The influence of lumbosacral transitional vertebrae on lumbar lordosis and the angle of pelvic incidence.

Pelvic incidence and lumbar lordosis have only normative values for spines comprising five lumbar and five sacral vertebrae. However, it is unclear how pelvic incidence and lumbar lordosis are affected by the common segmentation anomalies at the lumbo-sacral border leading to lumbosacral transitional vertebrae, including lumbarisations and sacralisations. In lumbosacral transitional vertebrae it is not trivial to identify the correct vertebral endplates to measure pelvic incidence and lumbar lordosis because ontogenetically the first sacral vertebra represents the first non-mobile sacral segment in lumbarisations, but the second segment in sacralisations. We therefore assessed pelvic incidence and lumbar lordosis with respect to both of these vertebral endplates. The type of segmentation anomaly was differentiated using spinal counts, spatial relationship with the iliac crest and morphological features. We found significant differences in pelvic incidence and lumbar lordosis between lumbarisations, sacralisations and the control group. The pelvic incidence in the sacralised group was mostly below the range of the lubarisation group and the control group when measured the traditional way at the first non-mobile segment (30.2°). However, the ranges of the sacralisation and lubarisation groups were completely encompassed by the control group when measured at the ontogenetically true first sacral vertebra. The mean pelvic incidence of the sacraliation group thus increased from 30.2° to 58.6°, and the mean pelvic incidence of the total sample increased from 45.6° to 51.2°, making it statistically indistinguishable from the control sample, whose pelvic incidence was 50.2°. Our results demonstrate that it is crucial to differentiate sacralisations from lumbarisation in order to assess the reference vertebra for pelvic incidence measurement. Due to their significant impact on spino-pelvic parameters, lumbosacral transitional vertebrae should be evaluated separately when examining pelvic incidence and lumbar lordosis.

Take it to the limit: The limitations of energetic explanations for birth timing in humans.

A hallmark of modern humans is that our newborns are neurologically immature compared to other primates. It is disputed whether this so-called secondary altriciality evolved due to remodelling of the pelvis associated with bipedal locomotion, as suggested by the obstetrical dilemma hypothesis, or from maternal energetic limitations during pregnancy. Specifically, the 'Energetics of Gestation and Growth' (EGG) hypothesis posits that birth is initiated when foetal energy requirements exceed the maximum sustained maternal metabolic rate during pregnancy at around 2.1 × basal metabolic rate (BMR) of the non-pregnant, non-lactating condition (NPNL). However, the metabolic threshold argued under the EGG framework is derived from one study with a small sample size of only 12 women from the UK. Accordingly, we performed a meta-analysis of all published studies on metabolic scopes during pregnancy to better account for variability. After excluding 3 studies with methodological issues, a total of 12 studies with 303 women from 5 high- and 3 low-income countries were analysed. On average, pregnancy was found to be less metabolically challenging than previously suggested. The studies revealed substantial variation in metabolic scope during pregnancy, which was not reflected by variation in birth timing. Further, in a third of the studies, the metabolic rates exceeded 2.1 × BMRNPNL. Our simulation of foetal energy requirements demonstrated that this metabolic threshold of 2.1 × BMRNPNL cannot realistically be crossed by the foetus around the time of birth. These findings imply that metabolic constraints are not the main limiting factor dictating gestation length.

Neuropathy in paediatric type 1 diabetes mellitus - clinical characterization and analysis of risk factors in the diabetes prospective follow-up registry DPV (Diabetes-Patienten-Verlaufsdokumentation)-registry.

