Charting a landmark-driven path forward for population genetics and ancient DNA research in Africa.

Population history-focused DNA and ancient DNA (aDNA) research in Africa has dramatically increased in the past decade, enabling increasingly fine-scale investigations into the continent's past. However, while international interest in human genomics research in Africa grows, major structural barriers limit the ability of African scholars to lead and engage in such research and impede local communities from partnering with researchers and benefitting from research outcomes. Because conversations about research on African people and their past are often held outside Africa and exclude African voices, an important step for African DNA and aDNA research is moving these conversations to the continent. In May 2023 we held the DNAirobi workshop in Nairobi, Kenya and here we synthesize what emerged most prominently in our discussions. We propose an ideal vision for population history-focused DNA and aDNA research in Africa in ten years' time and acknowledge that to realize this future, we need to chart a path connecting a series of "landmarks" that represent points of consensus in our discussions. These include effective communication across multiple audiences, reframed relationships and capacity building, and action toward structural changes that support science and beyond. We concluded there is no single path to creating an equitable and self-sustaining research ecosystem, but rather many possible routes linking these landmarks. Here we share our diverse perspectives as geneticists, anthropologists, archaeologists, museum curators, and educators to articulate challenges and opportunities for African DNA and aDNA research and share an initial map toward a more inclusive and equitable future.

Early agriculture and crop transitions at Kakapel Rockshelter in the Lake Victoria region of eastern Africa.

The histories of African crops remain poorly understood despite their contemporary importance. Integration of crops from western, eastern and northern Africa probably first occurred in the Great Lakes Region of eastern Africa; however, little is known about when and how these agricultural systems coalesced. This article presents archaeobotanical analyses from an approximately 9000-year archaeological sequence at Kakapel Rockshelter in western Kenya, comprising the largest and most extensively dated archaeobotanical record from the interior of equatorial eastern Africa. Direct radiocarbon dates on carbonized seeds document the presence of the West African crop cowpea (Vigna unguiculata (L.) Walp) approximately 2300 years ago, synchronic with the earliest date for domesticated cattle (Bos taurus). Peas (Pisum sativum L. or Pisum abyssinicum A. Braun) and sorghum (Sorghum bicolor (L.) Moench) from the northeast and eastern African finger millet (Eleusine coracana (L.) Gaertn.) are incorporated later, by at least 1000 years ago. Combined with ancient DNA evidence from Kakapel and the surrounding region, these data support a scenario in which the use of diverse domesticated species in eastern Africa changed over time rather than arriving and being maintained as a single package. Findings highlight the importance of local heterogeneity in shaping the spread of food production in sub-Saharan Africa.

Early first-trimester transvaginal ultrasound screening for Cesarean scar pregnancy in patients with previous Cesarean delivery: analysis of the evidence.

Obstetric hemorrhage is a leading cause of maternal morbidity and mortality. An important etiology of obstetric hemorrhage is placenta accreta spectrum. In the last two decades, there has been increased clinical experience of the devastating effect of undiagnosed, as well as late diagnosed, cases of Cesarean scar pregnancy. There is a growing body of evidence suggesting that Cesarean scar pregnancy is an early precursor of second- and third-trimester placenta accreta spectrum. As such, Cesarean scar pregnancy should be diagnosed in the early first trimester. This early diagnosis could be achieved by introducing regimented sonographic screening in pregnancies of patients with previous Cesarean delivery. This Opinion article evaluates the scientific and clinical basis of whether Cesarean scar pregnancy, with special focus on its early first-trimester discovery, complies with the accepted requirements of a screening test. Each of the 10 classical screening criteria of Wilson and Jungner were systematically applied to evaluate if the criteria were met by Cesarean scar pregnancy, to analyze if it is possible and realistic to carry out screening in a population-wide fashion.

Ancient herders enriched and restructured African grasslands.

