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.

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.

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.

Patagonian dust, Agulhas Current, and Antarctic ice-rafted debris contributions to the South Atlantic Ocean over the past 150,000 years.

Disentangling inputs of aeolian dust, ice-rafted debris (IRD), and eroded continental detritus delivered by ocean currents to marine sediments provide important insights into Earth System processes and climate. This study uses Sr-Nd-Pb isotope ratios of the continent-derived (lithogenic) fraction in deep-sea core TN057-6 from the subantarctic Southern Ocean southwest of Africa over the past 150,000 y to identify source regions and quantify their relative contributions and fluxes utilizing a mixing model set in a Bayesian framework. The data are compared with proxies from parallel core Ocean Drilling Program Site 1090 and newly presented data from potential South America aeolian dust source areas (PSAs), allowing for an integrated investigation into atmospheric, oceanic, and cryospheric dynamics. PSA inputs varied on glacial/interglacial timescales, with southern South American sources dominating up to 88% of the lithogenic fraction (mainly Patagonia, which provided up to 68%) during cold periods, while southern African sources were more important during interglacials. During the warmer Marine Isotope Stage (MIS) 3 of the last glacial period, lithogenic fluxes were twice that of colder MIS2 and MIS4 at times, and showed unique isotope ratios best explained by Antarctic-derived IRD, likely from the Weddell Sea. The IRD intrusions contributed up to 41% at times and followed Antarctic millennial warming events that raised temperatures, causing instability of icesheet margins. High IRD was synchronous with increased bioavailable iron, nutrient utilization, high biological productivity, and decreased atmospheric CO2. Overall, TN057-6 sediments record systematic Southern Hemisphere climate shifts and cryospheric changes that impacted biogeochemical cycling on both glacial/interglacial and subglacial timescales.

Oral lasofoxifene's effects on moderate to severe vaginal atrophy in postmenopausal women: two phase 3, randomized, controlled trials.

OBJECTIVE: The aim of this study was to demonstrate whether lasofoxifene improves vaginal signs/symptoms of genitourinary syndrome of menopause. METHODS: Two identical, phase 3 trials randomized postmenopausal women with moderate to severe vaginal symptoms to oral lasofoxifene 0.25 or 0.5 mg/d, or placebo, for 12 week. Changes from baseline to week 12 in most bothersome symptom, vaginal pH, and percentages of vaginal parabasal and superficial cells were evaluated. These coprimary endpoints were analyzed using analysis of covariance, except superficial cells, which were analyzed by the nonparametric, rank-based Kruskal-Wallis test. RESULTS: The two studies enrolled 444 and 445 women (mean age, ~60 y), respectively. Coprimary endpoints at week 12 improved with lasofoxifene 0.25 and 0.5 mg/d greater than with placebo ( P < 0.0125 for all). Study 1: most bothersome symptom (least square mean difference from placebo: -0.4 and -0.5 for 0.25 and 0.5 mg/d, respectively), vaginal pH (-0.65, -0.58), and vaginal superficial (5.2%, 5.4%), and parabasal (-39.9%, -34.9%) cells; study 2: most bothersome symptom (-0.4, -0.5), vaginal pH (-0.57, -0.67), and vaginal superficial (3.5%, 2.2%) and parabasal (-34.1%, -33.5%) cells. Some improvements occurred as early as week 2. Most treatment-emergent adverse events were mild or moderate and hot flushes were most frequently reported (lasofoxifene vs placebo: 13%-23% vs 9%-11%). Serious adverse events were infrequent and no deaths occurred. CONCLUSIONS: In two phase 3 trials, oral lasofoxifene 0.25 and 0.5 mg/d provided significant and clinically meaningful improvements in vaginal signs/symptoms with a favorable safety profile, suggesting beneficial effects of lasofoxifene on genitourinary syndrome of menopause.

Eurasian back-migration into Northeast Africa was a complex and multifaceted process.

Recent studies have identified Northeast Africa as an important area for human movements during the Holocene. Eurasian populations have moved back into Northeastern Africa and contributed to the genetic composition of its people. By gathering the largest reference dataset to date of Northeast, North, and East African as well as Middle Eastern populations, we give new depth to our knowledge of Northeast African demographic history. By employing local ancestry methods, we isolated the Non-African parts of modern-day Northeast African genomes and identified the best putative source populations. Egyptians and Sudanese Copts bore most similarities to Levantine populations whilst other populations in the region generally had predominantly genetic contributions from the Arabian peninsula rather than Levantine populations for their Non-African genetic component. We also date admixture events and investigated which factors influenced the date of admixture and find that major linguistic families were associated with the date of Eurasian admixture. Taken as a whole we detect complex patterns of admixture and diverse origins of Eurasian admixture in Northeast African populations of today.