OBJECTIVES: Data on the prevalence, clinical features and risk factors associated with paediatric diabetic neuropathy (DN) are scarce. METHODS: We retrospectively analysed data from the DPV registry, including patients under 20 years of age, treated for type 1 diabetes mellitus (T1D) between 2005 and 2021. Patients with non-diabetic neuropathy were excluded. Data came from centres in Austria, Germany, Luxembourg and Switzerland. RESULTS: 1,121 of the 84,390 patients included had been diagnosed with DN. Univariate analysis showed patients with DN to be older and predominantly female, with a longer duration of T1D, higher insulin dosages per kg and day, lower rates of insulin pump therapy, higher postprandial glucose-, higher HbA1c-and higher cholesterol levels, and higher diastolic and systolic blood pressure values. There was also a larger proportion of smokers and higher prevalence of diabetic retinopathy. Median duration of diabetes at diagnosis of DN was 8.3 years. Multivariable analysis, adjusted for demographics revealed an increased risk for DN among female patients and those who were older, underweight (BMI-SDS), smoked cigarettes or had a longer duration of T1D or higher levels of HbA1c and postprandial blood glucose. The presence of retinopathy and higher cholesterol levels were also linked to increased risk while not-using insulin pump therapy was not. CONCLUSIONS: DN can develop after just a short duration of T1D. Prevention may be achieved by a lowering of HbA1c-and postprandial glucose levels through improved glycaemic control. This warrants further investigation. The slight female predominance suggests further hormonal and genetic etiological factors.

Retrospective Pediatric Cohort Study Validates NEOS Score and Demonstrates Applicability in Children With Anti-NMDAR Encephalitis.

BACKGROUND AND OBJECTIVES: Anti-N-methyl-D-aspartate receptor encephalitis (NMDARE) is the most common form of autoimmune encephalitis in children and adults. Although our understanding of the disease mechanisms has progressed, little is known about estimating patient outcomes. Therefore, the NEOS (anti-NMDAR Encephalitis One-Year Functional Status) score was introduced as a tool to predict disease progression in NMDARE. Developed in a mixed-age cohort, it currently remains unclear whether NEOS can be optimized for pediatric NMDARE. METHODS: This retrospective observational study aimed to validate NEOS in a large pediatric-only cohort of 59 patients (median age of 8 years). We reconstructed the original score, adapted it, evaluated additional variables, and assessed its predictive power (median follow-up of 20 months). Generalized linear regression models were used to examine predictability of binary outcomes based on the modified Rankin Scale (mRS). In addition, neuropsychological test results were investigated as alternative cognitive outcome. RESULTS: The NEOS score reliably predicted poor clinical outcome (mRS ≥3) in children in the first year after diagnosis (p = 0.0014) and beyond (p = 0.036, 16 months after diagnosis). A score adapted to the pediatric cohort by adjusting the cutoffs of the 5 NEOS components did not improve predictive power. In addition to these 5 variables, further patient characteristics such as the "Herpes simplex virus encephalitis (HSE) status" and "age at disease onset" influenced predictability and could potentially be useful to define risk groups. NEOS also predicted cognitive outcome with higher scores associated with deficits of executive function (p = 0.048) and memory (p = 0.043). DISCUSSION: Our data support the applicability of the NEOS score in children with NMDARE. Although not yet validated in prospective studies, NEOS also predicted cognitive impairment in our cohort. Consequently, the score could help identify patients at risk of poor overall clinical outcome and poor cognitive outcome and thus aid in selecting not only optimized initial therapies for these patients but also cognitive rehabilitation to improve long-term outcomes.

Maternal age and the prevalence of congenital heart defects in Europe, 1995-2015: A register-based study.

