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Nuclear receptor subfamily 2 group F member 2 (NR2F2 or COUP-TF2) encodes a transcription factor which is expressed at high levels during mammalian development. Rare heterozygous Mendelian variants in NR2F2 were initially identified in individuals with congenital heart disease (CHD), then subsequently in cohorts of congenital diaphragmatic hernia (CDH) and 46,XX ovotesticular disorders/differences of sexual development (DSD); however, the phenotypic spectrum associated with pathogenic variants in NR2F2 remains poorly characterized. Currently, less than 40 individuals with heterozygous pathogenic variants in NR2F2 have been reported. Here, we review the clinical and molecular details of 17 previously unreported individuals with rare heterozygous NR2F2 variants, the majority of which were de novo. Clinical features were variable, including intrauterine growth restriction (IUGR), CHD, CDH, genital anomalies, DSD, developmental delays, hypotonia, feeding difficulties, failure to thrive, congenital and acquired microcephaly, dysmorphic facial features, renal failure, hearing loss, strabismus, asplenia, and vascular malformations, thus expanding the phenotypic spectrum associated with NR2F2 variants. The variants seen were predicted loss of function, including a nonsense variant inherited from a mildly affected mosaic mother, missense and a large deletion including the NR2F2 gene. Our study presents evidence for rare, heterozygous NR2F2 variants causing a highly variable syndrome of congenital anomalies, commonly associated with heart defects, developmental delays/intellectual disability, dysmorphic features, feeding difficulties, hypotonia, and genital anomalies. Based on the new and previous cases, we provide clinical recommendations for evaluating individuals diagnosed with an NR2F2-associated disorder.

A major rate-limiting step in developing more effective immunotherapies for GBM is our inadequate understanding of the cellular complexity and the molecular heterogeneity of immune infiltrates in gliomas. Here, we report an integrated analysis of 201,986 human glioma, immune, and other stromal cells at the single cell level. In doing so, we discover extensive spatial and molecular heterogeneity in immune infiltrates. We identify molecular signatures for nine distinct myeloid cell subtypes, of which five are independent prognostic indicators of glioma patient survival. Furthermore, we identify S100A4 as a regulator of immune suppressive T and myeloid cells in GBM and demonstrate that deleting S100a4 in non-cancer cells is sufficient to reprogram the immune landscape and significantly improve survival. This study provides insights into spatial, molecular, and functional heterogeneity of glioma and glioma-associated immune cells and demonstrates the utility of this dataset for discovering therapeutic targets for this poorly immunogenic cancer. Glioblastoma (GBM) is an immune cold tumour that is refractory to immunotherapy. Here, the authors identify molecular phenotypes of immune-suppressive and -promoting myeloid cells in GBM through single cell RNA sequencing and propose S100A4 as a regulator of immune suppressive T and myeloid cells in GBM.

Early Miocene land mammals from eastern North America are exceedingly rare. Over the past several decades a small, but significant, vertebrate fauna has been recovered by paleontologists and citizen scientists from the Belgrade Formation at the Martin Marietta Belgrade Quarry in eastern North Carolina. This assemblage has 12 land mammal taxa, including beaver (Castoridae), stem lagomorph, carnivorans (Mustelidae, Ailuridae), horses (Equidae), rhinoceros (Rhinocerotidae), tapir (Tapiridae), peccary (Tayassuidae), anthracothere (Anthracotheriidae), entelodont (Entelodontidae), and protoceratid (Protoceratidae). Taken together, the biochronology of this Maysville Local Fauna indicates a late Arikareean (Ar3/Ar4) to early Hemingfordian (He1) North American Land Mammal Age (NALMA). This interval, which includes the Runningwater Chronofauna, documents numerous important Holarctic immigrants, including Amphictis, Craterogale, and cf. Menoceras found at this locality. Strontium isotope stratigraphy (SIS) of shark teeth collected in situ from the Belgrade Formation yield an age of 21.4 ± 0.13 Ma, which validates the age of interbedded land mammals within this unit. It also is consistent with the late Arikareean (Ar3/Ar4) biochronology and Aquitanian Neogene marine stage. New SIS analyses of oysters (Striostrea gigantissima) and clams (Chione) from this mine, previously assigned to late Oligocene or Late Miocene, are significantly older (28.0 ± 0.22 Ma and 27.6 ± 0.26 Ma, respectively) than the land mammals. Depending upon stratigraphic interpretations, these may confirm an older marine facies within the Belgrade Formation. This locality is important because of its marine and terrestrial tie-ins that facilitate intercalibration of both NALMAs and Cenozoic marine stages. Extinct fossil mammals, herein referred to as the Maysville Local Fauna (L.F.)., are described from the Martin Marietta Belgrade Quarry in eastern North Carolina. The fossils have been collected over the past several decades by professional and citizen (amateur) paleontologists. These fossils come from a single sedimentary unit called the Belgrade Formation that has previously been dated as late Oligocene or Early Miocene age (about 17 to 21 million years ago). At least a dozen fossil mammal taxa of the Maysville L.F. are described here from the Belgrade Formation. These include five placental orders such as beavers (Rodentia), lagomorphs, (Lagomorpha), carnivores (Carnivora, including mustelids and ailurids), odd-toed ungulates (Perissodactyla, including horses, rhinos, and tapirs), and even-toed ungulates (Artiodactyla, including peccaries, anthracotheres, entelodonts, and protoceratids). The stage of evolution of this mammal fauna indicates an Early Miocene age, most probably between about 21 and 17 million years ago. The Maysville L.F. has similar land mammal species to those from localities elsewhere in North America, including Florida, Nebraska, and Texas. This was a very interesting time in land mammal evolution that has been termed the Runningwater Chronofauna, including the presence of several Old Word immigrant taxa (carnivores and rhino) that are index fossils to this time interval. Strontium ratios preserved in fossil shark teeth from the Belgrade Formation indicate an Early Miocene age of 21.4 ± 0.13 million years ago, similar to the land mammal age determinations. In contrast, analyses of bivalves (oyster and clams), presumably from another subunit within the same formation, indicate an older (28.0 ± 0.22 Ma and 27.6 ± 0.26 Ma) Late Oligocene age.

