Optimizing the timing of an end-of-outbreak declaration: Ebola virus disease in the Democratic Republic of the Congo.

Following the apparent final case in an Ebola virus disease (EVD) outbreak, the decision to declare the outbreak over must balance societal benefits of relaxing interventions against the risk of resurgence. Estimates of the end-of-outbreak probability (the probability that no future cases will occur) provide quantitative evidence that can inform the timing of an end-of-outbreak declaration. An existing modeling approach for estimating the end-of-outbreak probability requires comprehensive contact tracing data describing who infected whom to be available, but such data are often unavailable or incomplete during outbreaks. Here, we develop a Markov chain Monte Carlo-based approach that extends the previous method and does not require contact tracing data. Considering data from two EVD outbreaks in the Democratic Republic of the Congo, we find that data describing who infected whom are not required to resolve uncertainty about when to declare an outbreak over.

Evaluating language models for mathematics through interactions.

There is much excitement about the opportunity to harness the power of large language models (LLMs) when building problem-solving assistants. However, the standard methodology of evaluating LLMs relies on static pairs of inputs and outputs; this is insufficient for making an informed decision about which LLMs are best to use in an interactive setting, and how that varies by setting. Static assessment therefore limits how we understand language model capabilities. We introduce CheckMate, an adaptable prototype platform for humans to interact with and evaluate LLMs. We conduct a study with CheckMate to evaluate three language models (InstructGPT, ChatGPT, and GPT-4) as assistants in proving undergraduate-level mathematics, with a mixed cohort of participants from undergraduate students to professors of mathematics. We release the resulting interaction and rating dataset, MathConverse. By analyzing MathConverse, we derive a taxonomy of human query behaviors and uncover that despite a generally positive correlation, there are notable instances of divergence between correctness and perceived helpfulness in LLM generations, among other findings. Further, we garner a more granular understanding of GPT-4 mathematical problem-solving through a series of case studies, contributed by experienced mathematicians. We conclude with actionable takeaways for ML practitioners and mathematicians: models that communicate uncertainty, respond well to user corrections, and can provide a concise rationale for their recommendations, may constitute better assistants. Humans should inspect LLM output carefully given their current shortcomings and potential for surprising fallibility.

A Histone Methylation-MAPK Signaling Axis Drives Durable Epithelial-Mesenchymal Transition in Hypoxic Pancreatic Cancer.

The tumor microenvironment in pancreatic ductal adenocarcinoma (PDAC) plays a key role in tumor progression and response to therapy. The dense PDAC stroma causes hypovascularity, which leads to hypoxia. Here, we showed that hypoxia drives long-lasting epithelial-mesenchymal transition (EMT) in PDAC primarily through a positive-feedback histone methylation-MAPK signaling axis. Transformed cells preferentially underwent EMT in hypoxic tumor regions in multiple model systems. Hypoxia drove a cell autonomous EMT in PDAC cells, which, unlike EMT in response to growth factors, could last for weeks. Furthermore, hypoxia reduced histone demethylase KDM2A activity, suppressed PP2 family phosphatase expression, and activated MAPKs to post-translationally stabilize histone methyltransferase NSD2, leading to an H3K36me2-dependent EMT in which hypoxia-inducible factors played only a supporting role. Hypoxia-driven EMT could be antagonized in vivo by combinations of MAPK inhibitors. Collectively, these results suggest that hypoxia promotes durable EMT in PDAC by inducing a histone methylation-MAPK axis that can be effectively targeted with multidrug therapies, providing a potential strategy for overcoming chemoresistance. SIGNIFICANCE: Integrated regulation of histone methylation and MAPK signaling by the low-oxygen environment of pancreatic cancer drives long-lasting EMT that promotes chemoresistance and shortens patient survival and that can be pharmacologically inhibited. See related commentary by Wirth and Schneider, p. 1739.

Development and implementation of a pregnancy heart team at a Southeastern United States tertiary hospital: a qualitative study.