Grasslands are one of the world's most extensive terrestrial biomes and are central to the survival of herders, their livestock and diverse communities of large wild mammals1-3. In Africa, tropical soils are predominantly nutrient-limited4-6 but productive grassy patches in wooded grassland savannah ecosystems2,4 grow on fertile soils created by geologic and edaphic factors, megafauna, fire and termites4-6. Mobile pastoralists also create soil-fertility hotspots by penning their herds at night, which concentrates excrement-and thus nutrients-from grazing of the surrounding savannahs7-11. Historical anthropogenic hotspots produce high-quality forage, attract wildlife and increase spatial heterogeneity in African savannahs4,12-15. Archaeological research suggests this effect extends back at least 1,000 years16-19 but little is known about nutrient persistence at millennial scales. Here we use chemical, isotopic and sedimentary analyses to show high nutrient and 15N enrichment in on-site degraded dung deposits relative to off-site soils at five Pastoral Neolithic20 sites (radiocarbon dated to between 3,700 and 1,550 calibrated years before present (cal. BP)). This study demonstrates the longevity of nutrient hotspots and the long-term legacy of ancient herders, whose settlements enriched and diversified African savannah landscapes over three millennia.

Neogene continental denudation and the beryllium conundrum.

Reconstructing Cenozoic history of continental silicate weathering is crucial for understanding Earth's carbon cycle and greenhouse history. The question of whether continental silicate weathering increased during the late Cenozoic, setting the stage for glacial cycles, has remained controversial for decades. Whereas numerous independent proxies of weathering in ocean sediments (e.g., Li, Sr, and Os isotopes) have been interpreted to indicate that the continental silicate weathering rate increased in the late Cenozoic, beryllium isotopes in seawater have stood out as an important exception. Beryllium isotopes have been interpreted to indicate stable continental weathering and/or denudation rates over the last 12 Myr. Here we present a Be cycle model whose results show that variations in the 9Be weathering flux are counterbalanced by near-coastal scavenging while the cosmogenic 10Be flux from the upper atmosphere stays constant. As a result, predicted seawater 10Be/9Be ratios remain nearly constant even when global denudation and Be weathering rates increase by three orders of magnitude. Moreover, 10Be/9Be records allow for up to an 11-fold increase in Be weathering and denudation rates over the late Cenozoic, consistent with estimates from other proxies. The large increase in continental weathering indicated by multiple proxies further suggests that the increased CO2 consumption by continental weathering, driven by mountain-building events, was counterbalanced by other geological processes to prevent a runaway icehouse condition during the late Cenozoic. These processes could include enhanced carbonate dissolution via pyrite weathering, accelerated oxidation of fossil organic carbon, and/or reduced basalt weathering as the climate cooled.

Evidence for a Northern Hemispheric trigger of the 100,000-y glacial cyclicity.

The causes of the Mid-Pleistocene Transition, the shift from ∼41-ky to 100-ky interglacial-glacial cycles and more intense ice ages, remain intensely debated, as this fundamental change occurred between ∼1,250 and 650 ka without substantial changes in astronomical climate forcings. Recent studies disagree about the relative importance of events and processes in the Northern and Southern Hemispheres, as well as whether the shift occurred gradually over several interglacial-glacial cycles or abruptly at ∼900 ka. We address these issues using a north-to-south reconstruction of the Atlantic arm of the global meridional overturning ocean circulation, a primary means for distributing heat around the globe, using neodymium (Nd) isotopes. Results reveal a period of intense erosion affecting the cratonic shields surrounding the North Atlantic between Marine Isotope Stages (MIS) 27 and 25 (∼980 and 950 ka), reflected by unusually low Nd isotope ratios in deep North Atlantic seawater. This episode preceded a major ocean circulation weakening between MIS 25 and 21 (950 and 860 ka) that coincided with the first ∼100-ky-long interglacial-glacial onset of Northern Hemisphere glaciation at around 2.4 to 2.8 Ma. The data point to a Northern Hemisphere-sourced initiation for the transition, possibly induced through regolith loss and increased exposure of the crystalline bedrock, which would lead to increased friction, enabling larger ice sheets that are characteristic of the 100-ky interglacial-glacial cycles.

Provenance of Anthropogenic Pb and Atmospheric Dust to Northwestern North America.

