Identifying the Homology of the Short Human Pisiform and Its Lost Ossification Center

Background: The pisiform and calcaneus are paralogous bones of the wrist and ankle and are the only carpal and tarsal, respectively, to develop from two ossification centers with an associated growth plate in mammals. Human pisiforms and calcanei have undergone drastic evolutionary changes since our last common ancestor with chimpanzees and bonobos. The human pisiform is truncated and has lost an ossification center with the associated growth plate, while the human calcaneus has expanded and retained two ossification centers and a growth plate. Mammalian pisiforms represent a wide range of morphologies but extremely short pisiforms are rare and ossification center loss is even rarer. This raises the question of whether the sole human pisiform ossification center is homologous to the primary center or the secondary center of other species. We performed an ontogenetic study of pisiform and calcaneus ossification patterns and timing in macaques, apes, and humans ( Results: Human pisiforms ossify irregularly and lack characteristic features of other primates while they develop. Pisiform primary and secondary center ossification timing typically matches that of the calcaneus of non-human primates, while the human pisiform corresponds with calcaneal secondary center ossification. Finally, human pisiforms ossify at the same dental stages as pisiform and calcaneal secondary centers in other hominoids. Conclusions: These data indicate that the human pisiform is homologous to the pisiform epiphysis of other species, and that humans have lost a primary ossification center and associated growth plate while retaining ossification timing of the secondary center. This represents an exceptional evolutionary event and demonstrates a profound developmental change in the human wrist that is unusual not only among primates, but among mammals

From Lucy to Kadanuumuu: Balanced Analyses of Australopithecus afarensis Assemblages Confirm Only Moderate Skeletal Dimorphism

Sexual dimorphism in body size is often used as a correlate of social and reproductive behavior in Australopithecus afarensis. In addition to a number of isolated specimens, the sample for this species includes two small associated skeletons (A.L. 288-1 or Lucy and A.L. 128/129) and a geologically contemporaneous death assemblage of several larger individuals (A.L. 333). These have driven both perceptions and quantitative analyses concluding that Au. afarensis was markedly dimorphic. The Template Method enables simultaneous evaluation of multiple skeletal sites, thereby greatly expanding sample size, and reveals that A. afarensis dimorphism was similar to that of modern humans. A new very large partial skeleton (KSD-VP-1/1 or Kadanuumuu ) can now also be used, like Lucy, as a template specimen. In addition, the recently developed Geometric Mean Method has been used to argue that Au. afarensis was equally or even more dimorphic than gorillas. However, in its previous application Lucy and A.L. 128/129 accounted for 10 of 11 estimates of female size. Here we directly compare the two methods and demonstrate that including multiple measurements from the same partial skeleton that falls at the margin of the species size range dramatically inflates dimorphism estimates. Prevention of the dominance of a single specimen\u27s contribution to calculations of multiple dimorphism estimates confirms that Au. afarensis was only moderately dimorphic

Non-Standard Errors

In statistics, samples are drawn from a population in a data-generating process (DGP). Standard errors measure the uncertainty in estimates of population parameters. In science, evidence is generated to test hypotheses in an evidence-generating process (EGP). We claim that EGP variation across researchers adds uncertainty: Non-standard errors (NSEs). We study NSEs by letting 164 teams test the same hypotheses on the same data. NSEs turn out to be sizable, but smaller for better reproducible or higher rated research. Adding peer-review stages reduces NSEs. We further find that this type of uncertainty is underestimated by participants

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Missing Links

Recent analyses have identified more than 500 stretches of DNA that were lost from the human genome but still exist in chimpanzees and other mammals. Three stretches appear to be DNA switches, and loss of two of them freed brains to grow and humans to evolve pair bonding with mates. Loss of another switch from our ancestors may have refined our upright gait, which freed our hands to make and carry tools

Great apes and humans evolved from a long-backed ancestor

There is current debate whether the Homo/Pan last common ancestor (LCA) had a short, stiff lumbar column like great apes or a longer, flexible column observed in generalized Miocene hominoids. Beyond having only four segments, three additional features contribute to lumbar stiffening: the position of the transitional vertebra (TV), orientation of the lumbar spinous processes, and entrapment of lumbar vertebrae between the iliac blades. For great apes, these features would be homologous if inherited from a short-backed LCA but likely functionally convergent through dissimilar phenotypes if evolved from a long-backed LCA. We quantitatively and qualitatively analyzed human, ape, and monkey thoracic and lumbar vertebrae using 3D surface scanning and osteological measurements to compare spinous process morphology and sacral depth. We also used a large sample of hominoid vertebral counts to assess variation in the position of the TV and lumbosacral boundary. All extant hominoids modally place the TV at the ultimate thoracic. However, humans and orangutans place the TV at the 19th postcranial vertebral segment, whereas other apes place the TV at the 20th. Furthermore, chimpanzees, gorillas, and orangutans each have distinct patterns of spinous process angulation and morphology associated with lumbar stiffening, while human spinous process morphology is similar to that of longer backed gibbons, monkeys, and Miocene hominoids Morotopithecus and Pierolapithecus. Finally, chimpanzees are unique compared with other hominoids with a greater sacral depth facilitating lumbar entrapment, and there are differences among African apes with respect to the mechanisms governing variation in the lumbosacral boundary. These differences suggest that lumbar stiffening is convergent among great apes and that human bipedalism evolved from a more generalized long-backed ancestor. Such a model is more consistent with evidence of TV placement in Australopithecus