BACKGROUND: The United States has seen a significant rise in maternal mortality and morbidity associated with cardiovascular disease over the past 4 decades. Contributing factors may include an increasing number of parturients with comorbid conditions, a higher rate of pregnancy among women of advanced maternal age, and more patients with congenital heart disease who survive into childbearing age and experiencing pregnancy. In response, national medical organizations have recommended the creation of multidisciplinary obstetric-cardiac teams, also known as pregnancy heart teams, to provide comprehensive preconception counseling and coordinated pregnancy management that extend through the postpartum period. OBJECTIVE: We sought to describe the development and implementation of a pregnancy heart team for parturients with cardiac disease at a southeastern United States tertiary hospital. STUDY DESIGN: This was a qualitative study that was conducted among healthcare team members involved during the pregnancy heart team formation. Semi-structured interviews were conducted between April and May 2022, professionally transcribed, and the responses were thematically coded for categories and themes using constructs from The Consolidated Framework for Implementation Research. RESULTS: Themes identified included intentional collaboration to improve outpatient and inpatient coordination through earlier awareness of patients who meet the criteria and via documented care planning. The pregnancy heart team united clinicians around best practices and coordination to promote the success and safety of pregnancies and not only to minimize maternal health risks. Developing longitudinal care plans was critical among the pathway team to build on collective expertise and to provide clarity for those on shift to reduce hesitancy and achieve timely, vetted practices without additional consults. Establishing a proactive approach of specialists offering their perspectives was viewed as positively contributing to a culture of speaking up. Barriers to the successful development and sustainability of the pregnancy heart team included unmet administrative needs and clinician turnover within a context of shortages in staffing and high workload. CONCLUSION: This study described the process of developing and implementing a pregnancy heart team at 1 institution, thereby offering insights for future multidisciplinary care for maternal cardiac patients. Establishing pregnancy heart teams can enhance quality care for high-risk patients, foster learning and collaboration among physician and nursing specialties, and improve coordination to manage complex maternal cardiac cases.

Divergent transcriptomic signatures from putative mesenchymal stimuli in glioblastoma cells.

In glioblastoma, a mesenchymal phenotype is associated with especially poor patient outcomes. Various glioblastoma microenvironmental factors and therapeutic interventions are purported drivers of the mesenchymal transition, but the degree to which these cues promote the same mesenchymal transitions and the uniformity of those transitions, as defined by molecular subtyping systems, is unknown. Here, we investigate this question by analyzing publicly available patient data, surveying commonly measured transcripts for mesenchymal transitions in glioma-initiating cells (GIC), and performing next-generation RNA sequencing of GICs. Analysis of patient tumor data reveals that TGFß, TNFα, and hypoxia signaling correlate with the mesenchymal subtype more than the proneural subtype. In cultured GICs, the microenvironment-relevant growth factors TGFß and TNFα and the chemotherapeutic temozolomide promote expression of commonly measured mesenchymal transcripts. However, next-generation RNA sequencing reveals that growth factors and temozolomide broadly promote expression of both mesenchymal and proneural transcripts, in some cases with equal frequency. These results suggest that glioblastoma mesenchymal transitions do not occur as distinctly as in epithelial-derived cancers, at least as determined using common subtyping ontologies and measuring response to growth factors or chemotherapeutics. Further understanding of these issues may identify improved methods for pharmacologically targeting the mesenchymal phenotype in glioblastoma.

Coworkers Behaving Badly: How the Dark Triad Influences Responses to Witnessing Workplace Misconduct.

The "bad-begets-bad" phenomenon describes how witnessed or perceived misconduct in an organization promotes mental states and behavior that encourage further misconduct. Based in two perspectives on how the Dark Triad (DT) constructs (narcissism, Machiavellianism, psychopathy) differentiate, we proposed their roles in contributing to the bad-begets-bad phenomenon. A convenience sample of college students (N = 454) completed an online study in which they read vignettes depicting workplace misconduct wherein a reporting incentive was (incentive condition) or was not (no-incentive condition) offered. Subsequently, they reported their likelihood of possessing mental states (e.g., goals) and engaging in behavior broadly reflective of the bad-begets-bad phenomenon. Lastly, they completed the Short Dark Triad (SD3) questionnaire to assess narcissism, Machiavellianism, and psychopathy. We used a series of step-wise regression models to analyze the data. Consistent with the "malicious two" perspective on the DT, only Machiavellianism and psychopathy consistently predicted mental states and behavior reflective of the bad-begets-bad phenomenon. Also, consistent with the "cautious and adaptable Machiavellian perspective," only Machiavellianism interacted with the incentive condition to influence people's willingness to report misconduct (i.e., not further promote misconduct). Broadly, the data contribute to understanding the role of the DT in organizational settings and support two perspectives on how the DT should operate in the context of witnessing workplace misconduct.

