Thursday, March 28, 2019

A Model for Public Access to Trustworthy and Comprehensive Reporting of Research

A Model for Public Access to Trustworthy and Comprehensive Reporting of Research. Marina Broitman, Harold C. Sox, Jean Slutsky. JAMA, March 28, 2019. doi:10.1001/jama.2019.2807

The Patient-Centered Outcomes Research Institute (PCORI) was authorized by Congress in 2010 to fund comparative clinical effectiveness research. The legislation required the institute to guarantee peer review of all research results and to make those results publicly accessible within 90 days of their receipt, requirements that were the first of their kind for a US-based research funding organization. The authorizing legislation further stipulated that the peer review should assess the scientific integrity of each study and its adherence to the methodological standards established by the PCORI methodology committee.1 The law broadly defined the forms of peer review that would be acceptable.

The PCORI board of governors, after comment from patients, clinicians, professional interest groups, and journal editors, established a peer review process2 requiring all awardees to submit a comprehensive final report for PCORI-based external peer review. After final approval, the institute would post on its website lay and technical abstracts of the report; the complete, approved final report and study protocol; and a summary of the peer review critiques and the authors’ responses to those critiques. This Viewpoint describes the peer review system and the comprehensive report, which are the essential elements of this program, and discusses the problems each raise and the potential benefits.

The PCORI peer review process is similar to the review process at some journals in its use of methods experts and clinician-scientists as external reviewers. However, PCORI peer review is unique in its recruiting of patients, caregivers, health care professionals, and policy makers to critique the relevance and usefulness of the research. The institute engaged a contractor to manage the external peer review process to help ensure its impartiality. Each report receives 4 to 5 external reviews and a comprehensive review from the peer review editor.

The final research report is structured like a journal article, but is 3 to 4 times longer to accommodate a complete account of all study aims, methods, and results. The report also includes an account of the study’s adherence to the PCORI methodology standards1 and a section for patient engagement in research, in which the authors describe their partnership and collaborations with interested groups and individuals (including patients and other health care decision makers) in the development, implementation, and interpretation of the study. Per legislative requirements, the report must describe the study limitations and how the comparative effectiveness of the study interventions differs among various subgroups of study participants.

From October 6, 2016, to February 28, 2019, there were 275 final reports submitted for peer review and 206 had completed all revisions following peer review. As of February 28, 2019, PCORI has posted 177 publicly available lay and technical abstracts based on those reports as well as 41 of the full reports. Posting the study results could jeopardize journal publication; therefore, the institute waits 12 months after completion of peer review to post the final research report on its website unless the main study results have already been published in a journal article.

The institute met its legislative mandates. It established a peer review process and the requirement to write a comprehensive report, and it publishes lay and technical abstracts of the final report within 90 days of completing peer review. The vision of the sponsors of the legislation (ie, prompt public access to all study results following peer review) is achievable but at what cost and with what benefits? It is possible now to describe some of the challenges and speculate about potential benefits.

To assess the effects of requiring a comprehensive report, the institute surveyed 191 investigators about their experiences with final research report preparation and peer review and 52% responded. Some awardees raised complaints about the burden of writing a comprehensive final report and responding to peer review when they are preparing manuscripts to submit to journals. Others reported that writing the final report helped them to identify topics, text, and tables for focused articles. Many did not see an added value from the comprehensive final report, which increased their frustration with the time and effort involved. Survey respondents estimated that their research teams spent between 160 to 255 hours preparing the final report and responding to reviewer critiques.

The peer review process is taking longer than originally expected. Instead of the 4 to 6 months estimated by the PCORI board of governors,2 peer review takes a median of 8 to 9 months from submission to final acceptance. Unlike journals that can quickly reject unsuitable articles, the institute must accept and publicly post all reports. Some reports require many rounds of review and revision, which delays completion of peer review and public release of the results.

These problems are present and real, whereas the most substantial benefits lie in the future. First, the public is likely to benefit from a full report of research even when the results are unlikely to change practice. Because inconclusive studies are the least likely to be published in a scientific journal,3 the published body of evidence is incomplete and is likely biased toward positive results,4 which is a problem for systematic reviewers, guideline developers, and many others who rely on evidence to make decisions, including clinicians and patients. Journal articles and research registries each play a key role in informing the public, but a comprehensive final research report can fill a gap in public reporting by providing an in-depth account of a study, including all results and lessons learned from doing the research, regardless of study success.

Second, study authors may benefit from the institute’s peer review of their final research report before they submit manuscripts to a journal. Researchers can use the critiques by the PCORI peer reviewers to anticipate the concerns of journal reviewers and shape journal manuscripts accordingly. When the final research report for the institute is prepared (after publication of a journal article), authors can include information that journals typically do not publish such as a narrative account of how the study unfolded (including explanations of key decisions) and a full account of the patients and others who partnered with the researchers to conduct the study.

Dual peer review and publication could cause problems, especially when the description of research in a journal article conflicts with the final report. These differences are best handled by transparent reporting of the reasons for the discrepancies. When report authors disagree with the recommendations from the peer reviewers, both sides of the disagreement are captured in the peer review summary.

Third, a comprehensive final report supports the goal of increasing the efficiency of research by providing essentially unlimited space in which to describe how a 3- to 5-year study developed and evolved and to transmit all results and lessons learned to other researchers and funding agencies.5 Posted final research reports that provide all study results, including unpublished secondary or inconclusive results, may provide leads for others to investigate, describe pitfalls to avoid, or describe a line of investigation that led nowhere and should be avoided.

Fourth, the funder that requires a final research report can learn from systematically examining the research that it has supported, especially if reports have been peer reviewed. Ongoing review of its body of funded research could inform many aspects of the work of a funding agency such as the choice of high-priority research topics for funding announcements, instructions to applicants, the evaluation of research proposals, postaward negotiations to strengthen the study, and monitoring research while it is in progress. Peer review of adherence to the PCORI methodology standards has identified several recurring methodological shortcomings that the institute must address.

In the future, these potential benefits of requiring a peer-reviewed, publicly available comprehensive final report will be weighed against the costs. In a few years, it will be possible to determine if these final reports have expanded the reach of each research study, whether they are used in systematic reviews, and how lessons learned from peer review of the final reports have changed the way that the institute does its work. For the present, it may be enough to hope that an openly accessible peer-reviewed comprehensive final research report will help to increase public trust in research. It is possible that the sponsors of the legislation were on to something important when they set the institute on this path. However, the realization of their vision is in its infancy and its putative benefits are largely speculative. There is still much to learn.

The human nose could have evolved to separate olfactory inputs to enhance stereo olfaction; as humans became more sedentary in the Neolithic, maybe other functions appeared (detecting disease in newly dense human settlements)

The navigational nose: a new hypothesis for the function of the human external pyramid. Lucia F. Jacobs. Journal of Experimental Biology 2019 222: jeb186924. February 6 2019, doi: 10.1242/jeb.186924

ABSTRACT: One of the outstanding questions in evolution is why Homo erectus became the first primate species to evolve the external pyramid, i.e. an external nose. The accepted hypothesis for this trait has been its role in respiration, to warm and humidify air as it is inspired. However, new studies testing the key assumptions of the conditioning hypothesis, such as the importance of turbulence to enhance heat and moisture exchange, have called this hypothesis into question. The human nose has two functions, however, respiration and olfaction. It is thus also possible that the external nose evolved in response to selection for olfaction. The genus Homo had many adaptations for long-distance locomotion, which allowed Homo erectus to greatly expand its species range, from Africa to Asia. Long-distance navigation in birds and other species is often accomplished by orientation to environmental odors. Such olfactory navigation, in turn, is enhanced by stereo olfaction, made possible by the separation of the olfactory sensors. By these principles, the human external nose could have evolved to separate olfactory inputs to enhance stereo olfaction. This could also explain why nose shape later became so variable: as humans became more sedentary in the Neolithic, a decreasing need for long-distance movements could have been replaced by selection for other olfactory functions, such as detecting disease, that would have been critical to survival in newly dense human settlements.


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Human olfactory navigation

Olfaction is often underestimated as a sensory basis for navigation (Jacobs, 2012). This neglect is particularly acute in the study of human navigation (Jacobs et al., 2015). This is partly because primates, and particularly humans, have erroneously been assumed to have exceptionally poor olfactory abilities (Laska et al., 2000; McGann, 2017; Shepherd, 2004). Yet, in many species, including humans, the largest gene superfamilies are those for olfactory receptors (Hasin-Brumshtein et al., 2009). And while primates are indeed highly visual (Smith et al., 2007, 2014), visual acuity does not preclude the use of olfaction for long-distance movements in other highly visual animals such as birds (Wallraff, 2005).
Descriptive reports of humans using odors to navigate have a long history (Porteous, 1985; Gatty, 1983), especially in the visually impaired (Koutsoklenis and Papadopoulos, 2011), although there are to date only two experimental studies of olfactory navigation in humans. In the first study, humans were shown to accurately follow an odor trail of chocolate across a grassy field, and their accuracy was enhanced by stereo olfaction (Porter et al., 2007). In another study, humans were able to learn and map an arbitrary location in a room using only odor gradients (Jacobs et al., 2015).
Clearly, the human ability to orient to odors is not as highly developed as that of olfactory specialists, such as the domestic dog. First, the human internal nasal chamber is smaller than expected for a mammal of its body size (Zwicker et al., 2018). Its chamber lacks an olfactory recess, a feature found in the domestic dog that separates the olfactory air stream from the respiratory air stream. The recess is thought to retard and enhance the processing of air to extract odors (Craven et al., 2010, 2007).
But to make the analogy with birds once again: just because human olfaction is inferior does not mean it is not functional. Modern birds also have a reduced olfactory system in comparison to their archosaur ancestors (Zelenitsky et al., 2011). Yet, bird olfactory bulb size may be adapted to different ecological niches (Corfield et al., 2015), including long-distance travel: diverse bird species rely primarily on olfaction for orientation during migration and experimental displacement (Wallraff, 2005; Gagliardo, 2013; Holland et al., 2009; Wikelski et al., 2015). Air-borne odors can be stable across time and hence may offer unique value to navigators, as a long-distance sensory highway (Safi et al., 2016). This property of air-borne odors could lead to selection for olfactory navigation skills, even in highly visual and auditory species, such as birds and bipedal apes.