Needs assessment of menopause education in United States obstetrics and gynecology residency training programs.

OBJECTIVE: This study aimed to assess the variance in menopause education, educational resources, and the needs of obstetrics and gynecology (ObGyn) residency programs by conducting a national survey of program directors (PDs). METHODS: In 2022, an institutional review board-approved Web-based Qualtrics survey was designed and distributed electronically to 145 US ObGyn residency PDs. The survey consists of 15 questions. The main outcomes are reported using descriptive statistics. RESULTS: The survey was completed by 99 of 145 PDs (68.3%). Almost all participants (92.9%) strongly agreed that residents nationwide should have access to a standardized menopause curriculum that could be utilized in their programs. Only 31.3% reported having a menopause curriculum in their residency program. Of the programs with a menopause curriculum, 96.8% reported using lectures, 77.4% reported assigned readings, and 74.2% had either dedicated menopause clinics or other clinics with a high volume of menopausal patients. Of all programs surveyed, only 29.3% reported that trainees had dedicated time assigned to a menopause clinic. A total of 83 of 99 PDs agreed or strongly agreed that their programs needed more menopause educational resources, and most (89.7%) stated they were likely or very likely to use self-paced menopause modules that include performance feedback if available. CONCLUSIONS: Data from the needs assessment questionnaire revealed that menopause education and resources vary across residency programs, with the majority lacking a dedicated menopause curriculum. Most PDs expressed a desire for more educational resources and standardized training materials, and preferred to access an online national menopause curriculum.

SUMOylation of NaV1.2 channels regulates the velocity of backpropagating action potentials in cortical pyramidal neurons.

Voltage-gated sodium channels located in axon initial segments (AIS) trigger action potentials (AP) and play pivotal roles in the excitability of cortical pyramidal neurons. The differential electrophysiological properties and distributions of NaV1.2 and NaV1.6 channels lead to distinct contributions to AP initiation and propagation. While NaV1.6 at the distal AIS promotes AP initiation and forward propagation, NaV1.2 at the proximal AIS promotes the backpropagation of APs to the soma. Here, we show the small ubiquitin-like modifier (SUMO) pathway modulates Na+ channels at the AIS to increase neuronal gain and the speed of backpropagation. Since SUMO does not affect NaV1.6, these effects were attributed to SUMOylation of NaV1.2. Moreover, SUMO effects were absent in a mouse engineered to express NaV1.2-Lys38Gln channels that lack the site for SUMO linkage. Thus, SUMOylation of NaV1.2 exclusively controls INaP generation and AP backpropagation, thereby playing a prominent role in synaptic integration and plasticity.

Oral Ibrexafungerp for Vulvovaginal Candidiasis Treatment: An Analysis of VANISH 303 and VANISH 306.

Background: Ibrexafungerp is a novel antifungal treatment for acute vulvovaginal candidiasis (VVC). Using pooled data from two phase three studies (VANISH 303 and 306) in the treatment of acute VVC, this analysis sought to determine the effectiveness of ibrexafungerp in various patient subgroups that may impact outcomes. Materials and Methods: Data from VANISH 303 (NCT03734991) and VANISH 306 (NCT03987620) evaluating ibrexafungerp 300 mg twice daily (BID) for 1 day versus placebo, were pooled and analyzed to determine clinical cure rate, clinical improvement, and mycological cure at the test-of-cure visit (day 11 ± 3) and symptom resolution at the follow-up visit (day 25 ± 4) in the overall population. Patient subgroups analyzed included race, body mass index (BMI), baseline vulvovaginal signs and symptoms (VSS) score, and Candida species. Results: At the test-of-cure visit, patients receiving ibrexafungerp, compared with those who received placebo, had significantly higher rates of clinical cure (56.9% [214/376 patients] vs. 35.7% [65/182 patients]), clinical improvement (68.4% [257/376 patients] vs. 45.1% [82/182 patients]), and mycological cure (54.0% [203/376 patients] vs. 24.2% [44/182 patients]; all p < 0.0001). At the follow-up visit, patients receiving ibrexafungerp had sustained responses with higher symptom resolution rates (66.8% [251/376 patients]) versus placebo (48.4% [88/182 patients]; p < 0.0001). Race, BMI, baseline VSS score (including VSS severity score 13-18), and Candida species infection did not adversely affect clinical cure rates. Safety analysis results were consistent with the individual studies. Conclusions: Ibrexafungerp provides a safe and well-tolerated first-in-class fungicidal, 1-day oral treatment for patients with acute VVC, the first new therapy in >20 years. Clinical Trial Registration Number: NCT03734991.