BACKGROUND: Evidence on the direction and strength of association between maternal age and the prevalence of congenital heart defects (CHD) in different age group categories is conflicting. Some studies have illustrated different trends with an increase in prevalence in younger and older age groups while other studies have reported a linear relationship. Given the increase in maternal age over recent years, it is important to study the CHD prevalence by maternal age. OBJECTIVES: To examine the association between maternal age and the prevalence of CHD in Europe between 1995 and 2015 using population-based data from 24 registries belonging to the European Surveillance of Congenital Anomalies (EUROCAT) network. METHODS: Associations over time of all nonsyndromic CHD according to maternal age category and for three CHD severity groupings (severity group I: very severe; severity group II: severe; severity group III: less severe) were examined using Bayesian multilevel Poisson regression modeling. Further subgroup analyses were undertaken within four maternal age-bands: ≤24, 25-29, 30-34 and 35-44 years. Descriptive summaries are also presented. RESULTS: There were 51,608 nonsyndromic CHD cases in Europe over the 20-year study period. Total prevalence for all CHD combined was increased for younger mothers (≤24 years) and for mothers 35-44 years of age when compared with mothers aged 25-29 years (reference group) (IRR: 1.05, 95% CI: 1.02, 1.07). The total prevalence was increased for severity group I (very severe) only for younger mothers compared to those aged 25-29 years (IRR: 1.14, 95% CI: 1.04, 1.23). We found an increased prevalence of the following CHD subtypes: double outlet right ventricle (IRR:1.33, 95% CI: 1.09, 1.60), hypoplastic left heart syndrome (IRR: 1.18, 95% CI: 1.05, 1.32), hypoplastic right heart syndrome (IRR: 1.41, 95% CI: 1.05, 1.84), atrioventricular septal defect (IRR: 1.15, 95% CI: 1.01, 1.32), coarctation of aorta (IRR: 1.15, 95% CI: 1.03, 1.28) and atrial septal defect (IRR: 1.08, 95% CI: 1.02, 1.13). For older mothers (35-44 years) compared to the reference category, we observed an increased risk in the prevalence for severity group II (IRR: 1.09, 95% CI: 1.03, 1.14), severity group III (IRR: 1.05, 95% CI: 1.01, 1.08) and an increased prevalence of the CHD subtypes: Pulmonary valve stenosis (IRR: 1.22, 95% CI: 1.09, 1.34), ASD (IRR: 1.07, 95% CI: 1.02, 1.13), CoA (IRR: 1.18, 95% CI: 1.06, 1.32) and Tetralogy of Fallot (IRR: 1.14, 95% CI: 1.01, 1.28). Finally, for all age categories compared to the reference category, different associations of ASD and an increased prevalence of CoA was also observed. CONCLUSIONS: Based on data for cases of CHD from 24 European population-based registries, evidence of a positive association between maternal age and the total prevalence of CHD for younger (≤24 years old) and older (35-44 years old) mothers was observed. The results suggest that young maternal age (≤24 years old) is a factor associated with severe CHD phenotypes while a positive association between advanced maternal age (35-44 years old) and mild CHD phenotypes was observed.

Amniotic band syndrome and limb body wall complex in Europe 1980-2019.

Amniotic band syndrome (ABS) and limb body wall complex (LBWC) have an overlapping phenotype of multiple congenital anomalies and their etiology is unknown. We aimed to determine the prevalence of ABS and LBWC in Europe from 1980 to 2019 and to describe the spectrum of congenital anomalies. In addition, we investigated maternal age and multiple birth as possible risk factors for the occurrence of ABS and LBWC. We used data from the European surveillance of congenital anomalies (EUROCAT) network including data from 30 registries over 1980-2019. We included all pregnancy outcomes, including live births, stillbirths, and terminations of pregnancy for fetal anomalies. ABS and LBWC cases were extracted from the central EUROCAT database using coding information responses from the registries. In total, 866 ABS cases and 451 LBWC cases were included in this study. The mean prevalence was 0.53/10,000 births for ABS and 0.34/10,000 births for LBWC during the 40 years. Prevalence of both ABS and LBWC was lower in the 1980s and higher in the United Kingdom. Limb anomalies and neural tube defects were commonly seen in ABS, whereas in LBWC abdominal and thoracic wall defects and limb anomalies were most prevalent. Twinning was confirmed as a risk factor for both ABS and LBWC. This study includes the largest cohort of ABS and LBWC cases ever reported over a large time period using standardized EUROCAT data. Prevalence, clinical characteristics, and the phenotypic spectrum are described, and twinning is confirmed as a risk factor.

Prevalence of congenital heart defects in Europe, 2008-2015: A registry-based study.