Stereo olfaction

Comparative studies can offer clues as to what properties of the human nose would support such olfactory navigation. A primary function would be stereo olfaction, or the spatial separation of paired sensors to increase the accuracy of directional orientation, similar to stereo audition (von Békésy, 1964). von Békésy's (1964) hypothesis has been supported by studies from a wide range of invertebrate and vertebrate species: honey bee (Apis mellifera) (Martin, 1965), desert ant (Cataglyphis fortis) (Steck et al., 2010), fruit fly (Drosophila melanogaster) (Borst and Heisenberg, 1982), terrestrial snail (Achatina fulica) (Chase and Croll, 1981), giant garden slug (Limax maximus) (Gelperin, 1974), blacktip shark (Carcharhinus limbatus) (Gardiner et al., 2015) and sharks in general (Gardiner and Atema, 2010), brown bullhead catfish (Ictalurus nebulosus) (Bardach et al., 1967; Johnsen and Teeter, 1980), the bifurcated tongue of snakes (Schwenk, 1994), laboratory rat (Rattus norvegicus) (Rajan et al., 2006; Khan et al., 2012), eastern American mole (Scalopus aquaticus) (Catania, 2013), domestic dog (Canis lupus familiaris) (Craven et al., 2010) and human (Porter et al., 2007). The manipulation of crossing the inputs also eliminates the ability to orient in space to odors, both in animals with antennae (Martin, 1965) and in those with nares (Catania, 2013).
The critical variable in stereo olfaction is the physical separation of the catchment areas in the fluid, whether air or water, in which odorants are suspended. Sensor mobility will be critical in determining the volume of fluid sampled and the separation of the catchment areas, with greater separation allowing for greater accuracy in orientation. For example, a honey bee with two fixed antennae oriented less accurately to an odor source than a bee with two mobile antennae (Martin, 1965). For vertebrates with nares, Stoddart (1979) proposed that the key variable may instead be the length and flexibility of the neck, suggesting this could explain why vertebrates with less flexible necks, such as salamanders, have more widely spaced nares. This increased nasal breadth would theoretically increase the separation of the samples and hence compensate for the lack of head mobility seen in vertebrates with less flexible necks (Stoddart, 1979). The same reasoning has been used to study the separation of nostrils in sharks such as the hammerhead shark, where computational models predict that this separation increases the shark's accuracy in directional orientation (Rygg et al., 2013; Gardiner and Atema, 2010).
A third principle that has been proposed to enhance stereo olfaction, in addition to using the movement of antenniform structures or increasing the spatial separation of the nares, is the addition of a tube-like vestibule to the nares. The use of tube noses to increase the accuracy of stereo olfaction was first proposed by Stoddart (1979) to explain the distribution of tube noses in several bat families (Vespertilionidae subfamilies Nyctimeninae and Murininae; also in Pteropodidae). A recent study of the physics of siphons offers direct support for Stoddart's (1979) hypothesis. When fluids are siphoned into a simple vertical tube, the size and separation of the catchment area are determined by the velocity of movement of the fluid and the height of the tube entrance from the bed on which it stands. The greater the distance between the bed and the siphon opening, the greater the spatial separation between the siphon and the catchment area from which the siphon draws in fluids. There is a further additive effect of fluid velocity, such that a tall tube, pulling in fluid at a higher velocity, will be sampling from areas that are farther apart than a siphon that is flush with the bed's surface or is pulling in fluids at a lower velocity (True and Crimaldi, 2017).
This result has important implications for understanding the adaptive significance of tube noses. A longer tube would therefore increase the spatial separation of odor samples, effectively increasing the distance between the sensors. Additionally, the further separation of these samples could be controlled by varying the intensity of the inhalation, which would increase the velocity of the fluid, further separate the catchment areas and thus further enhance stereo olfaction.
The hypothesis that a tube nose enhances stereo olfaction may explain the presence of this trait not only in bats but in birds. Tube-nosed seabirds (Procellariiformes), which include shearwaters and albatrosses, are well known for their ability to orient to odors, such as the krill metabolites that are odor proxies for the presence of prey (Nevitt, 2008). Tube-nosed seabirds are also thought to use olfaction to orient during long-distance movements over water, in the absence of proximal visual landmarks (Reynolds et al., 2015; Safi et al., 2016; Dell'Ariccia et al., 2014). In addition, the relative size of the olfactory bulbs is also larger in aquatic bird species (Corfield et al., 2015). It is therefore possible that the demands faced by these seabirds have led to the evolution of tube-like appendages to further separate catchment areas and thus enhance olfactory navigation accuracy.
It is interesting that tube noses have evolved in vertebrate taxa that have evolved powered flight; relatively larger olfactory bulbs are associated with increased space use in homing pigeons (Mehlhorn and Rehkämper, 2009), which navigate using odors (Wallraff, 2005). Mapping an odor gradient may be done more accurately with the greater number of samples possible over larger distances and hence may be more valuable in species using long-distance movements, such as flying insects and vertebrates (Jacobs and Menzel, 2014). But this logic might also apply to terrestrial vertebrates that cover large distances, e.g. cursorial vertebrates, such as carnivores and humans; relatively larger olfactory bulbs are also found in terrestrial carnivores that range over longer distances (Gittleman, 1991). If increases in space use are associated with an increased use of olfactory navigation, then this constraint may be relevant to the genus Homo, the first hominid to significantly increase space use and leave Africa (Antón et al., 2014). To answer this, we must first consider the question of the hominid nose in the context of other primates.

Olfaction in Homo

Perhaps external nose morphologies in primates, including Homo, can also be explained by the olfactory spatial hypothesis (Jacobs, 2012). As a catarrhine, the genus Homo is one of the least olfactory primates, yet it is the only primate to have evolved a large external nose. The only exception to this is the catarrhine proboscis monkey (Nasalis larvatus), but in this case the external nose is used by males in audiovisual communication and does not appear to be specialized for olfaction (Koda et al., 2018).
The human external nose shows several unique features (Figs 1 and 2). The external pyramid encloses generally inferior-orienting nares, a trait not found in other great apes. The pyramid encloses the nares within the alae nasi, the cartilaginous structures surrounding each naris, separated by a third structure, the columella, a protrusion between the two alae. No current hypothesis posits a respiratory function for the alae nasi or columella.
Yet, such structures could theoretically enhance olfaction, specifically stereo olfaction. It is a testable hypothesis that the alae nasi could act as tube noses, where a greater length of nasal vestibule would correspond with greater separation of the catchment areas of inspired air. The unique inferior orientation of the human nares, separated by the columella, might also further separate the geometry of the catchment areas during inspiration. Finally, the external pyramid itself could increase the distance between the nares and, to a greater extent than that seen in platyrrhine monkeys, could also enhance stereo olfaction. These predictions could be tested by measuring the effect of nasal metrics on a human's accuracy in orienting to an odor gradient. Using standard methods, it should be possible to measure the effect of nasal breadth on orientation accuracy to odors distributed in plumes. If supported, then the navigational nose hypothesis could then be used to address the remaining questions about the human external nose: why did it appear when it did and why did nasal breadth and height subsequently become so variable in modern humans?

Why did it evolve?