An Analysis of 183 Heart Transplants for Pediatric or Congenital Heart Disease-Impact of High Panel Reactive Antibody.

BACKGROUND: We reviewed our management strategy and outcome data for all 179 patients with pediatric and/or congenital heart disease who underwent 183 heart transplants from January 1, 2011, to December 31, 2021, and evaluated the impact of elevated panel reactive antibody (PRA). METHODS: High PRA was defined as PRA >10%. Univariate associations with long-term survival were assessed with Cox proportional hazards models. Impact of high PRA on survival was estimated with multivariable models. RESULTS: PRA >10% was present in 60 of 183 transplants (32.8%), who were more likely to have prior cardiac surgery, higher number of prior cardiac operations, prior sternotomy, prior heart transplant, and positive crossmatch (24 of 60 [40.0%] vs 11 of 123 [8.9%], P < .0001). Univariate associations with long-term survival include acquired heart disease vs congenital or retransplant (hazard ratio [HR], 0.18; 95% CI, 0.053-0.593; P = .005), prior cardiac surgery (HR, 5.6; 95% CI, 1.32-23.75; P = .020), number of prior cardiac operations (HR, 1.3 for each additional surgery; 95% CI, 1.12-1.50; P = .0004), single ventricle (HR, 2.4; 95% CI, 1.05-5.48; P = .038), and preoperative renal dysfunction (HR, 3.4; 95% CI, 1.43-7.49; P = .002). In multivariate analysis, high PRA does not impact survival when controlling for each of the factors shown in univariable analysis to be associated with long-term survival. The Kaplan-Meier method provided the following survival estimates at 1 year (95% CI) and 5 years (95% CI) after cardiac transplantation: All patients, 93.6% (89.9%-97.3%) and 85.8% (80.0%-92.1%); PRA <10%, 96.6% (93.4%-99.9%) and 86.7% (79.6%-94.3%); and PRA >10%, 86.7% (78.0%-96.4%) and 83.8% (74.0%-95.0%). Despite high PRA being associated with higher mortality at 1 year (14.9% vs 3.8%, P = .035), no significant difference exists in Kaplan-Meier overall survival at 5 years posttransplant in patients with and without high PRA (log-rank P = .4). CONCLUSIONS: In our cohort, 5-year survival in patients with high PRA (PRA >10%) is similar to that in patients without high PRA (PRA <10%), despite the presence of more risk factors in those with high PRA. Individualized immunomodulatory strategies can potentially mitigate the risk of high PRA.

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.

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.

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.

High-precision measurement of U-Pu-Np-Am concentrations and isotope ratios in environmental reference materials by mass spectrometry.

