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This cross-sectional study estimates the costs incurred by the National Health Service (NHS) in England as a consequence of the unnecessary prescribing (i.e. non-indicated or dispensable) of dependency-forming medicines (antidepressants, opioids, gabapentinoids, benzodiazepines, Z-drugs). It assesses prescribing in primary care from April 2015-March 2018. Analyses were based upon the following data sets: the number of adults continuously prescribed dependency forming medications and the duration of prescriptions (obtained from Public Health England); the Net Ingredient Cost (NIC) and the dispensing costs for each medicine (obtained from the NHS Business Service Authority [NHSBSA]). Consultation costs were calculated based on guideline recommendations and the number of consultations evidenced in prior research for long-term medication monitoring. Across opioids, gabapentinoids, benzodiazepines, Z-drugs the total estimated unnecessary cost over three years (April 2015-March 2018) was £1,367,661,104 to £1,555,234,627. For antidepressants the total estimated unnecessary cost for one year was £37,321,783 to £45,765,504. The data indicate that the NHS in England may incur a significant estimated mean annual loss of £455,887,035 to £518,411,542 for opioids, gabapentinoids, benzodiazepines, Z-drugs and an estimated annual loss of £37,321,783 to £45,765,504 for antidepressants. Combined, this gives an estimated annual loss of £493,208,818 to £564,177,046 as a result of non-indicated or dispensable prescribing of dependency-forming medicines. Estimates are conservative and figures could be higher.

BackgroundCurrent British National Formulary (BNF) guidelines state that benzodiazepines and zolpidem, zopiclone, and zaleplon, commonly known as Z-drugs (BZD), be prescribed for no more than 4 weeks, although anecdotal data suggest that many patients are prescribed BZDs for much longer. As there are no recent, evidence-based estimates of long-term (>12 months) BZD use in England, the scale of this potential problem is unknown.AimTo produce the first reliable, evidence-based estimate of long-term BZD use in England.Design and settingEstimates of long-term BZD use in England were projected from data obtained from a survey conducted in 2014–2015 by the Bridge Project, a prescribed-drug withdrawal support charity in the North of England (Bradford).MethodPercentages of long-term users of BZD were derived from the survey, by sampling primary care GP surgeries with around 100 000 registered patients, and these were applied to English NHS patient numbers. The data were filtered to exclude the very young and old, and those with other health issues.ResultsThe mean percentage of registered patients prescribed BZDs for more than a year in the survey sample is 0.69% (95% confidence interval [CI] = 0.54 to 0.84). Applying this value to national patient numbers yields a mean projection of 296 929 (95% CI = 232 553 to 361 305) long-term users of BZD in England. The data also suggest that as many as 119 165 of these patients may be willing to accept prescribed drug dependency withdrawal services.ConclusionMore than a quarter of a million people in England are likely to be taking highly dependency-forming hypnotic medication far beyond the recommended time scales. As there is evidence that long-term use of BZDs causes adverse physiological and neurological effects, and protracted withdrawal (with associated complications), this represents a serious public health problem.

The semicircular canals of the inner ear constitute the organ of balance, tracking head rotation during movement and facilitating stabilisation of vision. Morphological characteristics of the canals are correlated with agility scores related to locomotion. To date, however, the relationship between canal morphology and specific locomotor behaviours, such as leaping, is unclear. Knowledge of such a relationship could strengthen the inferences of locomotion of extinct taxa. To test this, crania of two sets of closely related primate species (Presbytis melalophos and P. potenziani; Colobus guereza and C. polykomos) that differ in the percentage of leaping in their locomotor repertoire were examined using microscopic computed tomography. Three-dimensional virtual models of the bony labyrinth were derived, and the radius of curvature of each of the three canals was evaluated relative to cranial size. The findings are contradictory; one leaping form (P. melalophos) differs from its congener in possessing significantly larger lateral canals, a pattern seen in previous studies of primates, while the other leaper (C. guereza) has significantly smaller posterior canals than its close relative. These results undermine efforts to determine specific locomotor behaviours from the bony labyrinth of extinct primates.