The external pyramid first appeared in Homo erectus (Franciscus and Trinkaus, 1988) (Fig. 6). Early Homo evolved in an increasingly unpredictable climate, with periods of great aridity, and forest habitats changing to grasslands (Antón et al., 2014). This change in climate and habitat structure led to selection in Homo for a suite of traits to increase bipedal locomotory efficiency, such as increased lower limb length, which allowed archaic humans to forage more economically for widely dispersed resources (Steudel-Numbers, 2006; Bramble and Lieberman, 2004; Kuhn et al., 2016; Antón et al., 2014; Antón, 2012; Lieberman, 2011).
Fig. 6.
A reconstruction of Homo erectus. An early African Homo erectus, based on the skull KNM-ER 3733. Reproduced with permission from Gurche (2013).
Another major behavioral shift in Homo at this time was an increase in carnivory, a shift that brought the genus into direct competition with other mammalian carnivores (Churchill et al., 2016). Given this interspecific competition between humans and other African carnivores, it may be most fruitful to ask not what species humans are most closely related to but to which species they are most ecologically similar (Schaller and Lowther, 1969). Humans were competing not only with cursorial carnivores but also with olfactory specialists, species that used olfaction both to detect prey and to orient in space. Carnivory, space use and olfactory bulb size may be generally associated, as they are in terrestrial carnivores (Gittleman, 1986) and theropod dinosaurs (Zelenitsky et al., 2011, 2009); a similar association between carnivory, space use and olfaction may be seen in piscivorous birds (Wikelski et al., 2015) and sharks (Nosal et al., 2016).
Many African carnivores, such African lions (Panthera leo), wild dogs (Lycaon pictus) and spotted hyenas (Crocuta crocuta), are also highly social and hunt cooperatively (Smith et al., 2012). To compete in this environment, Homo sapiens also became, like their competitors, increasingly social, both hunting and breeding cooperatively (Hrdy, 2007). The ability to hunt cooperatively, even before the development of weaponry, changed many aspects of human socio-ecology. One behavior that may have evolved at this time is the use of endurance pursuit to capture large game (Carrier et al., 1984; Bramble and Lieberman, 2004). Endurance pursuit requires accurate spatial orientation, while tracking and returning to camp (Liebenberg, 2008). Such long-distance travel could also have selected for new navigational skills, such as olfactory navigation.
There are additional navigational costs of carnivory beyond prey search and handling. Carnivory carries with it a higher risk of foraging with zero return than does foraging for non-meat foods. Hence, a primary mechanism that has been shown to insure against such risk is to maintain large social networks for food sharing (Grove, 2009). In models of hunter–gatherer food sharing, greater cooperation and the elimination of free riders is supported primarily by increased mobility (Lewis et al., 2014). One of the true costs of carnivory may therefore be the need for cooperative hunting and a widely dispersed social network for food sharing, a behavior that would be made efficient with more accurate spatial navigation.
Thus, olfactory navigation in Homo could have represented an important new technical skill to increase the efficiency of space use. This, in turn, would have selected for mechanisms of stereo olfaction. It has also been proposed that it was these adaptations for increased mobility that allowed archaic humans to subsequently expand their species distribution (Kuhn et al., 2016); by 1.8 million years ago, Homo erectus had expanded out of Africa and become established in Georgia, Indonesia and possibly China (Antón et al., 2014).

Implications for sex differences

Both the conditioning hypothesis and the navigational hypothesis posit that the human external nose evolved as an adaptation for long-distance movement. Thus, both hypotheses are predicated on the same ecological demand: increased space use in an arid environment, necessitating efficient conditioning and efficient navigation. Individual differences in long-distance travel should therefore be reflected in nasal structure.
Although men generally have larger range sizes than women (Gaulin, 1992), women may also forage over long distances (Jones et al., 1994). Both may orient using odor and hence both could benefit from stereo olfaction. The advantage of stereo olfaction may operate at different spatial scales. In a landscape defined both by arrays of local landmarks and distant cues that supply compass directions, females weight proximal landmark cues more heavily than do males (Jacobs and Schenk, 2003; Chai and Jacobs, 2010; Bettis and Jacobs, 2013). But it is not clear at what scale stereo olfaction is most effective when tracking an odor plume; stereo olfaction is clearly important in close-range orientation to odors (Catania, 2013; Porter et al., 2007). Unlike a distant visual object that provides direction, plumes are not contiguous in space but are a collection of discrete filaments (Murlis et al., 1992). Thus, the local structure must be analyzed to deduce the global structure. In this light, stereo olfaction might be valuable for the analysis of both close and distant resources. The key factor is the added value of a second sensor, as has been recently demonstrated in an information theoretical model of optimal sampling for spatial orientation in an empirically measured odor plume (Boie et al., 2018). In short, the evolution of the external pyramid could have been equally adaptive for women building high-resolution maps of resources near the home base or men building low-resolution maps of distant resources.
The use of long-distance foraging by men, in particular endurance pursuit, may also explain sex differences in the relative size of the external and internal nose. In a sample of European-descent Americans, men had larger external noses, both absolutely and relative to body size, than did women (Holton et al., 2014). In a study using crania from diverse worldwide populations, males also had a relatively larger nasal chamber volume than women, including relative larger choanae, i.e. the posterior opening leading to the lungs (Bastir et al., 2011). The authors conclude that the larger internal chamber and choanae in males would allow a greater volume of air to be conditioned during exercise (Bastir et al., 2011). A similar sex difference in internal nose dimensions has been documented in imaging studies of German and Chinese adults, with men showing a relatively larger nasal aperture than women (Schlager and Rüdell, 2015).
Such sex differences in nose morphology could have arisen via sexual selection in males for enhanced respiration during long-distance travel. The choanae, for example, which are relatively larger in males, have a purely respiratory function (Bastir et al., 2011). Thus, while the original appearance of the external nose in Homo erectus may have been due to natural selection for increased space use in both sexes of the species, other nasal structures could have been shaped by sexual selection to enhance a male's ability to compete with other men, such as in endurance pursuit. Male hunting skill in hunter-gatherer societies can often be interpreted as a trait driven by female choice and may be the product of both natural selection for foraging and sexual selection for male–male competition (Hawkes and Bird, 2002).
Sexual selection for navigation might also explain patterns in olfactory bulb size. In a German sample, both absolute olfactory bulb size and olfactory function developed gradually between the ages of 6 and 17 (Hummel et al., 2011). It increased throughout adulthood to peak around age 40 and then declined in both women and men, although the absolute size of the olfactory bulb was consistently larger in men (Buschhüter et al., 2008). Forty is also the age at which mortality begins to increase in hunter–gatherers, peaking at a model adult death of 70 years (Gurven and Kaplan, 2007). Finally, olfactory bulb size is positively correlated with olfactory function (discrimination and threshold) in humans (Buschhüter et al., 2008; Hummel et al., 2011, 2013; Mazal et al., 2016; Seubert et al., 2013). This suite of characters in human males could be an adaptation for efficient foraging, a difference that might emerge at puberty and extend over the peak hunting years, where accurate spatial orientation to odors might be enhanced by a larger external nose, while the capacity for oxygen exchange would be increased by a larger internal nasal chamber and choanae.
In contrast, women might have evolved a different suite of olfactory specializations, in addition to the stereo olfaction afforded by an external nose. Women consistently outperform men on measures of odor identification, for both social and non-social odors (Doty and Cameron, 2009). In a cross-cultural study of Japanese, Italian and German participants, women more accurately identified the sex and individual identity of an axillary odor (Schleidt et al., 1981); in a study of American college students, women could more accurately identify their own axillary odor than could men (Platek et al., 2001). Thus, in social encounters, women may have access to more accurate olfactory information than men.
These sex differences could arise from sex differences in olfactory system plasticity. The olfactory system changes rapidly (e.g. within months) if given repeated exposures to an odor, even in humans that are initially anosmic to the odorant (e.g. androsterone) (Wysocki et al., 1989). Repeated exposures both decreased the threshold of detection and increased absolute olfactory bulb size in the subject (Haehner et al., 2008). Even when only one nostril is exposed to the odor, both olfactory bulbs increased 11–13% in volume after 4 months (Negoias et al., 2017). This effect of repeated exposure decreasing the threshold of detection for an odor is significantly stronger in women than in men (Dalton et al., 2002).
Therefore, experience-dependent sex differences in social experiences and hence olfactory exposure could lead to the observed female advantage in olfactory identification. These female advantages might also arise via sexual selection, in this case selection for enhanced social intelligence. This form of neural plasticity could also support related skills, such as tracking and mapping the distribution of other resources, e.g. food and medicinal plants, that could be identified most accurately by odor. Relevant to this, a new study has demonstrated that a human's ability to identify odors co-varies with their ability to learn landmark locations in a virtual environment. These cognitive skills also co-varied with the size and integrity of brain structures involved in both spatial navigation (right hippocampus) and olfaction (left orbitofrontal cortex) (Dahmani et al., 2018), in accordance with the olfactory spatial hypothesis (Jacobs, 2012). This tight relationship between olfaction and spatial memory could have evolved via selection for mapping resources via chemical cues.
The predictions of these proposed sex-specific specializations, whether long-distance travel in men or resource tracking in women, are amenable to empirical testing. Re-framing the human external nose as an olfactory structure could lead to new insights into human perception and brain plasticity and their modulation by natural and sexual selection.

Review of Mustafic et al.'s Main air pollutants and myocardial infarction: a systematic review and meta-analysis. JAMA. 307:713-721

Evaluation of a meta-analysis of air quality and heart attacks, a case study. S. Stanley Young and Warren B. Kindzierski. Critical Review in Toxicology, Jan 2019. https://doi.org/10.1080/10408444.2019.1576587

ABSTRACT: It is generally acknowledged that claims from observational studies often fail to replicate. An exploratory study was undertaken to assess the reliability of base studies used in meta-analysis of short-term air quality-myocardial infarction risk and to judge the reliability of statistical evidence from meta-analysis that uses data from observational studies. A highly cited meta-analysis paper examining whether short-term air quality exposure triggers myocardial infarction was evaluated as a case study. The paper considered six air quality components - carbon monoxide, nitrogen dioxide, sulphur dioxide, particulate matter 10um and 2.5um in diameter (PM10 and PM2.5), and ozone. The number of possible questions and statistical models at issue in each of 34 base papers used were estimated and p-value plots foreach of the air components were constructed to evaluate the effect heterogeneity of p-values used from the base papers. Analysis search spaces (number of statistical tests possible) in the base paperswere large, median=12,288 (interquartile range = 2496 — 58,368), in comparison to actual statistical test results presented. Statistical test results taken from the base papers may not provide unbiased measures of effect for meta-analysis. Shapes of p-value plots for the six air components were consistent with the possibility of analysis manipulation to obtain small p-values in several base papers. Results suggest the appearance of heterogeneous, researcher-generated p-values used in the meta-analysis rather than unbiased evidence of real effects for air quality. We conclude that this meta-analysis does not provide reliable evidence for an association of air quality components with myocardial risk.