We report results of precise and sensitive mass spectrometric measurements of uranium, plutonium, neptunium, and americium concentrations and isotope ratios in a variety of environmental reference materials. Most of our work has been done on NIST SRM 4350b, River Sediment, but we also present results for NIST SRM 4354, Lake Sediment; NIST SRMs 4355 and 4355a, Peruvian Soil; NIST SRM 4357, Ocean Sediment; NIST SRM 1648a, Urban Particulate Material; NIST SRM 1649b, Urban Dust; IAEA CRM 385, Ocean Sediment; USGS BCR-2, Columbia River Basalt; and USGS BHVO-2, Hawaiian Volcanic Observatory Basalt. These materials reflect a wide range in long-lived actinide concentrations (e.g. 1E4 to 1E10 atoms 239Pu/g) and isotope ratios. Measurements were performed in a clean laboratory by isotope dilution, multi-collector thermal ionization and multi-collector inductively coupled plasma mass spectrometry. In general, our results are in agreement with, but lower the uncertainty of, literature or certificate values for these reference materials. Our uranium results for the basalts also confirm previously reported high-precision mass spectrometric results from our laboratory. In many cases our measurements of U-Pu-Np-Am nuclides appear to be novel. Extensive results for NIST SRM 4350b, River Sediment, indicate that this material is heterogeneous for Pu-Np-Am concentrations and isotope ratios at a sample size of 5 g or lower. Pu-Np isotope ratios and a241Pu-241Am model age of 1954 reflect a mix of plutonium production operations at the nearby Hanford, Washington site, and global atmospheric fallout from nuclear weapons testing. Results for the oceanic sediment materials (NIST SRM 4357 and IAEA 385) collected near Sellafield, U.K. vary but are also indicative of local anthropogenic sources of varying Pu isotopic composition and a mean 241Pu-241Am model age of 1964. Large environmental fractionation between Pu and Np is observed for the ocean, river, and lake sediment reference materials. Novel measurements for the two air particulate SRMs indicate high U, Pu and Np concentrations for these collections in 1976-1977 with an anomalous regional fallout Pu isotopic signature. Results for BHVO-2 and other Hawaiian basalts indicate that those which erupted before or during the period of abundant atmospheric nuclear weapons testing (1950-1970) contain significant levels of Pu (on the order of 1E7 atoms 239Pu/g) with a global fallout Pu isotopic composition, compared to more recent eruptions which incorporated less Pu. Hence, Hawaiian basalts may provide an integrated temporal record of anthropogenic actinide fallout deposition from the atmosphere since eruption.

Deep Learning-Based Automated Echocardiographic Quantification of Left Ventricular Ejection Fraction: A Point-of-Care Solution.

BACKGROUND: We have recently tested an automated machine-learning algorithm that quantifies left ventricular (LV) ejection fraction (EF) from guidelines-recommended apical views. However, in the point-of-care (POC) setting, apical 2-chamber views are often difficult to obtain, limiting the usefulness of this approach. Since most POC physicians often rely on visual assessment of apical 4-chamber and parasternal long-axis views, our algorithm was adapted to use either one of these 3 views or any combination. This study aimed to (1) test the accuracy of these automated estimates; (2) determine whether they could be used to accurately classify LV function. METHODS: Reference EF was obtained using conventional biplane measurements by experienced echocardiographers. In protocol 1, we used echocardiographic images from 166 clinical examinations. Both automated and reference EF values were used to categorize LV function as hyperdynamic (EF>73%), normal (53%-73%), mildly-to-moderately (30%-52%), or severely reduced (<30%). Additionally, LV function was visually estimated for each view by 10 experienced physicians. Accuracy of the detection of reduced LV function (EF<53%) by the automated classification and physicians' interpretation was assessed against the reference classification. In protocol 2, we tested the new machine-learning algorithm in the POC setting on images acquired by nurses using a portable imaging system. RESULTS: Protocol 1: the agreement with the reference EF values was good (intraclass correlation, 0.86-0.95), with biases <2%. Machine-learning classification of LV function showed similar accuracy to that by physicians in most views, with only 10% to 15% cases where it was less accurate. Protocol 2: the agreement with the reference values was excellent (intraclass correlation=0.84) with a minimal bias of 2.5±6.4%. CONCLUSIONS: The new machine-learning algorithm allows accurate automated evaluation of LV function from echocardiographic views commonly used in the POC setting. This approach will enable more POC personnel to accurately assess LV function.

Helium in diamonds unravels over a billion years of craton metasomatism.

Chemical events involving deep carbon- and water-rich fluids impact the continental lithosphere over its history. Diamonds are a by-product of such episodic fluid infiltrations, and entrapment of these fluids as microinclusions in lithospheric diamonds provide unique opportunities to investigate their nature. However, until now, direct constraints on the timing of such events have not been available. Here we report three alteration events in the southwest Kaapvaal lithosphere using U-Th-He geochronology of fluid-bearing diamonds, and constrain the upper limit of He diffusivity (to D ≈ 1.8 × 10-19 cm2 s-1), thus providing a means to directly place both upper and lower age limits on these alteration episodes. The youngest, during the Cretaceous, involved highly saline fluids, indicating a relationship with late-Mesozoic kimberlite eruptions. Remnants of two preceding events, by a Paleozoic silicic fluid and a Proterozoic carbonatitic fluid, are also encapsulated in Kaapvaal diamonds and are likely coeval with major surface tectonic events (e.g. the Damara and Namaqua-Natal orogenies).