International audience; From the Miocene Sahelanthropus tchadensis to Pleistocene Homo sapiens, hominins are characterized by a derived anterior position of the foramen magnum relative to basicranial structures. It has been previously suggested that the anterior position of the foramen magnum in hominins is related to bipedal locomotor behavior. Yet, the functional relationship between foramen magnum position and bipedal locomotion remains unclear. Recent studies, using ratios based on cranial linear measurements, have found a link between the anterior position of the foramen magnum and bipedalism in several mammalian clades: marsupials, rodents, and primates. In the present study, we compute these ratios in a sample including a more comprehensive dataset of extant hominoids and fossil hominins. First, we verify if the values of ratios can distinguish extant humans from apes. Then, we test whether extinct hominins can be distinguished from non-bipedal extant hominoids. Finally, we assess if the studied ratios are effective predictors of bipedal behavior by testing if they mainly relate to variation in foramen magnum position rather than changes in other cranial structures. Our results confirm that the ratios discriminate between extant bipeds and non-bipeds. However, the only ratio clearly discriminating between fossil hominins and other extant apes is that which only includes basicranial structures. We show that a large proportion of the interspecific variation in the other ratios relates to changes in facial, rather than basicranial, structures. In this context, we advocate the use of measurements based only on basicranial structures when assessing the relationship between foramen magnum position and bipedalism in future studies.

Benzodiazepines and Z-drugs (BZDs), hypnotic drugs used for insomnia and anxiety, are prescribed millions of times a year in the UK. Although guidance from the relevant regulatory authorities (NICE and BNF) indicates them only for short-term use, the evidence suggests that many patients have been taking these drugs for much longer, often for decades. At present, there are no up-to-date, evidence-based estimates of the scale of long-term BZD use in the UK, which has prevented making a strong case for the need for withdrawal services. However, data obtained recently on BZD use from a number of GP surgeries (covering nearly 100,000 registered patients) in the North of England, allow such projections to be calculated. Scaling the results to a national level suggests that there are over a quarter of a million patients in the UK using BZDs for periods far longer than recommended. The projections also suggest that nearly half this number may be willing to accept help to stop their dependency on BZDs. These results indicate a serious problem, which should be addressed by more research into the harms associated with long-term BZD use, the provision of withdrawal services, and a national helpline to support patients with BZD dependency.

Several different factors have been hypothesized as explanations of variation in primate paranasal sinus size. Biomechanical forces, particularly those associated with mastication, are frequently evoked to account for differences in primate craniofacial pneumatization. To test whether masticatory stresses are responsible for maxillary sinus volume diversity, two platyrrhine species of the genus Cebus (C. apella and C. albifrons) were examined. The former has been identified as a hard object feeder, and many morphological differences between the two species are attributable to differences in the mechanical properties of their respective diets. Sinus volumes were derived from serial coronal CT scans of the crania of adults. Several external cranial measurements were used to scale sinus volume relative to the size of the face. Relative measures of maxillary sinus volume were compared using standard statistical techniques. In all comparisons, the two capuchin species do not differ from one another significantly at P < 0.05. Thus, this "natural experiment" fails to support the interpretation that biomechanical forces acting on the facial skeleton substantially affect the degree of paranasal pneumatization in primates. This result suggests that it is unlikely that the maxillary sinus performs any function in relation to masticatory stress; other factors must be responsible for the variation in sinus volume among primates.

Unlike most primates, extant cercopithecoids lack maxillary sinuses, which are pneumatic spaces in the facial skeleton lateral of the nasal cavity proper. Character state analysis of living cercopithecoids across well-supported topologies suggests that the sinus was lost at the origin of the superfamily, only to have evolved again convergently in extant macaques. Recent work has shown that a) the 'early loss' hypothesis is supported by the lack of any pneumatization in Victoriapithecus, a stem cercopithecoid, b) like extant macaques, the fossil cercopithecine Paradolichopithecus shows evidence of presence of the maxillary sinus (MS), and c) unlike extant colobines, the fossil colobine Libypithecus also possesses a maxillary sinus. To more fully assess the pattern of cercopithecoid sinus evolution, fossil taxa from both subfamilies (Colobinae, Cercopithecinae) were examined both visually and by computed tomography (CT). The observations were evaluated according to standard anatomical criteria for defining sinus spaces, and compared with data from all extant Old World monkey genera. Most taxa examined conformed to the pattern already discerned from extant cercopithecoids. Maxillary sinus absence in Theropithecus oswaldi, Mesopithecus, and Rhinocolobus is typical for all extant cercopithecids except Macaca. The fossil macaque Macaca majori possesses a well-developed maxillary sinus, as do all living species of the genus. Cercopithecoides, on the other hand, differs from all extant colobines in possessing a maxillary sinus. Thus, paranasal pneumatization has reemerged a minimum of two and possibly three times in cercopithecoids. The results suggest that maxillary sinus absence in cercopithecoids is due to suppression, rather than complete loss.