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As of April 2018 theWeb of Science indicated that this study had received enough citations to place it in the top 1% of the academic field of Clinical Medicine for the publication year 2012.

Positive Sanctions versus Imprisonment: Paying people to stay out of criminal life

Positive Sanctions versus Imprisonment. Murat C. Mungan. George Mason Law & Economics Research Paper No. 19-03. January 17, 2019. https://papers.ssrn.com/sol3/papers.cfm?abstract_id=3317552

Abstract: This article considers the possibility of simultaneously reducing crime, prison sentences, and the tax burden of …financing the criminal justice system by introducing positive sanctions, which are benefits conferred to individuals who refrain from committing crime. Specifically, it proposes a procedure wherein a part of the imprisonment budget is re-directed towards financing positive sanctions. The feasibility of reducing crime, sentences, and taxes through such reallocations depends on how effectively the marginal imprisonment sentence reduces crime, the crime rate, the effectiveness of positive sanctions, and how accurately the government can direct positive sanctions towards individuals who are most responsive to such policies. The article then highlights an advantage of positive sanctions over imprisonment in deterring criminal behavior: positive sanctions operate by transferring or creating wealth, whereas imprisonment operates by destroying wealth. Thus, the conditions under which positive sanctions are optimal are broader than those under which they can be used to jointly reduce crime, sentences, and taxes. The analysis reveals that when the budget for the criminal justice system is exogenously given, it is optimal to use positive sanctions when the imprisonment elasticity of deterrence is small, which is a condition that is consistent with the empirical literature. When the budget for the criminal justice system is endogenously determined, it is optimal to use positive sanctions as long as the marginal cost of public funds is not high.

Keywords: Positive sanctions, carrots, sticks, crime, deterrence, imprisonment, mass incarceration, over-incarceration
JEL Classification: K00, K14, K42

A Comparative Approach to Morphological, Behavioral and Neurophysiological Aspects of Sexual Signaling in Women and Nonhuman Primate Females

Sexual Attractiveness: a Comparative Approach to Morphological, Behavioral and Neurophysiological Aspects of Sexual Signaling in Women and Nonhuman Primate Females. Bernard Wallner et al. Adaptive Human Behavior and Physiology, March 28 2019. https://link.springer.com/article/10.1007/s40750-019-00111-6

Abstract
Objective and Methods: This review focuses on comparative data in nonhuman primates and humans in relation to signaling secondary sex characteristics (SSC), sexual behavior, and neurophysiology of sexuality during the female cycle.

Results: In monkeys and apes no clear distinction can be drawn between sex as a reproductive, social, or a pleasurable activity. Although female sexual behavior is not limited to a specific phase of the menstrual cycle, changes in body morphology and in behavior and psychology (for example, in feeding, risk taking, and mood) can occur across the cycle. In human and nonhuman primates, homologous biological mechanisms including specific areas of the brain, sex steroids, and receptors are involved in regulating female sexuality. Important aspects of this regulation include the interaction between the subcortical reward system and the social brain network and its projection to the prefrontal cortex. In humans, females advertise SSC permanently after the onset of puberty, but without significant changes across the cycle, whereas in other primate species, female sexual signaling can vary significantly across cycle stages and in fertile and non-fertile phases of the life cycle.

Conclusion: A great deal is now known about the regulation of female sexuality in primates and the use of sexual signals in terms of their variable expression and their information content for males. Human research has also elucidated the cultural mechanisms through which women communicate about their sexuality, including clothes and make-up. A full understanding of female sexuality in humans, therefore, requires knowledge of culture-biology interactions.

Keywords: Comparative primatology Sexual attractiveness Neurophysiological organization Behavior

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Introduction

Female ovarian cycles have been thoroughly studied in many species of mammals. A great deal of research on endocrine mechanisms in relation to behavioral expression rates throughout different cycle stages has elucidated both the proximate regulation and the functional significance of female sexual and reproductive strategies in mammals. Female sexuality involves complex interactions between neuroendocrine mechanisms in relation to neurotransmitter activities to modulate behavior. Such neurophysiological processes are only partially understood in primates.
In most mammals, sexual activities are limited to the periovulatory period of the female cycle. This period is characterized by elevated estrogen concentrations leading to ovulation, followed by an increase of progesterone secretion that facilitates the implantation of the egg into the uterus. In general, sexual activity is correlated with estrogen increase and is reduced at elevated progesterone levels. The period of the cycle in which females are sexually receptive and sexually active is termed estrus.
The best-investigated female sexual behavior in terms of physiology and neurobiology is the lordosis reflex in rodents. This is a posture in which females allow male intromission. Shortly before ovulation, males approach their mating partners and mount them. This sensory interaction enables the lordosis reflex, which is controlled by the sex steroids estradiol and progesterone. The behavioral aspect of this reflex is regulated by subcortical hypothalamic brain structures such as the ventromedial nucleus and the periacqueductal gray, where ovarian hormones find acting sites to facilitate the reflex (Flanagan-Cato ; Uphouse ). The regulation of lordosis behavior involves complex neurobiological circuits and their underlying neurochemistry. As illustrated by Beach (), females advertise their sexual readiness to males with their attractiveness, followed by proceptivity (behavioral signals to males such as solicitation to copulate), and then by receptivity to copulatory behavior with subsequent ejaculation.
These three aspects of female sexuality are related to hormonal changes during the female cycle and ultimately serve the process of reproduction. The Beach paradigm was thought to encompass more or less all non-primate mammalian species. In primates, instead, it has long been known that females do not limit their sexual behavior to specific cycle stages and to the corresponding hormone fluctuations (Dixson ). In humans in particular, copulations can occur during all cycle stages (Dixson ). This has led some to believe that human sexuality is completely emancipated from its biological regulation and entirely dependent on volitional and cultural factors. It is, however, very unlikely that humans continued to evolved by natural selection up to the Pleistocene, but then suddenly stopped after settling and farming (approx. 10,000 years ago). Rather, it is more likely that cultural and genetic processes mutually interacted throughout all human evolution (Richerson et al. ). Natural selection is still acting on certain traits in contemporary humans (Byars et al. ) and producing adaptations through culture-gene co-evolution. This process may operate much more quickly than previously thought (Field et al. ). Although there are some important differences between human female sexuality and female sexuality in nonhuman animals, the prevalent view emphasizes continuity rather discontinuity between humans and other animals, especially other primates. Therefore, in this article, we highlight the many similarities between humans and nonhuman primates in hormone secretions, neurophysiological subcortical organization, and female sexual behavior during the reproductive cycle, with particular emphasis on the signaling of Secondary Sexual Characteristics (SSC).

Hormones, Behavior and SSC

In nonhuman primates, similar to other mammals, during the female’s cycle, sex steroid hormones are regulated by the release of the pituitary gland peptides follicle-stimulating hormone (FSH) and luteinizing hormone (LH). FSH stimulates the growth of the sex cells, the ovarian follicles; LH in high concentrations induces ovulation in Graafian follicles that have been primed with FSH. Data on rhesus macaques show that preovulatory LH and FSH peaks affect estradiol increases and thus represent important prerequisites for a successful ovulation (Dixson ). More than 40 years ago, Dixson et al. () reported not only a periovulatory increase of estradiol in primates, but also a similar peak of the androgen testosterone. Later, Nadler et al. () demonstrated an association between estradiol and testosterone concentrations during the mid-cycle phase and maximum perineal swelling size in the common chimpanzee. Moreover, the mid-cycle estradiol and testosterone peaks in chimpanzees are comparable to those in women (Morris et al. ).

The Three-Fold Impact of SSC in Nonhuman Primates: Attractiveness, Fertility, and Sociality