BACKGROUND: The total prevalence of congenital heart defects (CHDs) varies by populations and over time. Studies that examine trends in the prevalence of CHD in different regions may shed light on our understanding of the occurrence of CHD and the impact of different risk factors. OBJECTIVES: To examine trends in total and live birth prevalence of nonsyndromic CHD in Europe between the years 2008 and 2015 and to investigate if the decreasing trend reported by previous studies is continuing. METHODS: Cases of CHD delivered between January 1, 2008 and December 31, 2015 notified to 25 population-based EUROCAT (European Surveillance of Congenital Anomalies) registries in 14 countries, formed the population-based case-series. Prevalence (total/live) rates and 95% confidence intervals were calculated as the number of cases per 10,000 births (live and stillbirths). Time trends in prevalence of all nonsyndromic CHDs and for three CHD severity groups (very severe, severe, and less severe) were plotted using a Poisson regression multilevel approach. RESULTS: The total prevalence of nonsyndromic CHD was 57.1 per 10,000 births (live births and stillbirths) for the 8-year period and remained stable across the three CHD severity groups while the live birth prevalence was 60.2 per 10,000 births. There was considerable variation in the reported total CHD prevalence and the direction of trends by registry. A decreasing prevalence of CHD was observed for the Norway and England/Wales registries, whereas the CHD prevalence increased for registries in Italy and Croatia. CONCLUSIONS: The total prevalence of CHD in Europe between the years 2008 and 2015 remained stable for all CHD and across the three CHD severity groups. The decreasing trend reported by previous studies has not continued. However, we found significant differences in the total and live birth prevalence by registry.

Prevalence of vascular disruption anomalies and association with young maternal age: A EUROCAT study to compare the United Kingdom with other European countries.

BACKGROUND: Younger mothers are at a greater risk of having a pregnancy with gastroschisis and the risk is higher in the United Kingdom than other European countries. Gastroschisis is thought to be a vascular disruption anomaly and the aim of this study was to analyze the prevalence of other possible vascular disruption anomalies to determine whether both the younger maternal age and the UK associations also occur with these anomalies. METHODS: All pregnancies with anomalies considered potentially due to vascular disruption from January 1, 2005 to December 31, 2017 from 26 European population-based congenital anomaly registries who were members of EUROCAT were analyzed. Multilevel models were used to allow for differences between registries when analyzing associations with maternal age, year of birth and whether the registry was in the United Kingdom. RESULTS: There were 5,220 cases with potential vascular disruption anomalies, excluding chromosomal and genetic conditions, with a prevalence of 8.85 per 10,000 births in the United Kingdom and 5.44 in the other European countries. The prevalence per 10,000 births of gastroschisis (4.45 vs. 1.56) and congenital constriction bands (0.83 vs. 0.42) was significantly higher in the United Kingdom, even after adjusting for maternal age. However, transverse limb reduction defects had a similar prevalence (2.16 vs. 2.14 per 10,000). The expected increased prevalence in younger mothers was observed for vascular disruption anomalies overall and for the individual anomalies: gastroschisis and congenital constriction bands. CONCLUSION: Vascular disruption anomalies that had an increased risk for younger mothers (such as gastroschisis) had a higher maternal age standardized prevalence in the United Kingdom, while vascular disruption anomalies with weaker associations with younger mothers (such as transverse limb reduction defects) did not have an increased prevalence in the United Kingdom, which may indicate a different etiology for these anomalies.

Life-history tradeoffs in a historical population (1896-1939) undergoing rapid fertility decline: Costs of reproduction?

Evolutionary demographers often invoke tradeoffs between reproduction and survival to explain reductions in fertility during demographic transitions. The evidence for such tradeoffs in humans has been mixed, partly because tradeoffs may be masked by individual differences in quality or access to resources. Unmasking tradeoffs despite such phenotypic correlations requires sophisticated statistical analyses that account for endogeneity among variables and individual differences in access to resources. Here we tested for costs of reproduction using N=13,663 birth records from the maternity hospital in Basel, Switzerland, 1896-1939, a period characterized by rapid fertility declines. We predicted that higher parity is associated with worse maternal and offspring condition at the time of birth, adjusting for age and a variety of covariates. We used Bayesian multivariate, multilevel models to simultaneously analyze multiple related outcomes while accounting for endogeneity, appropriately modeling non-linear effects, dealing with hierarchical data structures, and effectively imputing missing data. Despite all these efforts, we found virtually no evidence for costs of reproduction. Instead, women with better access to resources had fewer children. Barring limitations of the data, these results are consistent with demographic transitions reflecting women's investment in their own embodied capital and/or the adoption of maladaptive low-fertility norms by elites.