Everyone who has ever experienced a head cold is familiar with the paranasal sinuses, the bony hollows above and beside the nasal cavity that contribute, sometimes painfully, to upper respiratory tract disorders. These internal cranial structures have a wide distribution among eutherian mammals and archosaurs.1, 2 Sinuses have languished somewhat in the shadow of their better known and more accessible morphological cousins (dentition, postcrania), but new imaging techniques, growth studies, and explicit phylogenetic evaluation3 are beginning to fill in the gaps in our knowledge of the evolution of these enigmatic spaces in primates and promise to yield insights into the evolution of the facial skeleton.

Previous hypotheses of maxillary sinus size evolution have proposed one or more changes in the volume of the structure across hominoid phylogeny. These hypotheses have been used subsequently to support the phylogenetic placement of fossil taxa relative to the living Hominoidea. The null hypothesis, that no change in sinus volume independent of size has occurred in ape evolution, is evaluated here by scaling analysis. Mixed sex samples of adult dry crania for the extant ape genera were examined by computer tomography imaging and the volume of the maxillary sinus was obtained. Sinus volume was then regressed, using both least squares and reduced major axis models, against cranial size variables. The results clearly demonstrate that the null hypothesis of no change in relative sinus volume cannot be rejected; thus, there is no support for hypotheses that maxillary sinus volume, independent of cranial size, has changed in the course of hominoid evolution. This result, in turn, has implications for the phylogenetic placement of fossil taxa and highlights the need for the careful delineation of character states in studies of hominoid systematics.

In order to test the hypothesis that variation in the maxillary sinus volume (MSV) of anthropoid primates is related to skull architecture, a mixed sex sample of adult primate crania covering Hominoidea, Cercopithecoidea and Ceboidea was examined using CT scans. MSV was regressed against basicranial length, using reduced major axis analysis. 2 distinct scaling patterns emerged: while a large MSV seems to be a primitive condition of Anthropoidea, it is clearly reduced in Cercopithecoidea. Although some correlations exist between MSV and different indices of the facial skeleton, they are relatively weak and differed among the 3 groups. A full appreciation of epigenetic factors and the relation of the paranasal sinuses to different cranial components is necessary to highlight the biological role of skull pneumatization.

The relatively small Australopithecus africanus specimen Sts 5 has figured prominently in taxonomic debates, and the determination of this specimen as a young male or an elderly female has the potential to offer a great deal of resolution on this question. Sts 5 has been argued to be either a small, immature male or a mature female based on a variety of characters. A proposed model of continuous root remodeling and angular change for heavily worn dentition may account for the extremely short tooth roots, particularly for the anterior dentition, that Sts 5 demonstrates. The anterior tooth roots of Sts 5 are oriented vertically (relative to the alveolar plane), unlike those found in most other apes, humans, and fossil specimens, in which the tooth roots are roughly parallel with the plane of the nasoalveolar clivus. Computed tomography (CT) data of adult apes were examined and a relationship between the angle of the anterior tooth roots and their length was discovered, caused by heavily worn anterior dentition continuing to erupt to maintain occlusion. The extremely short and vertically oriented anterior roots observed in Sts 5 thus suggest that the specimen represents an aged female specimen with extremely worn dentition. Interestingly, this reorientation of anterior tooth roots helps account for the unusual nasoalveolar contour of Sts 5. The remodeling associated with the heavily worn teeth and reoriented roots thus resolves the taxonomic question raised by analyses identifying unusual prognathism of this small specimen.

Many morphological features of the Pleistocene fossil hominin Homo neanderthalensis, including the reputed large size of its paranasal sinuses, have been interpreted as adaptations to extreme cold, as some Neanderthals lived in Europe during glacial periods. This interpretation of sinus evolution rests on two assumptions: that increased craniofacial pneumatization is an adaptation to lower ambient temperatures, and that Neanderthals have relatively large sinuses. Analysis of humans, other primates, and rodents, however, suggests that the first assumption is suspect; at least the maxillary sinus undergoes a significant reduction in volume in extreme cold, in both wild and laboratory conditions. The second assumption, that Neanderthal sinuses are large, extensive, or even 'hyperpneumatized,' has held sway since the first specimen was described and has been interpreted as the causal explanation for some of the distinctive aspects of Neanderthal facial form, but has never been evaluated with respect to scaling. To test the latter assumption, previously published measurements from two-dimensional (2D) X-rays and new three-dimensional (3D) data from computed tomography (CT) of Neanderthals and temperate-climate European Homo sapiens are regressed against cranial size to determine the relative size of their sinuses. The 2D data reveal a degree of craniofacial pneumatization in Neanderthals that is both commensurate with the size of the cranium and comparable in scale with that seen in temperate climate H. sapiens. The 3D analysis of CT data from a smaller sample supports this conclusion. These results suggest that the distinctive Neanderthal face cannot be interpreted as a direct result of increased pneumatization, nor is it likely to be an adaptation to resist cold stress; an alternative explanation is thus required.