Performance of a novel spectroscopy-based tool for adjuvant therapy decision-making in hormone receptor-positive breast cancer: a validation study.

PURPOSE: Digistain Index (DI), measured using an inexpensive mid-infrared spectrometer, reflects the level of aneuploidy in unstained tissue sections and correlates with tumor grade. We investigated whether incorporating DI with other clinicopathological variables could predict outcomes in patients with early breast cancer. METHODS: DI was calculated in 801 patients with hormone receptor-positive, HER2-negative primary breast cancer and ≤ 3 positive lymph nodes. All patients were treated with systemic endocrine therapy and no chemotherapy. Multivariable proportional hazards modeling was used to incorporate DI with clinicopathological variables to generate the Digistain Prognostic Score (DPS). DPS was assessed for prediction of 5- and 10-year outcomes (recurrence, recurrence-free survival [RFS] and overall survival [OS]) using receiver operating characteristics and Cox proportional hazards regression models. Kaplan-Meier analysis evaluated the ability of DPS to stratify risk. RESULTS: DPS was consistently highly accurate and had negative predictive values for all three outcomes, ranging from 0.96 to 0.99 at 5 years and 0.84 to 0.95 at 10 years. DPS demonstrated statistically significant prognostic ability with significant hazard ratios (95% CI) for low- versus high-risk classification for RFS, recurrence and OS (1.80 [CI 1.31-2.48], 1.83 [1.32-2.52] and 1.77 [1.28-2.43], respectively; all P < 0.001). CONCLUSION: DPS showed high accuracy and predictive performance, was able to stratify patients into low or high-risk, and considering its cost and rapidity, has the potential to offer clinical utility.

Isolation may select for earlier and higher peak viral load but shorter duration in SARS-CoV-2 evolution.

During the COVID-19 pandemic, human behavior change as a result of nonpharmaceutical interventions such as isolation may have induced directional selection for viral evolution. By combining previously published empirical clinical data analysis and multi-level mathematical modeling, we find that the SARS-CoV-2 variants selected for as the virus evolved from the pre-Alpha to the Delta variant had earlier and higher peak in viral load dynamics but a shorter duration of infection. Selection for increased transmissibility shapes the viral load dynamics, and the isolation measure is likely to be a driver of these evolutionary transitions. In addition, we show that a decreased incubation period and an increased proportion of asymptomatic infection are also positively selected for as SARS-CoV-2 mutated to adapt to human behavior (i.e., Omicron variants). The quantitative information and predictions we present here can guide future responses in the potential arms race between pandemic interventions and viral evolution.

Analysis of the risk and pre-emptive control of viral outbreaks accounting for within-host dynamics: SARS-CoV-2 as a case study.

In the era of living with COVID-19, the risk of localised SARS-CoV-2 outbreaks remains. Here, we develop a multiscale modelling framework for estimating the local outbreak risk for a viral disease (the probability that a major outbreak results from a single case introduced into the population), accounting for within-host viral dynamics. Compared to population-level models previously used to estimate outbreak risks, our approach enables more detailed analysis of how the risk can be mitigated through pre-emptive interventions such as antigen testing. Considering SARS-CoV-2 as a case study, we quantify the within-host dynamics using data from individuals with omicron variant infections. We demonstrate that regular antigen testing reduces, but may not eliminate, the outbreak risk, depending on characteristics of local transmission. In our baseline analysis, daily antigen testing reduces the outbreak risk by 45% compared to a scenario without antigen testing. Additionally, we show that accounting for heterogeneity in within-host dynamics between individuals affects outbreak risk estimates and assessments of the impact of antigen testing. Our results therefore highlight important factors to consider when using multiscale models to design pre-emptive interventions against SARS-CoV-2 and other viruses.

Efficiency, Safety, Quality, and Empathy: Balancing Competing Perioperative Challenges in the Elderly.