Industrial activities release aerosols containing toxic metals into the atmosphere, where they are transported far from their sources, impacting ecosystems and human health. Concomitantly, long-range-transported mineral dust aerosols play a role in Earth's radiative balance and supply micronutrients to iron-limited ecosystems. To evaluate the sources of dust and pollutant aerosols to Alaska following the 2001 phase-out of leaded gasoline in China, we measured Pb-Sr-Nd isotopic compositions of particles collected in 2016 from snow pits across an elevational transect (2180-5240 m-a.s.l) in Denali National Park, USA. We also determined Pb flux and enrichment from 1991-2011 in the Denali ice core (3870 m-a.s.l). Chinese coal-burning and non-ferrous metal smelting account for up to 64% of Pb deposition at our sites, a value consistent across the western Arctic. Pb isotope ratios in the aerosols did not change between 2001 and 2016, despite the ban on lead additives. Emissions estimates demonstrate that industrial activities have more than compensated for the phase-out of leaded gasoline, with China emitting ∼37,000 metric tons year-1 of Pb during 2013-2015, approximately 78% of the Pb from East Asia. The Pb flux to Alaska now equals that measured in southern Greenland during peak pollution from North America.

Key new pieces of the HIMU puzzle from olivines and diamond inclusions.

Mantle melting, which leads to the formation of oceanic and continental crust, together with crust recycling through plate tectonics, are the primary processes that drive the chemical differentiation of the silicate Earth. The present-day mantle, as sampled by oceanic basalts, shows large chemical and isotopic variability bounded by a few end-member compositions. Among these, the HIMU end-member (having a high U/Pb ratio, µ) has been generally considered to represent subducted/recycled basaltic oceanic crust. However, this concept has been challenged by recent studies of the mantle source of HIMU magmas. For example, analyses of olivine phenocrysts in HIMU lavas indicate derivation from the partial melting of peridotite, rather than from the pyroxenitic remnants of recycled oceanic basalt. Here we report data that elucidate the source of these lavas: high-precision trace-element analyses of olivine phenocrysts point to peridotite that has been metasomatized by carbonatite fluids. Moreover, similarities in the trace-element patterns of carbonatitic melt inclusions in diamonds and HIMU lavas indicate that the metasomatism occurred in the subcontinental lithospheric mantle, fused to the base of the continental crust and isolated from mantle convection. Taking into account evidence from sulfur isotope data for Archean to early Proterozoic surface material in the deep HIMU mantle source, a multi-stage evolution is revealed for the HIMU end-member, spanning more than half of Earth's history. Before entrainment in the convecting mantle, storage in a boundary layer, upwelling as a mantle plume and partial melting to become ocean island basalt, the HIMU source formed as Archean-early Proterozoic subduction-related carbonatite-metasomatized subcontinental lithospheric mantle.

A monumental cemetery built by eastern Africa's first herders near Lake Turkana, Kenya.

Monumental architecture is a prime indicator of social complexity, because it requires many people to build a conspicuous structure commemorating shared beliefs. Examining monumentality in different environmental and economic settings can reveal diverse reasons for people to form larger social units and express unity through architectural display. In multiple areas of Africa, monumentality developed as mobile herders created large cemeteries and practiced other forms of commemoration. The motives for such behavior in sparsely populated, unpredictable landscapes may differ from well-studied cases of monumentality in predictable environments with sedentary populations. Here we report excavations and ground-penetrating radar surveys at the earliest and most massive monumental site in eastern Africa. Lothagam North Pillar Site was a communal cemetery near Lake Turkana (northwest Kenya) constructed 5,000 years ago by eastern Africa's earliest pastoralists. Inside a platform ringed by boulders, a 119.5-m2 mortuary cavity accommodated an estimated minimum of 580 individuals. People of diverse ages and both sexes were buried, and ornaments accompanied most individuals. There is no evidence for social stratification. The uncertainties of living on a "moving frontier" of early herding-exacerbated by dramatic environmental shifts-may have spurred people to strengthen social networks that could provide information and assistance. Lothagam North Pillar Site would have served as both an arena for interaction and a tangible reminder of shared identity.

O-RADS US Risk Stratification and Management System: A Consensus Guideline from the ACR Ovarian-Adnexal Reporting and Data System Committee.