Extant cercopithecoid monkeys, except macaques, are distinguished among primates by their lack of paranasal pneumatization, including the maxillary sinus (MS). Analysis of this structure, widespread among Eutheria, suggests that its loss occurred in the cercopithecoid common ancestor; thus, the presence of the MS in macaques is not strictly homologous to that in other primates. CT analysis of the fossil species Victoriapithecus macinnesi supports this view, demonstrating the lack of the MS in this stem cercopithecoid. Recent evidence, however, has documented the presence of the MS in extinct cercopithecoids from the late Miocene and Pliocene. This study reports on CT examination of two fossil crania attributed to Cercopithecoides williamsi from South Africa, dated in the range, 3.0-1.5 Ma. BF 42a is a complete cranium from Bolts Farm; MP113 is an intact facial skeleton, including the anterior cranial vault, from the Makapansgat Limeworks. Both demonstrate MS presence, unknown in extant colobines and unexpected in most cercopithecoid monkeys. The relative size of the MS of BF 42a is similar to that of extant tropical and subtropical macaques. The presence of sinuses in several extinct colobines suggests that our understanding of the evolutionary history of these primates, and of the MS, is incomplete, and that other fossil cercopithecoids should be examined for this feature. The developmental plasticity exhibited in this feature, indicated by multiple loss and reemergence, provides further evidence that paranasal pneumatization has undergone a complex history of suppression and expression.

Adaptation to climate occupies a central position in biological anthropology. The demonstrable relationship between temperature and morphology in extant primates (including humans) forms the basis of the interpretation of the Pleistocene hominin Homo neanderthalensis as a cold-adapted species. There are contradictory signals, however, in the pattern of primate craniofacial changes associated with climatic conditions. To determine the direction and extent of craniofacial change associated with temperature, and to understand the proximate mechanisms underlying cold adaptations in vertebrates in general, dry crania from previous experiments on cold- and warm-reared rats were investigated using computed tomography scanning and three-dimensional digitization of cranial landmarks. Aspects of internal and external cranial morphology were compared using standard statistical and geometric morphometric techniques. The results suggest that the developmental response to cold stress produces subtle but significant changes in facial shape, and a relative decrease in the volume of the maxillary sinuses (and nasal cavity), both of which are independent of the size of the skull or postcranium. These changes are consistent with comparative studies of temperate climate primates, but contradict previous interpretations of cranial morphology of Pleistocene Hominini.

The primate superfamily Cercopithecoidea (or Old World monkeys) is characterized by a widespread lack of the maxillary sinus, a paranasal pneumatic space found in most other eutherian mammals. Previous discus- sions of the distribution of pneumatization in the group, however, have been ambiguous and contradictory, and have been further complicated by discussion of a poorly defined structure named the "lateral recess," linked im- plicitly to the maxillary sinus. Computed tomography (CT) was applied to dry crania of all cercopithecoid genera to evaluate the morphological relevance of the term "lat- eral recess." Results suggest that the "lateral recess" is a structural consequence of changes in skull form unrelated to pneumatization. Thus, the term should be abandoned. All Old World monkeys (except the genus Macaca) are found to lack the maxillary sinus, but a previously unde- scribed bulla, only separated from the nasal cavity ante- riorly, was discovered in the Chinese golden monkey Rhi- nopithecus. If this bulla is related to the paranasal sinuses, it suggests that the initial change in cercopithe- coid cranial evolution was a suppression of pneumatic development, which may have been subsequently reversed twice in the history of the group, in Macaca and Rhi- nopithecus. J. Morphol. 258:193-199, 2003. © 2003 Wiley-Liss, Inc.

Macaques (genus Macaca) are unique among cercopithecids in that they possess a maxillary sinus, and among anthropoids in that they demonstrate a relatively weak relationship between the size of this sinus and the cranium. To test the hypothesis that extrinsic factors may contribute to maxillary sinus size variation, a sample of 46 Japanese macaque (M. fuscata) crania from known localities were subjected to computed tomography (CT) imaging, and sinus volume and nasal cavity area were analyzed relative to latitude and temperature variables. The results suggest that the environmental factors are significant determinants of nasal cavity size in Japanese macaques, but that the relationships between the environment and maxillary sinus volume (MSV) are probably a passive consequence of changes in the size of the nasal cavity. The sinus shrinks as the nasal cavity expands, due to an increased need to condition inspired air in colder climates. This in turn suggests that the sinus itself does not contribute significantly to upper respiratory function.