Sex classification using the human sacrum: Geometric morphometrics versus conventional approaches.

The human pelvis shows marked sexual dimorphism that stems from the conflicting selective pressures of bipedal locomotion and parturition. The sacrum is thought to reflect this dimorphism as it makes up a significant portion of the pelvic girdle. However, reported sexual classification accuracies vary considerably depending on the method and reference sample (54%-98%). We aim to explore this inconsistency by quantifying sexual dimorphism and sex classification accuracies in a geographically heterogeneous sample by comparing 3D geometric morphometrics with the more commonly employed linear metric and qualitative assessments. Our sample included 164 modern humans from Africa, Europe, Asia, and America. The geometric morphometric analysis was based on 44 landmarks and 56 semilandmarks. Linear dimensions included sacral width, corpus depth and width, and the corresponding indices. The qualitative inspection relied on traditional macroscopic features such as proportions between the corpus of the first sacral vertebrae and the alae, and sagittal and coronal curvature of the sacrum. Classification accuracy was determined using linear discriminant function analysis for the entire sample and for the largest subsamples (i.e., Europeans and Africans). Male and female sacral shapes extensively overlapped in the geometric morphometric investigation, leading to a classification accuracy of 72%. Anteroposterior corpus depth was the most powerful discriminating linear parameter (83%), followed by the corpus-area index (78%). Qualitative inspection yielded lower accuracies (64-76%). Classification accuracy was higher for the Central European subsample and diminished with increasing geographical heterogeneity of the subgroups. Although the sacrum forms an integral part of the birth canal, our results suggest that its sex-related variation is surprisingly low. Morphological variation thus seems to be driven also by other factors, including body size, and sacrum shape is therefore likely under stronger biomechanical rather than obstetric selection.

Dynamic finite-element simulations reveal early origin of complex human birth pattern.

Human infants are born neurologically immature, potentially owing to conflicting selection pressures between bipedal locomotion and encephalization as suggested by the obstetrical dilemma hypothesis. Australopithecines are ideal for investigating this trade-off, having a bipedally adapted pelvis, yet relatively small brains. Our finite-element birth simulations indicate that rotational birth cannot be inferred from bony morphology alone. Based on a range of pelvic reconstructions and fetal head sizes, our simulations further imply that australopithecines, like humans, gave birth to immature, secondary altricial newborns with head sizes smaller than those predicted for non-human primates of the same body size especially when soft tissue thickness is adequately approximated. We conclude that australopithecines required cooperative breeding to care for their secondary altricial infants. These prerequisites for advanced cognitive development therefore seem to have been corollary to skeletal adaptations for bipedal locomotion that preceded the appearance of the genus Homo and the increase in encephalization.

Sex determination accuracy using the human sacrum in a Central European sample.

The sacrum is often used for sex estimation of human remains. However, reported sexual classification accuracies based on the sacrum produce highly discrepant estimates ranging from 54% to 98% depending on the method and reference sample. Here, we therefore aim to evaluate the sacrum's efficacy in differentiating males from females by comparing three different approaches in a homogeneous Central European sample (n = 58, 27 males and 31 females) obtained from the 19th century Weisbach collection. Specifically, we investigated the sacrum by 1) a qualitative visual inspection, 2) traditional linear metrics, namely, sacral width, corpus width, and the associated corporo-basal index, and 3) geometric morphometrics (GM) using a 3D configuration of 100 landmarks and semilandmarks. Classification accuracies for the qualitative approach ranged from 69% to 81%. The investigated quantitative methods based on linear dimensions led to comparable classification accuracies of 62% for sacral width and 78% for the corporo-basal index. However, absolute corpus width had a stronger discriminative power (86%), similar to the PC scores from shape space (87%). Unexpectedly, the GM approach, which considered the shape of the entire sacrum, did not classify better than linear variables. This was exceeded only when sacrum shape was combined with corpus width or another measure of size, like the natural logarithm of the centroid size, yielding a classification accuracy of 95%. The male and female group means differed mainly in the general height-to-width relationship and corpus-to-alae proportions, corroborating patterns previously described in the literature. Our results suggest that the sacrum is markedly less effective than the hipbone for sex determination, which is at odds with its central position within the pelvic girdle and thus its supposed obstetric relevance.