Females of many nonhuman primate species exhibit sexually attractive signals during their cycle. The most prominent signals are coloration and/or perineal swelling. The coloration and degree of anogenital swelling size may affect the vulva area, the clitoris, to some extent the perineal region, and the area around the ischial callosities (Dixson ). Both coloration and perineal swelling can vary dramatically among females in a group. Their expression rates are controlled by the sex steroids estradiol and progesterone. Estradiol enlarges swellings by transferring water into the intercellular tissue, and an increased blood flow causes more intensive coloration (Bradley and Mundy ). After ovulation, the luteal steroid progesterone reduces the swellings (Wildt et al. ). Both the intensity of coloration and the size of the swelling are most pronounced during the periovulatory period (Wallner et al. ; Möhle et al. ).
These periods are correlated with the highest copulation frequencies, and the probability of fertilization is highest as well. Nonetheless, studies on Barbary macaques indicate that sexual interactions are not limited to the periovulatory period and are therefore displayed independently of the probability of fertilization, e.g., pregnant females with perineal swellings can copulate as much as non-pregnant ones (Küster and Paul ). However, fluctuations in swelling size and/or coloration are often correlated with low sex hormone secretion rates and with sexual behavior. Lactating females too can show sexual solicitation behavior and copulations (Brauch et al. ). A comparison between non-lactating and lactating females in Japanese macaques revealed more intensive red coloration and copulations (with and without ejaculations) for non-lactating females during sexually active periods (Wallner et al. ). However, copulations (with and without male ejaculation) were not uncommon among lactating females, although they showed slight changes in coloration intensity and their sex steroid production was significantly lower compared to non-lactating females. Less well-understood is the functional significance of changes in coloration intensity and size of the perineal swellings in Tibetan macaques, as females in this species do not exhibit any typical behavior associated with estrus and they copulate frequently outside the mating season (when SSC are not obviously expressed) (Li et al. , ). Non-reproductive copulations were not observed in pregnant or lactating individuals and typically involved adolescent males. Such copulations often occurred after social conflicts, whereby females approached males and solicited copulation, suggesting a social function of sexual behavior (Li et al. ).
Ovariectomy does not suppress female sexual behavior in Old and New World monkeys. In stumptail (Baum et al. ) and rhesus macaques (Chambers and Phoenix ) ovariectomized females show some sexual receptivity, and in the common marmoset (Kendrick and Dixson ) males still exhibit high copulation frequencies with ovariectomized females. Baboon females that had been ovariectomized hardly drew the attention of singly housed males when placed in visual, olfactory, and auditory contact with them (Girolami and Bielert ). Nonetheless, if the same females were provided with large artificial swellings, then the males became sexually aroused and masturbated.
Masturbation is not unique to humans (Dixson ), but self-stimulation of genitalia is nearly exclusively reported in Old World monkeys and apes (Dubuc et al. ). This type of behavior is shown under captive, semi-free, and wild conditions. Barbary macaque females implanted with contraceptives exhibit perineal swellings during non-sexual periods. Males seemed to be more attracted to females with enlarged swellings (Wallner et al. ). They inspected — sniffed and touched — the anogenital region of these females and masturbated frequently in their presence. Almost no mounting behavior was performed, suggesting that visible sexual traits stimulate self-directed sexual behavior in males (Wallner, pers. obs.).
A study on same-sex mounting behavior in Japanese macaque females showed that females were able to self-stimulate their vulvar, perineal and anal (VPA) regions. Females also mounted other females and while doing so, they rubbed their VPA on their partners or stroked their VPA with their own tail (Vasey and Duckworth ). Because the VPA region mediates sexual arousal in both humans and in nonhuman primates, the authors of this study interpreted the behavior of macaque females as providing an immediate sexual reward. Such sexual sensation from genitalia activates the mesolimbic brain areas (Georgiadis and Kringelbach ), resulting in the perception of pleasure. Early research suggested that nonhuman primates mate exclusively in a dorso-ventral position, whereas humans prefer face-to-face sexual intercourse to facilitate female orgasm. Early studies also suggested that that nonhuman primate females are not able to experience orgasm. Both suggestions proved wrong: lesser and great apes engage in face-to-face copulation, and female orgasm has been recently reported in a number of monkey species (Dixson ).
Bonobos display unique patterns of socio-sexual behavior for nonhuman primates. In bonobos, sexual interactions occur daily, and independent of female cycle stages and therefore of reproduction. Sexual interactions involve a variety of sexual behaviors and include individuals of all age and sex combinations (Manson et al. ). Chimpanzees also exhibit perineal swellings beyond ovulation periods. Wallen and Zehr () noted, “The system of hormonally modulated sexual motivation combined with a physical capacity to mate at any time has evolved in primates to balance the social and reproductive uses of sex.” This clearly applies to female sexuality in great apes such as bonobos and chimpanzees. In orangutans, females do not express SSC, suggesting that ovulation is concealed (Pawlowski ). Knott et al. () investigated sexual interactions in Bornean orangutans. Near ovulation, females copulated with dominant, flanged males with large cheek pads, but during cycle stages with low probability of fertilization, females preferred less dominant, unflanged males. The authors suggested that in a species with concealed ovulation where males use frequent sexual coercion, such female sexual strategies may minimize male aggression. Differentiated female preferences for mating with adult and adolescent males at different cycle stages was also reported in Phayre’s leaf monkeys. During periovulatory periods (POP), females were more proceptive and receptive to adult males, but they preferred adolescent males during non-periovulatory periods (NPOP). Interestingly, adult males seemed to recognize female fertility better than adolescent individuals did (Lu et al. ). Another study investigated female chimpanzee mating preferences during POP and NPOP. Female proceptivity correlated with male mating success and female resistance behavior reduced male mating success, during POP. Proceptivity was also positively related with male mating success during NPOP. These data indicate the influence of female choice on male mating success during different cycle stages in chimpanzees (Stumpf and Boesch ). In white-handed gibbons, cycling females showed increased group-leading activities compared to pregnant or lactating females. The behavior probably served a non-ecological function, and helped females search for potential mating partners (Barelli et al. ).
Female SSC-related signals are attractive to males and may stimulate male sexual arousal. Females, in turn, may benefit from received increased social and sexual attention from males. For example, Barbary macaque females implanted with contraceptives can develop enlarged swellings during non-reproductive periods and, if so, they have more affiliative interactions and fewer agonistic interactions with males, and they receive more agonistic aid and more grooming from males (Wallner et al. , ). Similarly, female chimpanzees with swellings enjoy significantly more social benefits than those without swellings. In addition to their increased affiliative interactions with males, they gain greater access to food resources. Pregnant chimpanzee females with large perineal swellings may find it easier to transfer from one group to another without being attacked by males (Wallis , ). Furthermore, baboon males strategically approach swollen females when entering a new group (Goodall ), and affiliate temporarily with them.
Why males find SSC signals attractive is more difficult to interpret. In other words, the information content, if any, of these signals remains unclear. Pagel () argued that large perineal swellings are reliable indicators of female reproductive quality and health. Such signals must be the evolutionary result of intra-sexual female competition for males. This reliable indicator hypothesis was supported by data from wild olive baboons, showing that females that exhibited larger swellings during their sexually active periods had more affiliative interactions with males and produced more offspring than females with smaller swellings (Domb and Pagel ). Critics of this study, however, were able to show major flaws in the statistical data analyses. Subsequent studies failed to replicate these results and to show better reproductive performance for females with larger swellings (Setchell et al. ; see Fitzpatrick et al. ). Nevertheless, there are indications that conceptive swellings are larger than non-conceptive ones and that males do prefer to mate with females during those cycles with higher chance of fertilization (Fitzpatrick et al. ).
With regard to coloration, non-lactating Japanese macaque females had more intense red coloration, especially at the nipple and hindquarter regions, and all of them conceived during the sexually active period compared to those who were lactating (Wallner et al. ). In mandrills, multiparous females had brighter faces, possibly signaling their history of successful reproduction and current fertility, than nulliparous females (Setchell et al. ). Rhesus macaque males preferred females with more reddened hindquarters, whereas females paid more attention to faces of males and females with intense red coloration; the latter may be associated with female-female competition as well (Gerald et al. ; Dubuc et al. ). Similarly, Japanese macaque males were more interested in faces with more intense red coloration, and especially in faces with increased color contrast (Pflüger et al. ).
Female SSC signals in relation to ovulation are generally prominent in primate species that live in multi-male, multi-female groups with promiscuous mating systems. In contrast, in species that live in one-male units, with polygynous or monogamous mating systems, SSC signals such as sexual swellings are rare and seem to be less related to advertising female fertility. The ultimate reason for such differences seems to be intrasexual competition for mating partners during periovulatory periods in promiscuous species compared to one-male units [...exception is the white-handed gibbon...].