Although baby boomer generation accounts for a little more than 15% of the US population, the cohort represents a disproportionate percentage of patients undergoing surgery. As this group continues to age, a multitude of challenges have arisen in health care regarding the safest and most effective means of providing anesthesia services to these patients. Many elderly patients may be exquisitely sensitive to the effects of anesthesia and surgery and may experience cognitive and physical decline before, during, or after hospital admission. In this review article, the authors briefly examine the physiologic processes underlying aging and explore steps necessary to deliver safe, empathetic care.

Revisiting the ego-syntonic assumption: Investigating neuroticism and harmony with thoughts of negative emotions.

It has been assumed that personality disorders or constituent traits are ego-syntonic, but studies that have addressed this claim have revealed ego-dystonicity. Across three studies (two preregistered), we addressed some methodological weaknesses in these past studies that may conceal ego-syntonicity. Participants (total N = 1,331) completed measures of neuroticism and then imagined experiences that predominantly induced either fear, sadness, or anger (Studies 1 and 2) or recalled past experiences that predominantly elicited each emotion (Study 3). Subsequently, participants judged their emotional reactions on the two ego-syntonicity dimensions of (a) consonance with the self and (b) acceptance (evaluation). Across the studies, neuroticism generally had positive and about moderate-sized relations to consonance judgments and between trivial-sized and small-sized relations to acceptance judgments that were most often positive (Studies 1 and 2) but sometimes negative (Study 3); mean-level analyses suggested that people with relatively higher neuroticism indicated their emotional experiences were, most often, somewhat consonant with the self and acceptable. Regardless, in Study 3, the sample, including those relatively higher in neuroticism, indicated their recalled emotions were too extreme. Broadly, the data suggest that people relatively higher (vs. lower) in neuroticism may regard their contextualized negative emotion as more consonant with the self but not necessarily as more acceptable. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Understanding how transmembrane domains regulate interactions between human BST-2 and the SARS-CoV-2 accessory protein ORF7a.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of COVID, replicates at intracellular membranes. Bone marrow stromal antigen 2 (BST-2; tetherin) is an antiviral response protein that inhibits transport of viral particles after budding within infected cells. RNA viruses such as SARS-CoV-2 use various strategies to disable BST-2, including use of transmembrane 'accessory' proteins that interfere with BST-2 oligomerization. ORF7a is a small, transmembrane protein present in SARS-CoV-2 shown previously to alter BST-2 glycosylation and function. In this study, we investigated the structural basis for BST-2 ORF7a interactions, with a particular focus on transmembrane and juxtamembrane interactions. Our results indicate that transmembrane domains play an important role in BST-2 ORF7a interactions and mutations to the transmembrane domain of BST-2 can alter these interactions, particularly single-nucleotide polymorphisms in BST-2 that result in mutations such as I28S. Using molecular dynamics simulations, we identified specific interfaces and interactions between BST-2 and ORF7a to develop a structural basis for the transmembrane interactions. Differences in glycosylation are observed for BST-2 transmembrane mutants interacting with ORF7a, consistent with the idea that transmembrane domains play a key role in their heterooligomerization. Overall, our results indicate that ORF7a transmembrane domain interactions play a key role along with extracellular and juxtamembrane domains in modulating BST-2 function.

Contact-number-driven virus evolution: A multi-level modeling framework for the evolution of acute or persistent RNA virus infection.

Viruses evolve in infected host populations, and host population dynamics affect viral evolution. RNA viruses with a short duration of infection and a high peak viral load, such as SARS-CoV-2, are maintained in human populations. By contrast, RNA viruses characterized by a long infection duration and a low peak viral load (e.g., borna disease virus) can be maintained in nonhuman populations, and the process of the evolution of persistent viruses has rarely been explored. Here, using a multi-level modeling approach including both individual-level virus infection dynamics and population-scale transmission, we consider virus evolution based on the host environment, specifically, the effect of the contact history of infected hosts. We found that, with a highly dense contact history, viruses with a high virus production rate but low accuracy are likely to be optimal, resulting in a short infectious period with a high peak viral load. In contrast, with a low-density contact history, viral evolution is toward low virus production but high accuracy, resulting in long infection durations with low peak viral load. Our study sheds light on the origin of persistent viruses and why acute viral infections but not persistent virus infection tends to prevail in human society.

Is "sadistic pleasure" a contrived process of signaling one's antagonism?