Structural mapping of GABRB3 variants reveals genotype-phenotype correlations.

PURPOSE: Pathogenic variants in GABRB3 have been associated with a spectrum of phenotypes from severe developmental disorders and epileptic encephalopathies to milder epilepsy syndromes and mild intellectual disability (ID). In this study, we analyzed a large cohort of individuals with GABRB3 variants to deepen the phenotypic understanding and investigate genotype-phenotype correlations. METHODS: Through an international collaboration, we analyzed electro-clinical data of unpublished individuals with variants in GABRB3, and we reviewed previously published cases. All missense variants were mapped onto the 3-dimensional structure of the GABRB3 subunit, and clinical phenotypes associated with the different key structural domains were investigated. RESULTS: We characterized 71 individuals with GABRB3 variants, including 22 novel subjects, expressing a wide spectrum of phenotypes. Interestingly, phenotypes correlated with structural locations of the variants. Generalized epilepsy, with a median age at onset of 12 months, and mild-to-moderate ID were associated with variants in the extracellular domain. Focal epilepsy with earlier onset (median: age 4 months) and severe ID were associated with variants in both the pore-lining helical transmembrane domain and the extracellular domain. CONCLUSION: These genotype-phenotype correlations will aid the genetic counseling and treatment of individuals affected by GABRB3-related disorders. Future studies may reveal whether functional differences underlie the phenotypic differences.

The morphological consequences of segmentation anomalies in the human sacrum.

OBJECTIVES: Despite the high frequency of segmentation anomalies in the human sacrum, their evolutionary and clinical implications remain controversial. Specifically, inconsistencies involving the classification and counting methods obscure accurate assessment of lumbosacral transitional vertebrae. Therefore, we aim to establish more reliable morphological and morphometric methods for differentiating between sacralizations and lumbarizations in clinical and paleontological contexts. MATERIALS AND METHODS: Using clinical CT data from 145 individuals aged 14-47 years, vertebral counts and the spatial relationship between the sacrum and adjoining bony structures were assessed, while the morphological variation of the sacrum was assessed using geometric morphometrics based on varied landmark configurations. RESULTS: The prevalence of lumbosacral and sacrococcygeal segmentation anomalies was 40%. Lumbarizations and sacralizations were reliably distinguishable based on the spatial relationship between the iliac crest and the upward or downward trajectory of the linea terminalis on the sacrum. Different craniocaudal orientations of the alae relative to the corpus of the first sacral vertebra were also reflected in the geometric morphometric analyses. The fusion of the coccyx (32%) was frequently coupled with lumbarizations, suggesting that the six-element sacra more often incorporate the coccyx rather than the fifth lumbar vertebra. CONCLUSIONS: Our approach allowed the consistent identification of segmentation anomalies even in isolated sacra. Additionally, our outcomes either suggest that homeotic border shifts often affect multiple spinal regions in a unidirectional way, or that sacrum length is highly conserved perhaps due to functional constraints. Our results elucidate the potential clinical, biomechanical, and evolutionary significance of lumbosacral transitional vertebrae.

New insights on hip bone sexual dimorphism in adolescents and adults using deformation-based geometric morphometrics.