Women: Behavioral and Morphological Variation

Women’s sexual behavior may fluctuate significantly during their cycle. Burleson et al. () investigated allosexual and autosexual behavior in heterosexual and lesbian women with or without a partner. Allosexual behavior increased during the follicular and ovulatory phases in women living with a partner compared to those without a partner. In contrast, the frequencies of autosexual behavior were elevated during the follicular and ovulatory cycle phases in both heterosexual and lesbian women living without a partner vs those with a partner. A longitudinal study of female sexual behavior during five cycle phases - namely menstrual, postmenstrual, ovulatory, luteal and premenstrual - showed peak sexual activities during ovulation (Harvey ). That study used temperature charts to identify different cycle stages. A more recent investigation assessed sexual activities in relation to the preovulatory LH increase. Women initiated more sexual activities during the preovulatory LH surge and showed increased sexual desire and fantasies 3 days earlier (Bullivant et al. ). Pillsworth et al. () showed that sexual desire in paired women was mainly expressed during the periovulatory phase, and that among these women increased conception probability was correlated with sexual desire. Interestingly, the duration of partnership was positively related to sexual desire in extra-pair-relationships during periods of increased fertility. Another study on sexual fantasies in relation to menstrual cycle phases in single-living women showed increased sexual fantasies during preovulatory elevated LH secretion; these fantasies decreased after ovulation (Dawson et al. ). During follicular and periovulatory periods the number of sexual fantasies increased while emotional content increased in conjunction with ovulation (Dawson et al. ).
It has been argued that during fertile cycle phases, paired women may engage in short-term extra-pair relationships to mate with partners of high genetic quality (such as high testosterone levels, masculinity, dominance, symmetry) (e.g., Gangestad and Thornhill ). Two recent meta-analyses of these studies, however, provided mixed support this conclusion (Gildersleeve et al. ; Wood et al. ) and subsequent, rigorous investigations have failed to replicate some of the initial findings (Jones et al. , ; Jünger et al. ). Evidence concerning the influence of hormones on sexual desire during different cycle stages seems to be also conflicting. Roney and Simmons () found a significant negative correlation between progesterone increases and women’s desire for their partner and other men. In contrast, mid-cycle stages were related to high extra-pair and in-pair desire, although the correlation between desire and estradiol was only marginally significant. Contrary to these results, another study showed that higher estradiol levels are associated with an increased extra-pair sexual interest, whereas higher progesterone concentrations predict greater in-pair interest (Grebe et al. ). Finally, recent studies have provided some further conflicting evidence as to whether changes in estradiol and progesterone concentrations across the cycle are associated with changes in female general sexual desire vs female desire for particular types of sexual relationships (Jones et al. ; Shirazi et al. ).
Many studies of women’s mate preferences in relation to the menstrual cycle compare fertile vs luteal phases. During fertile periods, women do generally prefer masculine men who are assertive and competitive, have lower voices, or scents associated with body symmetry (Gangestad et al. ; Garver-Apgar et al. ). For example, in one study, women’s preference for male scents related to symmetric body features was positively related to women’s estrogen and testosterone levels, but negatively to their progesterone (Garver-Apgar et al. ). Furthermore, women with lower urinary estrone-3-glucuronide concentrations showed stronger cyclic shifts (non-fertile/fertile) in their preferences for masculine voices (Feinberg et al. ; but see Jünger et al. for negative results). Finally, cycle stage apparently plays an important role in being motivated to detect erotic stimuli in art. During the first half of the menstrual cycle, women emphasized more erotic stimuli in paintings compared to the second half of the cycle (Rudski et al. ).
Aside from behavioral changes, different energetic needs are also evident during the menstrual cycle. Lissner et al. () described two peaks of energy intake during the cycle: the first at the middle of the follicular phase, and the second at the middle of the luteal phase. Especially during the luteal phase, women crave more carbohydrate- and fat-containing food (Davidsen et al. ). From a physiological point of view, such food consumption behavior is relevant because energy is needed to produce the endocrine surges necessary for ovulation and for the successful implantation of fertilized eggs into the uterus tissue. Another study showed that consuming sweet food and its preference rating increase during the pre-ovulatory phase (Bowen and Grunberg ). Both, nonhuman primates and humans, however, show increased luteal energy intake compared to follicular phases (Dye and Blundell ). Czaja and Goy () carried out classical studies on food intake under estrogen and progesterone treatment in rhesus macaques and guinea pigs. In both species, the food intake decreased around the time of ovulation and increased during other cyclic periods. Estrogen administration to ovariectomized females showed a clear downregulation of feeding behavior. Ovariectomized females, however, did not change their feeding behavior after progesterone administration compared with control individuals in both species. Most recently, Roney and Simmons () tested hormonal predictors of daily self-reported food intake in naturally cycling women. They reported that estradiol negatively and progesterone positively predicted food intake, and that a decrease in eating during the fertile phase of the cycle was mediated by the two hormones. These associations between hormones and food intake were mirror images of those found for sexual desire, and were very similar to those reported in nonhuman primates.
In addition to sexual desire/preferences and food intake, a great deal of research has documented also changes in mood and cognitive function in relation to the menstrual cycle. Some of this research has involved estrogen replacement therapy (reviewed by Shively and Bethea ; see also Voytko , for data in female macaques). In women, the premenstrual syndrome and its association with depression are relatively well investigated (e.g., Forrester-Knauss et al. ). Interestingly, Shively et al. () were able to relate lower ovarian function and impaired HPA activity with signs of depression in subordinate macaque females.

Risky Behavior During Menstrual Cycle

Sexual interactions are per se related to physical risks for both sexes (Wallen and Zehr ). For example, T lymphatic viruses are sexually transmitted in humans and in several species of nonhuman primates (see Junglen et al. ). Simian and human immunodeficiency viruses (SIV, HIV) are among the most infamous sexually transmitted diseases. The Center for Disease Control and Prevention (https://www.cdc.gov/) has indicated that in the U.S. individuals between 15 and 24 years of age represent 27% of the sexually active population, yet they account for 50% of sexually transmitted infections. In their fact sheet of infections, gonorrhea ranks number one (70%) followed by chlamydia (63%), HPV (49%), genital herpes (45%), HIV (26%), and syphilis (20%). These data, however, do not reveal whether infections are related to specific menstrual cycle stages. Regarding the type of infection, women in the 15–24 years range seem to be most vulnerable to chlamydia infections. Interestingly, some of these pathogens - such as chlamydia (Chlamydia trachomatis) or syphilis (Treponema pallidum) – have also been detected in captive apes (Rushmore et al. ), although little research on sexually transmitted diseases has been conducted in wild nonhuman primates.
Molecular immune defense genes seem to evolve faster in promiscuous primate species, and especially in species that live in larger groups (Wlasiuk and Nachman ). Nunn et al. () found that white blood cell counts were significantly higher in primate species in which females have more mating partners, and therefore the risk of sexually transmitted diseases is higher. A recent study analyzed the evolution of the seminal protein gene semenogelin 2 (SEMG2) in primates, which is responsible for the semen coagulation rate (Dorus et al. ). The results showed that promiscuous species exhibit higher rates of SEMG2 polymorphism, which results in faster coagulation rates. The species with the highest evolution rate is the common chimpanzee. Interestingly, the relationship between the rate of evolution of SEMG2 and residual testis size is higher in humans than in polygynous (orangutan, gorilla) or monogamous (gibbon) species (Dorus et al. ). A similar correlation is evident between midpiece sperm volume (the location of mitochondria) and residual testis size in humans (Anderson and Dixson ). Both results indicate a selection process favoring moderate promiscuity in humans. Based on these findings and the previously mentioned female desire for extra-pair sex during fertile cycle stages, it may be argued that women’s fertility periods are associated with risky behavior.
In female baboons, an increased risk of injury (presumably related to reproductive competition) has been documented during days with a high conception probability (Archie et al. ). Promiscuous female baboons signal their periovulatory period with exaggerated swellings, which may attract the males’ sexual attention but also aggression from males and females. Women seem to have developed strategies to reduce their exposure to risk during fertile cycle periods. During ovulation, women engage in less risky behaviors to avoid sexual assaults (Bröder and Hohmann ) and show an increase in handgrip strength in response to a sexual assault vignette, suggesting the existence of behavioral adaptations to reduce the probability of conception as a result of rape (Petralia and Gallup ). However, strong individual differences probably exist among women in their tendency to engage in sex-related risky behavior in relation to their age, personality, chronotype (i.e., morningness-eveningness), and hormonal profiles (e.g. Maestripieri ). It is possible that variation in female risky behavior during the cycle may be influenced by cortisol and its interaction with sex hormones. A study on a rural Mayan population showed increased urinary cortisol during the follicular phase and between day 4 and 10 after ovulation. Interestingly, higher cortisol during the follicular phase was associated with progestin concentrations, suggesting an impairment of implantation processes (Nepomnaschy et al. ).

Women’s Advertising During Different Cycle Phases

Do human females differ from other primate females in advertising their sexual attractiveness in relation to different cycle stages? In contrast to some primate SSC signals such as exaggerated sexual swellings, which fluctuate across the cycle in relation to changes in estrogen and progesterone concentrations (Wallner et al. , ), women have permanent developed SSC such as the waist-to-hip ratio, buttocks, and breasts. Nonetheless, cyclic changes in body morphology are evident also in women (reviewed in Farage et al. ). Most of these changes are related to physiological parameters such as lipid content of skin, collagen production, pigmentation, hydration, thermoregulation, functional aspects of the immune system or changes of water compartments and subcutaneous fat tissue. Whether these cyclic modifications are detectable by men remains unclear (Puts et al. ; for evidence, instead, that cyclic modifications in faces are detectable by women, see Necka et al. , ; Hurst et al. ; Krems et al. ).
Some of the most obvious changes occur in the subcutaneous fat regions of the thighs and abdomen (Perin et al. ). In these areas, fat increases up to 4% during menstruation, and the fat content is lowest during the first half (follicular stage) of the cycle. Fowler et al. () used magnetic resonance imaging to detect changes in the female breast volume during the cycle. During the period between day 16 and 28, which more or less corresponds to the luteal phase, the water content increased by 24%, and parenchymal volume by 38%. In comparison, during menstruation, water content decreased by 17%, and parenchymal volume by 30%. This represents a major volume change for the breast tissue, which is analogous to changes in anogenital swellings in nonhuman primates. However, the volume increase in swellings is mediated by estrogens and is based on a shift of intracellular water into the interstitial tissue, whereas the volume increase in the breast tissue seems to be mediated by luteal progesterone. Whether these subcutaneous fat changes during the cycle are temporal SSC, which signal attractiveness in women remains unclear.
There are, however, hints that women try to enhance their sexual attractiveness during particular phases of the cycle. A study on more than 300 women revealed some associations between clothing preferences, sexual motivation, and hormone concentrations (Grammer et al. ). Higher sexual motivation was associated with the tendency to wear sheer clothing (which allows the woman’s body or undergarments to be seen through its fabric), whereas salivary estradiol concentrations were correlated with the amount of skin exposure and with clothing tightness. Moreover, women significantly change their consumer behavior across the cycle and spend more time and money on cosmetics, fashion, and jewelry during the periovulatory phase (Durante and Griskevicius ; Durante et al. ). There is also some evidence that these changes in behavior are influenced by hormones and that they reflect female-female competition for mating partners (Durante and Griskevicius ; Durante et al. ).
These findings indicate that women are aware of their cycle stage and use their clothes or make-up to attract men’s attention on particular body regions such as their lips, breasts, or hips (see Haselton and Gildersleeve ). Gait also changes during the cycle, such that particular postures are used that help advertise SSC such as the waist and hips. Guéguen showed that during the periovulatory phase women walk more slowly and that men find this sexier, suggesting that gait is a critical behavior used by women to display and enhance their physical attractiveness. Wearing shoes with high heels may influence the walking performance of women during periovulatory cycle stages. Wearing high heels enables women to change significantly the lumbar curvature and the inclination of the pelvis (Smith ). Visually, this yields a posture signaling a hollow-back and exposing the waist and hips more prominently. Evidently, men recognize it as a supernormal stimulus and associate it with female attractiveness. High heels also influence the gait of women by reducing stride length and increasing the rotation of the hip.
In conclusion, advertising physical attractiveness is an important adaptive trait in the context of sexual interactions in many nonhuman primates and in humans. [