The Ovarian-Adnexal Reporting and Data System (O-RADS) US risk stratification and management system is designed to provide consistent interpretations, to decrease or eliminate ambiguity in US reports resulting in a higher probability of accuracy in assigning risk of malignancy to ovarian and other adnexal masses, and to provide a management recommendation for each risk category. It was developed by an international multidisciplinary committee sponsored by the American College of Radiology and applies the standardized reporting tool for US based on the 2018 published lexicon of the O-RADS US working group. For risk stratification, the O-RADS US system recommends six categories (O-RADS 0-5), incorporating the range of normal to high risk of malignancy. This unique system represents a collaboration between the pattern-based approach commonly used in North America and the widely used, European-based, algorithmic-style International Ovarian Tumor Analysis (IOTA) Assessment of Different Neoplasias in the Adnexa model system, a risk prediction model that has undergone successful prospective and external validation. The pattern approach relies on a subgroup of the most predictive descriptors in the lexicon based on a retrospective review of evidence prospectively obtained in the IOTA phase 1-3 prospective studies and other supporting studies that assist in differentiating management schemes in a variety of almost certainly benign lesions. With O-RADS US working group consensus, guidelines for management in the different risk categories are proposed. Both systems have been stratified to reach the same risk categories and management strategies regardless of which is initially used. At this time, O-RADS US is the only lexicon and classification system that encompasses all risk categories with their associated management schemes.

α1-Antitrypsin infusion for treatment of steroid-resistant acute graft-versus-host disease.

Corticosteroid resistance after acute graft-versus-host disease (SR-aGVHD) results in high morbidity and mortality after allogeneic hematopoietic cell transplantation. Current immunosuppressive therapies for SR-aGVHD provide marginal effectiveness because of poor response or excessive toxicity, primarily from infection. α1-Antitrypsin (AAT), a naturally abundant serine protease inhibitor, is capable of suppressing experimental GVHD by downmodulating inflammation and increasing ratios of regulatory (Treg) to effector T cells (Teffs). In this prospective multicenter clinical study, we sought to determine the safety and response rate of AAT administration in SR-aGVHD. Forty patients with a median age of 59 years received intravenous AAT twice weekly for 4 weeks as first-line treatment of SR-aGVHD. The primary end point was overall response rate (ORR), the proportion of patients with SR-aGVHD in complete (CR) or partial response by day 28 without addition of further immunosuppression. Treatment was well tolerated without drug-related adverse events. A significant increase in serum levels of AAT was observed after treatment. The ORR and CR rates by day 28 were 65% and 35%, respectively, and included responses in all aGVHD target organs. At day 60, responses were sustained in 73% of patients without intervening immunosuppression. Infectious mortality was 10% at 6 months and 2.5% within 30 days of last AAT infusion. Consistent with preclinical data, correlative samples showed an increase in ratio of activated Tregs to Teffs after AAT treatment. These data suggest that AAT is safe and may be potentially efficacious in treating SR-aGVHD. This trial was registered at www.clinicaltrials.gov as #NCT01700036.

Trajectories of cultural innovation from the Middle to Later Stone Age in Eastern Africa: Personal ornaments, bone artifacts, and ocher from Panga ya Saidi, Kenya.

African Middle Stone Age (MSA) populations used pigments, manufactured and wore personal ornaments, made abstract engravings, and produced fully shaped bone tools. However, ongoing research across Africa reveals variability in the emergence of cultural innovations in the MSA and their subsequent development through the Later Stone Age (LSA). When present, it appears that cultural innovations manifest regional variability, suggestive of distinct cultural traditions. In eastern Africa, several Late Pleistocene sites have produced evidence for novel activities, but the chronologies of key behavioral innovations remain unclear. The 3 m deep, well-dated, Panga ya Saidi sequence in eastern Kenya, encompassing 19 layers covering a time span of 78 kyr beginning in late Marine Isotope Stage 5, is the only known African site recording the interplay between cultural and ecological diversity in a coastal forested environment. Excavations have yielded worked and incised bones, ostrich eggshell beads (OES), beads made from seashells, worked and engraved ocher pieces, fragments of coral, and a belemnite fossil. Here, we provide, for the first time, a detailed analysis of this material. This includes a taphonomic, archeozoological, technological, and functional study of bone artifacts; a technological and morphometric analysis of personal ornaments; and a technological and geochemical analysis of ocher pieces. The interpretation of the results stemming from the analysis of OES beads is guided by an ethnoarcheological perspective and field observations. We demonstrate that key cultural innovations on the eastern African coast are evident by 67 ka and exhibit remarkable diversity through the LSA and Iron Age. We suggest the cultural trajectories evident at Panga ya Saidi were shaped by both regional traditions and cultural/demic diffusion.