Morphological variation of the human pelvis, and particularly the hip bone, mainly results from both female-specific selective pressure related to the give birth of large-headed newborns, and constraints in both sexes for efficient bipedal locomotion, abdominal stability, and adaptation to climate. Hip bone morphology has thus been extensively investigated using several approaches, although the nuances of inter-individual and sex-related variation are still underappreciated, and the effect of sex on ontogenetic patterns is debated. Here, we employ a landmark-free, deformation-based morphometric approach to explore variation in modern human hip bone shape and size from middle adolescence to adulthood. Virtual surface models of the hip bone were obtained from 147 modern human individuals (70 females and 77 males) including adolescents, and young and mature adults. The 3D meshes were registered by rotation, translation, and uniform scaling prior to analysis in Deformetrica. The orientation and amplitude of deviations of individual specimens relative to a global mean were assessed using Principal Component Analysis, while colour maps and vectors were employed for visualisation purposes. Deformation-based morphometrics is a time-efficient and objective method free of observer-dependent biases that allows accurate shape characterisation of general and more subtle morphological variation. Here, we captured nuanced hip bone morphology revealing ontogenetic trends and sex-based variation in arcuate line curvature, greater sciatic notch shape, pubic body and rami length, acetabular expansion, and height-to-width proportions of the ilium. The observed ontogenetic trends showed a higher degree of bone modelling of the lesser pelvis of adolescent females, while male variation was mainly confined to the greater pelvis.

Possible vertebral brucellosis infection in a Neanderthal.

The La Chapelle-aux-Saints 1 skeleton of an old (>60-year-old) male Neanderthal is renowned for the advanced osteoarthritis of its spinal column and hip joint, and their implications for posture and lifestyle in these Mid- to Late Pleistocene humans. Reassessment of the pathologic lesions reveals erosions at multiple non-contiguous vertebrae and reactive bone formation extending far beyond the left hip joint, which suggests the additional diagnosis of brucellosis. This implies the earliest secure evidence of this zoonotic disease in hominin evolution. Brucellosis might have been transmitted via butchering or eating raw meat and is well compatible with the range of prey animals documented for Neanderthals. The associated infertility could have represented an important aspect of health in these late archaic humans.

Prevention of Neural Tube Defects in Europe: A Public Health Failure.

Objective: Thirty years ago it was demonstrated that folic acid taken before pregnancy and in early pregnancy reduced the risk of a neural tube defect (NTD). Despite Public Health Initiatives across Europe recommending that women take 0.4 mg folic acid before becoming pregnant and during the first trimester, the prevalence of NTD pregnancies has not materially decreased in the EU since 1998, in contrast to the dramatic fall observed in the USA. This study aimed to estimate the number of NTD pregnancies that would have been prevented if flour had been fortified with folic acid in Europe from 1998 as it had been in the USA. Design and Setting: The number of NTD pregnancies from 1998 to 2017 that would have been prevented if folic acid fortification had been implemented in the 28 countries who were members of the European Union in 2019 was predicted was predicted using data on NTD prevalence from 35 EUROCAT congenital anomaly registries and literature searches for population serum folate levels and folic acid supplementation. Results: From 1998 to 2017 an estimated 95,213 NTD pregnancies occurred amongst 104 million births in the 28 countries in the EU, a prevalence of 0.92 per 1,000 births. The median serum folate level in Europe over this time period was estimated to be 14.1 µg/L. There is a lack of information about women taking folic acid supplements before becoming pregnant and during the first trimester of pregnancy, with one meta-analysis indicating that around 25% of women did so. An estimated 14,600 NTD pregnancies may have been prevented if the European countries had implemented fortification at the level adopted by the USA in 1998 and 25% of women took folic acid supplements. An estimated 19,500 NTD pregnancies would have been prevented if no women took folic acid supplements. Conclusions: This study suggests that failure to implement mandatory folic acid fortification in the 28 European countries has caused, and continues to cause, neural tube defects to occur in almost 1,000 pregnancies every year.

Epidemiology of Pierre-Robin sequence in Europe: A population-based EUROCAT study.