Neurophysiology of Sexual Behavior

The eighteenth century Venetian Giacomo Casanova stated, “Only man is capable of real pleasure, because he is gifted with the power of thought, and he expects the desire, he studied it, he gives and remembers her, if he has enjoyed it (https://www.aphorismen.de/zitat/67814). Casanova suggests that three main aspects of human sexuality are pleasure, desire, and thought, and implies that human beings are perhaps unique in the animal kingdom in that for humans, sex in mainly in the brain. In reality, the neurophysiological regulation of sexuality shares many similarities in humans and other primates. Pleasure and desire are mainly located in subcortical midbrain structures, which are homologous among primates. Therefore, it is likely that the way human beings desire sex and experience sexual pleasure is very similar to the other primates do it. With regard to thinking about sex, especially conscious thinking, the situation is more complicated, as humans are unique among the primates for having a large neocortex that allows for conscious thinking. The phylogenetic increase in the size of the neocortex from monkeys to apes to humans seems to be related both to the rate of neuronal projections from the midbrain to the neocortex as well as to how the neocortex has evolved (Raghanti et al. ).
The vertebrate brain has several areas that regulate the emotional aspects of sex as well as the performance of sexual acts. The comprehensive comparative analysis by O'Connell and Hofmann () pointed out that brain regions representing the social behavior network and the mesolimbic reward system are particularly important for the sensation of pleasure. The size of the hypothalamic nuclei in the social behavior network is sexually dimorphic. The larger male nucleus of the preoptic area (POA) and the bed nucleus of stria terminalis (BNST) are exposed to testosterone during ontogenetically sensitive periods (Hofman and Swaab ). Such exposure produces concentration-dependent androgen receptor fields, which are essential for promoting male reproductive behaviors during adulthood. An important functional role of the POA is to integrate external and internal information to facilitate mating behavior and gender identity (Garcia-Falgueras et al. ). Research on female macaques has revealed neuronal activity in the ventromedial hypothalamus (VMH) and POA areas during sexual activity (see Dixson ). The sex drive in humans and in nonhuman primates is regulated by both androgens and estrogens (Fisher et al. ; but see Cappelletti and Wallen ).
A dopaminergic influence in the POA on sexual arousal has also been documented (Schober and Pfaff ). The mesolimbic reward system is one of the best investigated brain areas in medicine and biology. Comparative studies on fishes, amphibians, reptiles and mammals have revealed analogous functional neuroanatomic structures (O'Connell and Hofmann ). The monoamine neurotransmitter dopamine and its two-class receptor system (Missale et al. ; Beaulieu and Gainetdinov ) are key players in these mesolimbic structures. They mediate pleasure associated with predictive, motivational or attentional sensations in relation to learning processes (Berridge and Kringelbach ). The dopaminergic system is linked to the prefrontal cortex to mediate cognitive processes generated subcortically in association with sex-related emotion and behavior. In the prefrontal cortex, the enzyme catechol-o-methyltransferase is responsible for deactivating dopamine (Cumming et al. ), while the dopamine transporter protein regulates the duration of dopamine receptor activation (Giros and Caron ). Comparative analyses of cortical dopaminergic innervation in humans and nonhuman primates reveal no quantitative differences between chimpanzees, macaques, and humans. However, the sublaminar patterns of innervation differ in specific areas between humans and the other two species (Raghanti et al. ).
The main brain structures of the mesolimbic reward system are the striatum (STR: compulsive behavior), ventral tegmental area (VTA: motivation, reproduction, parental care), medial amygdala (meAMY: aggression reproduction, parental care, social recognition), ventral pallidum (VP: emotional learning, parental behavior), nucleus accumbens (NAcc: emotional learning, impulsivity, motivation, parental care), and the hippocampus (HIP: spatial learning) (see O'Connell and Hofmann ; Berridge and Kringelbach ). In humans the subcortical and cortical cognitive aspects of sexual pleasure are related to neural activity in the medial orbitofrontal, mid insular, and the anterior cingulate areas (de Araujo et al. ). Most of the research on the orbitofrontal cortex has focused on sensory integration and reward value in relation to food (Kringelbach ). According to Rilling () the reciprocal behavior of food-sharing among non-related hunter-gatherer populations provides a window into important neurobiological aspects of human social evolution. fMRI studies confirmed that the orbitofrontal cortex is also activated during reciprocal prosocial interactions (Waytz et al. ). We argue that in addition to food-sharing and other prosocial behaviors, sexual reward also played an important role in the evolution of the primate orbitofrontal cortex in relation to subcortical brain areas (see Rudebeck and Murray , and Wikenheiser and Schoenbaum ). Interestingly, both brain areas - the social behavior network and the reward system - consist of highly interactive nodes and overlapping structures, which represent an integrated evolutionary ancient social decision-making network (O'Connell and Hofmann ).

Sex Steroid Hormones and their Receptors

Sex steroid hormones, in particular brain estrogen concentrations, significantly modulate changes in women’s mood, cognition or sexuality across the menstrual cycle. The actions of estrogen in the brain depend on estrogen receptors, which occur in two isoforms: ERα and ERβ. The latter mediate subcortical cognition processes between hormonal components and expressed behavior. Patchev et al. () demonstrated that activating ERα receptors in neonatal female rats resulted in impaired ovarian function and reduced sexual behavior in adulthood. This treatment affected the morphology of the subcortical brain areas such as the periventricular nucleus of the hypothalamus (AVPV; it produces GnRH in humans and nonhuman primates) and POA, namely, it made these areas more masculine. In contrast, activation of ERβ receptors failed to alter later female sexual behavior or responsiveness to estrogens and did not affect the morphology of the POA. In situ hybridization in ovariectomized and hysterectomized female macaques showed the distribution density of ERβ mRNAs for subcortical hypothalamic, limbic and midbrain areas. Administering estrogens did not alter overall receptor densities but, progesterone treatment down-regulated the receptor signal in specific hypothalamic and hippocampal regions (Gundlah et al. ). Generally, estradiol influences ERα receptors in subcortical areas such as POA and VMH (both areas belong to social behavior network, which coordinates sexual activity and is multi-connected with the reward system) in ewes (Fergani et al. ). Higher estradiol and lower progesterone concentrations are related to elevated receptor activity and affect sexual behavior under the influence of an LH surge in both areas (Fergani et al. ). This scenario seems to be typical for mammalian mid-cycle stages. Similar results were documented for a macaque species, in which estrogen receptor activity was investigated in several brain areas in mated and unmated females. Mated females had significantly increased receptor activities in POA and VMH regions compared to unmated ones (Michael et al. ). Another primate study focused on the ERα and progesterone receptor density in hypothalamic regions of ovariectomized aged and young rhesus macaque females after long-term estradiol treatment. The hormonal treatment mimicked therapeutic supplements in peri-menopausal women. Surprisingly, old macaque females maintained estrogen receptor expression, and long-term estradiol supplementation only marginally influenced the receptor density (Naugle et al. ). In humans, there is evidence that brain masculinization is AR (androgen-receptor)-mediated rather than ER-mediated but the issue remains controversial (Luoto and Rantala ; Motta-Mena and Puts ; Puts and Motta-Mena ).
The impact of estrogen on the central dopaminergic system and on the brain reward system is also significant. Menopausal women more often exhibit symptoms of Parkinson and schizophrenia diseases, which are related to decreased dopamine production or transmission rates compared to individuals with cycling estrogen fluctuations (Cyr et al. ). Moreover, decreased dopamine release also seems to be related to the development of drug addiction. Accordingly, Lynch et al. () indicated that in adults drug abuse is more likely in males than in females; in adolescent individuals, however, drug addiction is only marginally different between the sexes. Studies of self-administration of alcohol in rats and vervet monkeys showed that females consume higher amounts of alcohol than males. In rhesus macaques, however, the sex difference was reversed (Lynch et al. ). Short-term self-administration of heroin did not differ in in male and females rats. In contrast, extended access to this drug was associated with higher self-administration in females (Lynch et al. ). Cycling women show a dependence of euphoria on d-amphetamine with regard to behaviors such as liking, wanting, or energy, and intellectual improvements during later follicle periods (Justice and de Wit ). Moreover, estradiol seems to improve subjective feelings of pleasure and feeling “high” in association with amphetamine (Sofuoglu et al. ). Nicotine withdrawal, instead, correlated with premenstrual symptoms during the late luteal phase of the cycle (Allen et al. ). These and other studies have shown that estradiol decreases the dopamine reuptake and therefore increases dopamine concentration in the synaptic cleft. This accelerates the binding rate for dopamine at D1 and D2 receptors, while reducing it for D3 receptors in the mesolimbic reward system (see Almey et al. ). Ultrastructural analyses of estrogen receptors within dopamine terminal regions such as the medial prefrontal cortex identified such receptors in extranuclear sites of neurons and glia; the highest densities were recorded at axons and terminals (Almey et al. ).
The described neuro-circuitry of the reward system, which includes the interplay between the dopaminergic system and estrogen, also plays a significant role in female decision making. In one study of rats, females were tested using an effort-discounting task with different types of reward: pressing a lever once yielded two pellets, pressing it many more times yielded four pellets. The results showed that ovariectomized females expressed a preference for the high-reward lever, whereas females treated with estradiol selected the low-reward lever. Moreover, the application of ERα receptor agonists, independently of ERβ agonists, resulted in high reward/high cost preferences, but simultaneous application of agonists for both receptor types decreased the choice for such high benefit/high cost options (Uban et al. ).
In addition to the dopaminergic system, it is important to consider also estrogen effects on the serotonergic brain system in relation to female sexual behavior. Introducing ovarian hormones into the dorsal raphe nuclei region of macaque brains altered the mRNA expression rates of components involved in serotonin metabolism (Pecins-Thompson et al. ). The rhombencephalic raphe nuclei complex is the origin of the serotonergic system. From here serotonergic fibers project into almost all brain areas (Holloway et al. ). Lower brain serotonin concentrations are related, for example, to depression, anxiety, and impaired cognition (Wallner and Machatschke ). Application of estrogen with or without progesterone increased tryptophan hydroxylase-I mRNA, but decreased mRNAs of MOA-A and concentrations of the serotonin re-uptake transporter. The latter impairs the relocation of serotonin metabolites from the postsynaptic membrane into presynaptic regions. All of these manipulations affect central serotonergic function (Smith et al. ), and serotonergic pathways are known to influence fluctuations in female mood and behavior during the menstrual cycle.
From neurophysiological research we conclude that the actions of estrogen and its related receptor system in the brain influence female behavior in a socio-sexual context. The distribution rate and density of receptor fields in subcortical brain areas enable estrogens to exert a major influence on female sexuality, food intake, mood changes, feelings of pleasure, and cognitive function in different phase of the cycles, in which estrogen concentrations vary significantly.