Developmental Identity Versus Typology: Lucy Has Only Four Sacral Segments

OBJECTIVES: Both interspecific and intraspecific variation in vertebral counts reflect the action of patterning control mechanisms such as Hox. The preserved A.L. 288-1 ( Lucy ) sacrum contains five fused elements. However, the transverse processes of the most caudal element do not contact those of the segment immediately craniad to it, leaving incomplete sacral foramina on both sides. This conforms to the traditional definition of four-segmented sacra, which are very rare in humans and African apes. It was recently suggested that fossilization damage precludes interpretation of this specimen and that additional sacral-like features of its last segment (e.g., the extent of the sacral hiatus) suggest a general Australopithecus pattern of five sacral vertebrae. METHODS: We provide updated descriptions of the original Lucy sacrum. We evaluate sacral/coccygeal variation in a large sample of extant hominoids and place it within the context of developmental variation in the mammalian vertebral column. RESULTS: We report that fossilization damage did not shorten the transverse processes of the fifth segment of Lucy\u27s sacrum. In addition, we find that the extent of the sacral hiatus is too variable in apes and hominids to provide meaningful information on segment identity. Most importantly, a combination of sacral and coccygeal features is to be expected in vertebrae at regional boundaries. DISCUSSION: The sacral/caudal boundary appears to be displaced cranially in early hominids relative to extant African apes and humans, a condition consistent with the likely ancestral condition for Miocene hominoids. While not definitive in itself, a four-segmented sacrum accords well with the long-back model for the Pan/Homo last common ancestor. Am J Phys Anthropol 160:729-739, 2016. © 2016 Wiley Periodicals, Inc

Metapodial or Phalanx? An Evolutionary and Developmental Perspective on the Homology of the First Ray\u27s Proximal Segment

The first mammalian metapodial (MP1) has periodically been argued to actually be a phalanx, because the first ray has one less element than the four posterior rays, and because the MP1 growth plate is proximal like those of all phalanges, rather than distal as in metapodials 2-5. However, growth plates are formed at both ends in non-therian tetrapod metapodials, and phylogenetic analysis demonstrates that growth plate loss is a therian synapomorphy that postdates the establishment of the mammalian phalangeal formula. These data, along with results of developmental and morphological studies, suggest that the MP1 is not a phalanx. The singular, proximal growth plates in MPs 2-5 are likely to be an adaptation to dynamic erect quadrupedal gait which was characterized by conversion of the posterior metapodials into rigid struts with the carpus/tarsus. While the adaptive significance of the reversed ossification of MP1 is less clear, we present three functional/developmental hypotheses

The Role of Hox in Pisiform and Calcaneus Growth Plate Formation and the Nature of the Zeugopod/Autopod Boundary.

The mesopodium forms at the boundary between the zeugopod and autopod and is composed of short nodular bones that typically lack growth plates. Hoxa11 and Hoxa13 are expressed in mutually exclusive proximal-distal domains that demarcate the zeugopod/autopod boundary. Similarly, Hoxd genes are deployed in two distinct phases during limb development. The early phase corresponds to proximal segments including the zeugopod, and a late phase occurs in the digits. This arrangement produces a gap of low Hoxd expression that is traditionally viewed to correspond to the mesopodium. In contrast to the other mesopodials, the mammalian pisiform and calcaneus form true growth plates. We show that these bones, along with other proximal mesopodials, develop within the Hoxa11 and Hoxd11 expression domains. We also observe that the pisiform growth plate becomes disorganized with Hoxa11 or Hoxd11 loss of function, indicating a direct role for Hox11 in its development. Hoxa13 loss of function has minimal effect on the pisiform and proximal calcaneus as these bones still form secondary centers and undergo longitudinal growth. Consideration of the phenotypes resulting from hypodactyly (Hd) and synpolydactyly homolog (spdh) mutations, which result from altered HOXA13 and HOXD13 proteins, respectively, confirms that Hox13 plays a limited role in the development of the pisiform and calcaneus and suggests that they lie within the early phase of Hox expression. Therefore, with respect to patterns of ossification and gene expression, these bones share much more in common with the zeugopod than the autopod. Such an interpretation fits with the timing of autopod origins during tetrapod evolution