OBJECTIVE: Sadistic pleasure presumably incorporates processes that support an authentic enjoyment of others' pain. However, antagonism confirmation theory, grounded in social-psychological theorizing on identity maintenance and the notion of ego-syntonicity, suggests that individuals higher in sadism report greater pleasure in response to others' pain because such reports are immoral responses that confirm their self-views. This alternative conception has yet to be tested. METHOD: In two preregistered experiments (total N = 968), participants completed measures of sadism, read about situations involving others' pain, and rated their pleasure. We manipulated the extent to which pleasure from others' pain could be used to signal morality or antagonism. RESULTS: We found that relatively sadistic people indicated greater pleasure across the studies but, like relatively non-sadistic people, they altered their pleasure ratings to signal greater morality or less antagonism. CONCLUSIONS: The findings fail to support antagonism confirmation theory, but they support recent perspectives on sadism that suggest that sadistic people may occasionally care about seeming moral (or not seeming antagonistic) and that sadism may be somewhat ego-dystonic in this respect.

A Closer Examination of the Integrity Scale's Construct Validity.

People's commitment to moral principles affects how they self-regulate and directs people down different ethical paths. The Integrity Scale was designed to assess the strength of people's commitment to moral principles. Here, we sought to contribute to evaluating the construct validity of the Integrity Scale. We related the scale to various theoretically relevant criteria including low antagonism features, social-cognitive foundations for morality, self-control, rationality, and self-presentation behavior. Suggestive of the scale's construct validity, the present research showed that scores on the Integrity Scale related to (a) reduced antagonistic-personality features relevant to exploitation and dishonesty more so than immodesty, tough-heartedness, fearlessness, or cynicism; (b) enhanced social-cognitive skills (e.g., cognitive empathy processes); (c) enhanced self-control; (d) enhanced capacities for and reliance on rationality in decision making (e.g., intelligence and cognitive-reflection skill); and (e) enhanced reliance on self-presentation tactics that portray an identity based in high levels of integrity.

Inference of the SARS-CoV-2 generation time using UK household data.

The distribution of the generation time (the interval between individuals becoming infected and transmitting the virus) characterises changes in the transmission risk during SARS-CoV-2 infections. Inferring the generation time distribution is essential to plan and assess public health measures. We previously developed a mechanistic approach for estimating the generation time, which provided an improved fit to data from the early months of the COVID-19 pandemic (December 2019-March 2020) compared to existing models (Hart et al., 2021). However, few estimates of the generation time exist based on data from later in the pandemic. Here, using data from a household study conducted from March to November 2020 in the UK, we provide updated estimates of the generation time. We considered both a commonly used approach in which the transmission risk is assumed to be independent of when symptoms develop, and our mechanistic model in which transmission and symptoms are linked explicitly. Assuming independent transmission and symptoms, we estimated a mean generation time (4.2 days, 95% credible interval 3.3-5.3 days) similar to previous estimates from other countries, but with a higher standard deviation (4.9 days, 3.0-8.3 days). Using our mechanistic approach, we estimated a longer mean generation time (5.9 days, 5.2-7.0 days) and a similar standard deviation (4.8 days, 4.0-6.3 days). As well as estimating the generation time using data from the entire study period, we also considered whether the generation time varied temporally. Both models suggest a shorter mean generation time in September-November 2020 compared to earlier months. Since the SARS-CoV-2 generation time appears to be changing, further data collection and analysis is necessary to continue to monitor ongoing transmission and inform future public health policy decisions.

Generation time of the alpha and delta SARS-CoV-2 variants: an epidemiological analysis.