BACKGROUND: Pierre Robin sequence (PRS) is a rare congenital anomaly. Respiratory disorders and feeding difficulties represent the main burden. OBJECTIVE: The aim of this study was to investigate the epidemiology of PRS using a cohort of cases from EUROCAT, the European network of population-based registries of congenital anomalies. METHODS: We analysed cases of PRS born in the period 1998-2017 collected by 29 population-based congenital anomaly registries in 17 different countries. We calculated prevalence estimates, prenatal detection rate, survival up to 1 week, and proportions of associated anomalies. The effect of maternal age was tested using a Poisson regression model. RESULTS: Out of 11 669 155 surveyed births, a total of 1294 cases of PRS were identified. The estimate of the overall prevalence was 12.0 per 100 000 births (95% CI 9.9, 14.5). There was a total of 882 (68.2%) isolated cases, and the prevalence was 7.8 per 100 000 births (95% CI 6.7, 9.2). A total of 250 cases (19.3%) were associated with other structural congenital anomalies, 77 cases (6.0%) were associated with chromosomal anomalies and 77 (6.0%) with genetic syndromes. The prenatal detection rate in isolated cases was 12.0% (95% CI 9.8, 14.5) and increased to 16.0% (95% CI 12.7, 19.7) in the sub-period 2008-2017. The prevalence rate ratio of non-chromosomal cases with maternal age ≥35 was higher than in cases with maternal age <25 for total (PRR 1.26, 95% CI 1.05, 1.51) and isolated cases (PRR 1.33, 95% CI 1.00, 1.64). Survival of chromosomal cases (94.2%) and multiple anomaly cases (95.3%) were lower than survival of isolated cases (99.4%). CONCLUSIONS: This epidemiological study using a large series of cases of PRS provides insights into the epidemiological profile of PRS in Europe. We observed an association with higher maternal age, but further investigations are needed to test potential risk factors for PRS.

The obstetrical dilemma hypothesis: there's life in the old dog yet.

The term 'obstetrical dilemma' was coined by Washburn in 1960 to describe the trade-off between selection for a larger birth canal, permitting successful passage of a big-brained human neonate, and the smaller pelvic dimensions required for bipedal locomotion. His suggested solution to these antagonistic pressures was to give birth prematurely, explaining the unusual degree of neurological and physical immaturity, or secondary altriciality, observed in human infants. This proposed trade-off has traditionally been offered as the predominant evolutionary explanation for why human childbirth is so challenging, and inherently risky, compared to that of other primates. This perceived difficulty is likely due to the tight fit of fetal to maternal pelvic dimensions along with the convoluted shape of the birth canal and a comparatively low degree of ligamentous flexibility. Although the ideas combined under the obstetrical dilemma hypothesis originated almost a century ago, they have received renewed attention and empirical scrutiny in the last decade, with some researchers advocating complete rejection of the hypothesis and its assumptions. However, the hypothesis is complex because it presently captures several, mutually non-exclusive ideas: (i) there is an evolutionary trade-off resulting from opposing selection pressures on the pelvis; (ii) selection favouring a narrow pelvis specifically derives from bipedalism; (iii) human neonates are secondarily altricial because they are born relatively immature to ensure that they fit through the maternal bony pelvis; (iv) as a corollary to the asymmetric selection pressure for a spacious birth canal in females, humans evolved pronounced sexual dimorphism of pelvic shape. Recently, the hypothesis has been challenged on both empirical and theoretical grounds. Here, we appraise the original ideas captured under the 'obstetrical dilemma' and their subsequent evolution. We also evaluate complementary and alternative explanations for a tight fetopelvic fit and obstructed labour, including ecological factors related to nutrition and thermoregulation, constraints imposed by the stability of the pelvic floor or by maternal and fetal metabolism, the energetics of bipedalism, and variability in pelvic shape. This reveals that human childbirth is affected by a complex combination of evolutionary, ecological, and biocultural factors, which variably constrain maternal pelvic form and fetal growth. Our review demonstrates that it is unwarranted to reject the obstetrical dilemma hypothesis entirely because several of its fundamental assumptions have not been successfully discounted despite claims to the contrary. As such, the obstetrical dilemma remains a tenable hypothesis that can be used productively to guide evolutionary research.