Cercopithecoid monkeys are unique among primates in that all species (except macaques) lack a maxillary sinus, an unusual condition among eutherian mammals. Although this uncommon distribution of cra- nial pneumatization was noted previously, the phyloge- netic ramifications have not been investigated fully. Re- cently, character state optimization analysis of computed tomography (CT) data from extant Old World monkeys suggested that the loss of the sinus may have occurred at the origin of the group, unlike previous hypotheses posit- ing only a reduction in size of the structure. To critically evaluate the "early loss" hypothesis, a recently recovered complete cranium of Victoriapithecus macinnesi from Maboko Island, Kenya, was examined by CT to determine the extent of its cranial pneumatization. This taxon is crucial for evaluating character state evolution in Old World monkeys, due to its phylogenetic position, preced- ing the cercopithecine/colobine split. CT analysis reveals only cancellous bone lateral of the nasal cavity, indicating that Victoriapithecus does not pos- sess a maxillary sinus. Phylogenetic evaluation of the fossil with extant catarrhine taxa strongly supports the early loss of the sinus in cercopithecoids. The results sug- gest that the maxillary sinus found in the genus Macaca is not homologous with that of other eutherians, which may provide insights into the origin and function (if any) of the paranasal pneumatizations. Am J Phys Anthropol 117: 293-296, 2002. © 2002 Wiley-Liss, Inc.

0047-2484/$ e see front matter 2011 Elsevier Ltd. doi:10.1016/j.jhevol.2011.08.002 In the preceding comment, Holton et al. (2011) cast doubt on the results reported by Rae et al. (2011) on the absence of cold adaptation in the facial skeleton of Neanderthals. Four specific claims in particular deserve to be addressed, to clarify the position of the present authors and the precise nature of the new data reported by Holton et al. Holton et al. interpret our findings as “incorrectly assum[ing] that paranasal sinuses play an important role in respiratory physiology”. We assumed no such thing; in fact, members of our group previously published two separate papers (Rae et al., 2003, 2006) showing that it is very unlikely that sinuses have anything to do with respiratory function. Oddly enough, both of these papers are also cited by Holton et al. Bothworks, however, are clear in showing that extreme cold stress has a demonstrable, predictable effect on the paranasal sinuses, whatever their ‘function’. This effect is not seen in Neanderthals. The focus of the research of Holton et al. has been the nasal cavity proper. By ‘ignoring’ this region, the authors suggest that we have missed the big picture.1 Our interpretation, understandably, is different. We are well aware that previous work by Franciscus and colleagues has suggested that some aspects of the Neanderthal internal nasal region suggest cold adaptation. We are also aware that other anatomical features associated with climate (including external nasal anatomy) show exactly the opposite pattern. This is precisely why their previous contribution was entitled “The paradox of a wide nasal aperture in cold-adapted Neanderthals”. Our contribution was intended to test those two alternative interpretations using another anatomical region, still with a demonstrable relationship with extreme cold stress, but that had not been

There is considerable variation in mid-late Pleistocene hominin paranasal sinuses, and in some taxa distinctive craniofacial shape has been linked to sinus size. Extreme frontal sinus size has been reported in mid-Pleistocene specimens often classified as Homo heidelbergensis, and Neanderthal sinuses are said to be distinctively large, explaining diagnostic Neanderthal facial shape. Here, the sinuses of fossil hominins attributed to several mid-late Pleistocene taxa were compared to those of recent H. sapiens. The sinuses were investigated to clarify differences in the extent of pneumatisation within this group and the relationship between sinus size and craniofacial variation in hominins from this time period. Frontal and maxillary sinus volumes were measured from CT data, and geometric morphometric methods were used to identify and analyse shape variables associated with sinus volume. Some mid-Pleistocene specimens were found to have extremely large frontal sinuses, supporting previous suggestions that this may be a diagnostic characteristic of this group. Contrary to traditional assertions, however, rather than mid-Pleistocene Homo or Neanderthals having large maxillary sinuses, this study shows that H. sapiens has distinctively small maxillary sinuses. While the causes of large sinuses in mid-Pleistocene Homo remain uncertain, small maxillary sinuses in H. sapiens most likely result from the derived craniofacial morphology that is diagnostic of our species. These conclusions build on previous studies to overturn long-standing but unfounded theories about the pneumatic influences on Neanderthal craniofacial form, whilst opening up questions about the ecological correlates of pneumatisation in hominins.