BK virus encephalitis and end-stage renal disease in a child with hematopoietic stem cell transplantation.

BK virus encephalitis after HSCT is uncommon. Several reports of native kidney BKVN in patients with HSCT, hematologic malignancies, human immunodeficiency virus infection, and non-renal solid organ transplantation have been described. However, an uncommon combination of BK encephalitis and ESRD of native kidneys secondary to BK virus in a child with HSCT has not been described. We report a 10-year-old boy who presented with a gradually rising serum creatinine during treatment for severe autoimmune hemolytic anemia, which he developed 9 months after receiving an allogeneic HSCT for aplastic anemia. There was no proteinuria or hematuria present. Serum BK virus load was 5 × 106  copies/mL. A renal biopsy showed evidence of BKVN. He developed fever, seizures, and confusion, and the (CSF) showed significant presence of the BK virus (1 × 106  copies/mL) along with biochemical evidence of viral encephalitis. Cerebrospinal fluid cultures were negative. Despite significant clinical symptoms and presence of BK virus in CSF, the magnetic resonance brain imaging findings were minimal. With reduction of immunosuppression, there was resolution of BK encephalitis but BKVN remained resistant to multiple anti-BK virus agents, including leflunomide and cidofovir. He eventually became dialysis-dependent and, 6 years later, received a renal transplant from his mother. This case illustrates that BK virus in severely immunocompromised HSCT recipient may lead to BK encephalitis and BKVN of native kidneys, even without hemorrhagic cystitis, leading to ESRD. Knowledge of such is important for appropriate timely evaluation and management.

Purified and specific cytoplasmic pollen extract: a non-hormonal alternative for the treatment of menopausal symptoms.

Research into non-hormonal, alternative therapies is necessary for women for whom menopausal hormone therapy is contraindicated or for women who do not wish to take hormones. This review focuses on one such non-hormonal option, namely, purified and specific cytoplasmic pollen extract, or PureCyTonin®. This extract has been evaluated in several preclinical and clinical studies, where it demonstrated its value as a safe and non-estrogenic alternative for menopause. This review presents the beneficial effects of PureCyTonin® in the treatment of menopausal symptoms (e.g. hot flushes) in healthy women, as well as in premenstrual syndrome. We discuss the mechanism of action of PureCyTonin®, an SSRI-'like' therapy. The lack of estrogenic effect demonstrated in preclinical studies suggests that PureCyTonin® may also be a suitable option for the management of menopausal symptoms in women with breast cancer.

Eltrombopag for Treating Thrombocytopenia after Allogeneic Stem Cell Transplantation.

Thrombocytopenia after allogeneic hematopoietic stem cell transplantation (allo-SCT) can pose significant problems in management of patients. Eltrombopag is a small-molecule thrombopoietin receptor agonist that has been approved for use in immune thrombocytopenic purpura and aplastic anemia; but its use after allo-SCT is limited. Between 2014 and 2017, we treated 13 patients with eltrombopag for poor platelet engraftment without evidence of relapse at the time of initiation, including 6 patients with primary platelet engraftment failure and 7 with secondary platelet engraftment failure. Eltrombopag was started at an initial dose of 25 or 50 mg per day, and dose adjustments were made in accordance with the manufacturer's recommendation. The cumulative incidence of platelet recovery to ≥50,000/µL without the need for transfusion for at least 7 days was defined as response. The overall response rate was 62% (n = 8). Of the 6 patients with primary isolated platelet failure, 3 (50%) responded, and of the 7 patients with secondary platelet failure, 5 (71%) responded. The median time to response was 33 days (range, 11 to 68 days). In addition, no significant differences in platelet recovery were noted in patients with adequate and decreased bone marrow megakaryocytic reserve (60% and 67%, respectively). Although eltrombopag was well tolerated, and no patient discontinued treatment because of adverse events, only 3 patients were alive at the end of the observation period, with relapse and graft-versus-host disease accounting for majority of the deaths. This suggested that despite the relatively good overall response rate to eltrombopag, inadequate platelet engraftment is a harbinger of poor outcome in allo-SCT.

