many populations have experienced dramatic secular trends in growth and adult height over the last century.

Patient-reported outcome measures for systemic lupus erythematosus clinical trials: a review of content validity, face validity and psychometric performance.

BACKGROUND: Despite overall progress in treatment of autoimmune diseases, patients with systemic lupus erythematosus (SLE) experience many inflammatory symptoms representing an unmet medical need. This study aimed to create a conceptual model of the humanistic and economic burden of SLE, and review the patient-reported outcomes (PROs) used to measure such concepts in SLE clinical trials. METHODS: A conceptual model for SLE was developed from structured review of published articles from 2007 to August 2013 identified from literature databases (MEDLINE, EMBASE, PsycINFO, EconLit) plus other sources (PROLabels, FDA/EMA websites, Clinicaltrials.gov). PROs targeting key symptoms/impacts were identified from the literature. They were reviewed in the context of available guidance and assessed for face and content validity and psychometric properties to determine appropriateness for use in SLE trials. RESULTS: The conceptual model identified fatigue, pain, cognition, daily activities, emotional well-being, physical/social functioning and work productivity as key SLE concepts. Of the 68 articles reviewed, 38 reported PRO data. From these and the other sources, 15 PROs were selected for review, including SLE-specific health-related quality of life (HRQoL) measures (n = 5), work productivity (n = 1), and generic measures of fatigue (n = 3), pain (n = 2), depression (n = 2) and HRQoL (n = 2). The Functional Assessment of Chronic Illness Therapy - Fatigue Scale (FACIT-Fatigue), Brief Pain Inventory (BPI-SF) and LupusQoL demonstrated the strongest face validity, conceptual coverage and psychometric properties measuring key concepts in the conceptual model. All PROs reviewed, except for three Lupus-specific measures, lacked qualitative SLE patient involvement during development. The Hospital Anxiety and Depression Scale (HADS), Short Form [36 item] Health Survey version 2 (SF-36v2), EuroQoL 5-dimensions (EQ-5D-3L and EQ-5D-5L) and Work Productivity and Activity Impairment Questionnaire: Lupus (WPAI:Lupus) showed suitability for SLE economic models. CONCLUSIONS: Based on the identification of key symptoms and impacts of SLE using a scientifically sound conceptual model, we conclude that SLE is a condition associated with high unmet need and considerable burden to patients. This review highlights the availability and need for disease-specific and generic patient-reported measures of relevant domains of disease signs and symptoms, HRQoL and work productivity, providing useful insight for SLE clinical trial design.