Conclusion

Women share with nonhuman primates subcortical brain areas, which are essential to modulate behavioral and physiological changes in relation to different reproductive cycle stages. These homologous regions represent evolutionarily conserved structures documented in nearly all vertebrates. The interconnected social behavior network and the mesolimbic reward system are responsible for a basic integration of sexual behavior and its related reward sensations. These sensations are not limited to sexuality, but also include food intake (Adam and Epel ) and prosocial interactions (Rilling ). Here, emotional rewards are produced mainly via the dopaminergic system. Research on rhesus macaques has revealed two types of dopamine neurons, one excited by reward-predicting stimuli and the other inhibited by punishment-predicting stimuli (in this case, an airpuff). Importantly, more neurons are excited by both stimuli combined (Matsumoto and Hikosaka ). These results indicate that the dopamine system can differentiate between positive and negative signals. Matsumoto and Hikosaka () proposed the existence of two functionally distinct dopamine neurons, the airpuff-inhibited and the airpuff-excited type. They would be located in subcortical brain areas belonging to the mesolimbic reward system. In mammals, the mesolimbic reward system and other dopaminergic systems project to the prefrontal cortex, but the innervation density of the cortical striatum differs between humans and nonhuman primates (Raghanti et al. ). Moreover, the distribution of estradiol receptors in subcortical (Gonzales et al., 2007) and cortical areas suggests that value-oriented signals can be transformed into distinctive behaviors modulated by estradiol concentrations during different cycle phases. Such hormonal modulations are apparently homologous and stable in physiological and behavioral expression rates across species (Uban et al. ). Regardless of differences in the ways in which some primate species advertise or conceal ovulation, there may still be functional similarities in the way sexual stimuli are perceived, processed, and communicated. One important difference between humans and other primates may concern women’s strategic behavioral decisions in relation to their fertility. Women have to make sure that the prospective fathers of their children are able and willing to invest significant resources in themselves and their children to an extent that is rarely observed in nonhuman primates.
Pair-bonding mechanisms have evolved in humans to make possible cooperative investment in children between reproducing partners. Such social bonds, however, should not be confused with sexual monogamy. The earliest primate ancestors may have had a solitary lifestyle similar to that of nocturnal mammals. Their descendants adopted a multi-male, multi-female social system approximately 52 million years ago, and subsequently evolved pair-living and one-male groups (harems) approximately 16 million years ago. Across all primates, monogamy is a less frequent social system than harems or multi-male, multi-female societies (Shulez et al. ). Nonetheless, social bonding between the sexes is probably tighter in one-male units than in multi-male, multi-female groups. At the level of mechanisms, these bonds are mediated by the neuropeptides oxytocin and vasopressin, which are produced in the magnocellular neurons of the paraventricular and supraoptic nuclei of the hypothalamus. These neurons project into areas of the mesolimbic reward system, such as amygdala or hippocampus, and into regions of the social behavior network, such as the BNST or the POA (Meyer-Lindenberg et al. ). The projections into these subcortical brain areas suggest that social bonding mechanisms may be related to sexual activities, and in particular to their emotional positive rewards (Young and Wang ). Both brain areas are evolutionarily relatively old. Therefore, we suggest that the neural circuits regulating sex – its emotional positive reward in relation to pair-bonding - were established after the evolution of single-male units in humans and nonhuman primates. This means that the origin of advertising female sexually attractive signals is older and originated in multi-male, multi-female primate societies.
Women’s pre-fertilization selection process for socially compatible and genetically valuable partners with high status and resources is time-consuming and subject to female-female mating competition. Women’s fat reserves, which are needed for succesful ovulation, gestation, and lactation, can contribute to permanent signals of sexual attractivenss such as large breasts and buttocks, which may signal physical and genetic fitness. Such permanent sexual signaling may allow females lengthier periods of mate assessment and more opportunities for mate choice without losing the interest of prospective partners. Studies have shown that men find attractive particular values of the waist-to-hip ratio as well as of the body mass index, which signals general health (Singh ; see also Havlíček et al. and commentaries). Additionally, breast morphology and size in fertile females may enhance the sexual attractiveness of the so-called hourglass body shape in women (see Dixson ). A question may arise as to whether men can perceive changes in female SSC in relation to culture-specific norms such as using different clothing during different cycle phases. For example (see also 2.4), the water content and parenchymal tissue volume increase in women during the luteal period and decreases during menstruation. As wearing clothes is common in most human societies, men are probably unable to recognize subtle cyclic changes in women’s bodies when these are covered by clothes. It is also unclear whether men can detect changes the bodies of women with whom they are in permanent, stable relationships. Male perception and interpretation of the information content of female SSC may result from direct comparison of their shape and size between women, independent of their cycle stage. Such individual differences may provide information about a woman’s health or reproductive fitness. In this context the American College of Radiology classified different mammographic density stages based on the fat-to-parenchymal tissue content in relation to the risk of developing cancer. Overall, a higher proportion of parenchymal tissue compared to fat is related to cancer (type 1, ≤ 25% of parenchymal tissue; type 2, ≤ 50%; type 3, ≤ 75%; type 4, ≥ 75% parenchymal tissue). This classification shows that the ratio can vary extremely. Therefore, the fat content of female SSC communicates information about health and energy resources available for reproduction and parental investment. But the attractiveness in particular breast sizes and/or shapes is not necessarily a fitness marker insofar as a significantly reduced fat proportion is related to less available energy resources and to increased health risks (see above). In this context, more subtle changes in other body parts during the cycle - the lipid content of the skin, the fat content of the thighs and abdomen, pigmentations, etc. – would provide significant information but they are presumably not reliably detectable by men, even those living in long-term partnerships.
Importantly, women do change their behavior in relation to cycle phases. Some of these changes are obviously linked to their culture. During periovulatory periods, women advertise their fertility not only by changing their gait, but also by wearing particular clothes and make-up; their consumer behavior and food consumption are also different. Advertising fertility through make-up or clothes would be analogous to cyclic changes in sexual swellings or face coloration in nonhuman primate females. Functionally, both the morphological changes in nonhuman primates and the behavioral strategies in humans are caused by female intra-sexual competition for valuable mates and by male mate choice. Interestingly, neither the morphological changes described in nonhuman primates nor the culture-specific behaviors of women seem to reliably signal fertility, ovulation, or readiness to mate: exaggerated swellings are also expressed during non-fertile cycle phases and sexy clothes can be worn by women in all phases of the cycle. Possibly, the culturally developed use of specific clothes to enhance and accentuate sexually attractive body areas in women can be interpreted as an example of culture – biology co-adaptation that better highlights permanently attractive SSC under competitive partner market conditions (Puts ).
If the female SSC of nonhuman primates and humans do not directly inform males about females’ fertility, − they might, in some cases, signal females’ genetic fitness and physical condition. For example, wearing particular clothes may allow women to make some of their attractive bodily characteristics, such as a thin waist and wide hips, more visible to men. Since women’s preferences for clothes and men’s preferences for body shapes are known to be different in relation to cultures and historical periods, a full understanding of female sexual signaling and male responses to it in humans requires the integration of biological and cultural analyses.