Simple Adnexal Cysts: SRU Consensus Conference Update on Follow-up and Reporting.

This multidisciplinary consensus update aligns prior Society of Radiologists in Ultrasound (SRU) guidelines on simple adnexal cysts with recent large studies showing exceptionally low risk of cancer associated with simple adnexal cysts. Most small simple cysts do not require follow-up. For larger simple cysts or less well-characterized cysts, follow-up or second opinion US help to ensure that solid elements are not missed and are also useful for assessing growth of benign tumors. In postmenopausal women, reporting of simple cysts greater than 1 cm should be done to document their presence in the medical record, but such findings are common and follow-up is recommended only for simple cysts greater than 3-5 cm, with the higher 5-cm threshold reserved for simple cysts with excellent imaging characterization and documentation. For simple cysts in premenopausal women, these thresholds are 3 cm for reporting and greater than 5-7 cm for follow-up imaging. If a cyst is at least 10%-15% smaller at any time, then further follow-up is unnecessary. Stable simple cysts at initial follow-up may benefit from a follow-up at 2 years due to measurement variability that could mask growth. Simple cysts that grow are likely cystadenomas. If a previously suspected simple cyst demonstrates papillary projections or solid areas at follow-up, then the cyst should be described by using standardized terminology. These updated SRU consensus recommendations apply to asymptomatic patients and to those whose symptoms are not clearly attributable to the cyst. These recommendations can reassure physicians and patients regarding the benign nature of simple adnexal cysts after a diagnostic-quality US examination that allows for confident diagnosis of a simple cyst. Patients will benefit from less costly follow-up, less anxiety related to these simple cysts, and less surgery for benign lesions.

Progressive multifocal leukoencephalopathy after allogeneic stem cell transplantation: Case report and review of the literature.

Progressive multifocal leukoencephalopathy (PML) is a rare, yet typically fatal complication of allogeneic stem cell transplantation. It is caused by reactivation of the John Cunningham (JC) virus in an immunocompromised host. This report describes an unfortunate case of PML in a recipient of an allogeneic stem cell transplant for acute myelogenous leukemia. The JC virus was undetectable in the patient's cerebrospinal fluid by polymerase chain reaction (PCR); however, a positive diagnosis was made after a brain biopsy. This and other published cases demonstrate that recipients of allogeneic stem cells can develop PML. Moreover, early diagnosis of the disease is often difficult and, as demonstrated in this case, screening with PCR does not appear to have strong diagnostic significance. With no effective treatment presently available, restoration of immune function is the only intervention that can affect prognosis. Further prospective studies are needed to understand the pathophysiology and treatment of this disease.

Single-molecule analysis reveals widespread structural variation in multiple myeloma.

Multiple myeloma (MM), a malignancy of plasma cells, is characterized by widespread genomic heterogeneity and, consequently, differences in disease progression and drug response. Although recent large-scale sequencing studies have greatly improved our understanding of MM genomes, our knowledge about genomic structural variation in MM is attenuated due to the limitations of commonly used sequencing approaches. In this study, we present the application of optical mapping, a single-molecule, whole-genome analysis system, to discover new structural variants in a primary MM genome. Through our analysis, we have identified and characterized widespread structural variation in this tumor genome. Additionally, we describe our efforts toward comprehensive characterization of genome structure and variation by integrating our findings from optical mapping with those from DNA sequencing-based genomic analysis. Finally, by studying this MM genome at two time points during tumor progression, we have demonstrated an increase in mutational burden with tumor progression at all length scales of variation.