BACKGROUND: In May, 2021, the delta (B.1.617.2) SARS-CoV-2 variant became dominant in the UK, superseded by the omicron (B.1.1.529) variant in December, 2021. The delta variant is associated with increased transmissibility compared with the alpha variant, which was the dominant variant in the UK between December, 2020, and May, 2021. To understand transmission and the effectiveness of interventions, we aimed to investigate whether the delta variant generation time (the interval between infections in infector-infectee pairs) is shorter-ie, transmissions are happening more quickly-than that of the alpha variant. METHODS: In this epidemiological analysis, we analysed transmission data from an ongoing UK Health Security Agency (UKHSA) prospective household study. Households were recruited to the study after an index case had a positive PCR test and genomic sequencing was used to determine the variant responsible. By fitting a mathematical transmission model to the data, we estimated the intrinsic generation time (which assumes a constant supply of susceptible individuals throughout infection) and the household generation time (which reflects realised transmission in the study households, accounting for susceptible depletion) for the alpha and delta variants. FINDINGS: Between February and August, 2021, 227 households consisting of 559 participants were recruited to the UKHSA study. The alpha variant was detected or assumed to be responsible for infections in 131 households (243 infections in 334 participants) recruited in February-May, and the delta variant in 96 households (174 infections in 225 participants) in May-August. The mean intrinsic generation time was shorter for the delta variant (4·7 days, 95% credible interval [CI] 4·1-5·6) than the alpha variant (5·5 days, 4·7-6·5), with 92% posterior probability. The mean household generation time was 28% (95% CI 0-48%) shorter for the delta variant (3·2 days, 95% CI 2·5-4·2) than the alpha variant (4·5 days, 3·7-5·4), with 97·5% posterior probability. INTERPRETATION: The delta variant transmits more quickly in households than the alpha variant, which can be attributed to faster depletion of susceptible individuals in households and a possible decrease in the intrinsic generation time. Interventions such as contact tracing, testing, and isolation might be less effective if transmission of the virus occurs quickly. FUNDING: National Institute for Health Research, UK Health Security Agency, Engineering and Physical Sciences Research Council, and UK Research and Innovation.

We are who we thought we were: Confirming one's own antagonism levels.

Although many processes might contribute to the self-perpetuating nature of antagonistic personality, we proposed and tested the "antagonism-confirmation" perspective on this phenomenon. This perspective states that antagonistic personality is based in tendencies to confirm (vs. disconfirm) the self's beliefs about its personality. Importantly, this explanation uniquely predicts that antagonism-related personality constructs should relate to strategically adopting behaviors that vary on only their signification of higher or lower antagonism levels (and nothing more). In apparent privacy, nonclinical participants completed a color-gazing task, wherein antagonistic people ostensibly see colors become more (more-intense condition) or less intense (less-intense condition) while gazing at them. Consistent with the antagonism-confirmation perspective, antagonism-related personality constructs related to perceiving colors as turning more intense in the more-intense (vs. less-intense) condition. These effects could not be attributed to demand and occurred among a subsample of participants that indicated providing completely authentic responses. Furthermore, participants higher in antagonism-related personality constructs reported a greater likelihood of possessing antagonistic characteristics and that these characteristics were more beneficial; mediation evidence suggested that these reports were influenced by their confirmatory responding on the color-gazing task. Antagonism-confirmation tendencies might partly account for why antagonistic personality persists; broadly, the findings highlight the critical nature of identity management as a feature of antagonistic personality. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Integrative geochronology calibrates the Middle and Late Stone Ages of Ethiopia's Afar Rift.

The Halibee member of the Upper Dawaitoli Formation of Ethiopia's Middle Awash study area features a wealth of Middle and Later Stone Age (MSA and LSA) paleoanthropological resources in a succession of Pleistocene sediments. We introduce these artifacts and fossils, and determine their chronostratigraphic placement via a combination of established radioisotopic methods and a recently developed dating method applied to ostrich eggshell (OES). We apply the recently developed 230Th/U burial dating of OES to bridge the temporal gap between radiocarbon (14C) and 40Ar/39Ar ages for the MSA and provide 14C ages to constrain the younger LSA archaeology and fauna to ∼24 to 21.4 ka. Paired 14C and 230Th/U burial ages of OES agree at ∼31 ka for an older LSA locality, validating the newer method, and in turn supporting its application to stratigraphically underlying MSA occurrences previously constrained only by a maximum 40Ar/39Ar age. Associated fauna, flora, and Homo sapiens fossils are thereby now fixed between 106 ± 20 ka and 96.4 ± 1.6 ka (all errors 2σ). Additional 40Ar/39 results on an underlying tuff refine its age to 158.1 ± 11.0 ka, providing a more precise minimum age for MSA lithic artifacts, fauna, and H. sapiens fossils recovered ∼9 m below it. These results demonstrate how chronological control can be obtained in tectonically active and stratigraphically complex settings to precisely calibrate crucial evidence of technological, environmental, and evolutionary changes during the African Middle and Late Pleistocene.