IntroductionCommunity health workers (CHWs) play a critical role in extending healthcare services to underserved populations, especially in low-income and middle-income countries. Professional CHWs (proCHWs), who are salaried, skilled, supplied and supervised, are essential for achieving Universal Health Coverage and other global health goals. Despite the growing recognition of proCHWs, there is limited understanding of the global financing landscape for these workers. This study analyses the availability of data detailing the allocation of funding from major global development organisations for proCHWs.MethodsThe study was conducted by the Community Health Impact Coalition (CHIC) using a two-stage approach. First, eight major global funders were selected through a consultative process with CHIC members, chosen based on their perceived influence, leadership in community health and scale of financial commitments. The second stage involved mapping and analysing the funding availability of these organisations through desk reviews, brief consultations and analysis of public funding databases. The transparency of proCHW-specific funding data was assessed using a classification system: ‘yes’ (full availability), ‘partial’ (moderate availability) and ‘no’ (low/no availability).ResultsThe analysis revealed a gap in accessible data required to quantify the funding for CHWs, particularly proCHWs, across the eight organisations. Only two organisations, The Global Fund and the President’s Malaria Initiative, provided partial data visibility, while none fully disclosed specific funding amounts for proCHW programmes. Most organisations did not systematically track or report CHW investments, making it challenging to assess global funding flows.ConclusionsThe study highlights gaps in the availability of data related to funding for proCHWs, hampering the ability to track and evaluate investments in proCHW programmes. The study recommends global funders improve the specificity of their data reporting and integrate proCHW indicators into standard reporting tools. Enhanced data reporting is essential for optimising investments in proCHW programmes and advancing global health equity.

A number of factors contribute to the difficulty providers experience in treating borderline personality disorder (BPD). One complicating factor for treatment effectiveness is the presence of comorbid affective psychopathology (e.g., depression, anxiety). Participants were 176 adults (60 % female; M age  = 32.20) in a partial hospital program. Using a mediation model, the current study examined the relationship among traits of BPD, affective symptomatology, and general functioning post-treatment. Additional analyses explored whether change in the perception of therapeutic skill implementation moderated the relationship among traits of BPD, affective symptomatology, and general functioning. Little improvement/worsening of depression during partial hospitalization, but not changes in anxiety, mediated the relationship between traits of BPD and poor general functioning. Additionally, regardless of changes in perception of cognitive- or dialectical-behavioral skill implementation, little improvement/worsening depressive symptomatology continued to mediate the negative relationship noted above. This study has important implications for treatment of BPD and suggests that targeting depressive symptoms in short-term settings may be crucial in acute stabilization.

Screening for breast and colorectal cancer has resulted in reductions in mortality; however, questions remain regarding how these interventions are being diffused to all segments of the population. If an intervention is less amenable to diffusion, it could be associated with disparities in mortality rates, especially in rural vs urban areas. To compare the prevalence of breast and colorectal cancer screening adherence and to identify factors associated with screening adherence among women residing in rural vs urban areas in the United States. This population-based cross-sectional study of women aged 50 to 75 years in 11 states was conducted from 2017 to 2020. Adherence to cancer screening based on the US Preventative Services Task Force guidelines. For breast cancer screening, women who had mammograms in the past 2 years were considered adherent. For colorectal cancer screening, women who had (1) a stool test in the past year, (2) a colonoscopy in the past 10 years, or (3) a sigmoidoscopy in the past 5 years were considered adherent. Rural status was coded using Rural Urban Continuum Codes, and other variables were assessed to identify factors associated with screening. The overall sample of 2897 women included 1090 (38.4%) rural residents; 2393 (83.5%) non-Hispanic White women; 263 (9.2%) non-Hispanic Black women; 68 (2.4%) Hispanic women; 1629 women (56.2%) aged 50 to 64 years; and 712 women (24.8%) with a high school education or less. Women residing in urban areas were significantly more likely to be adherent to colorectal cancer screening compared with women residing in rural areas (1429 [82%] vs 848 [78%]; P = .01), whereas the groups were equally likely to be adherent to breast cancer screening (1347 [81%] vs 830 [81%]; P = .78). Multivariable mixed-effects logistic regression analyses confirmed that rural residence was associated with lower odds of being adherent to colorectal cancer screening (odds ratio [OR], 0.81; 95% CI, 0.66-0.99, P = .047). Non-Hispanic Black race was associated with adherence to breast cancer screening guidelines (OR, 2.85; 95% CI, 1.78-4.56; P < .001) but not colorectal cancer screening guidelines. In this cross-sectional study, women residing in rural areas were less likely to be adherent to colorectal cancer screening guidelines but were similarly adherent to breast cancer screening. This suggests that colorectal cancer screening, a more recent intervention, may not be as available in rural areas as breast cancer screening, ie, colorectal screening has lower amenability.

Objectives. Fruit and vegetable cost is a presumed barrier to intake. We sought to determine whether fruit and vegetable cost and consumers’ race and income would predict availability of fruits and vegetables in homes of schoolchildren in the Birmingham, Ala, area. Methods. Data on availability of 27 fruit and vegetable items were obtained from homes of 1355 children (32% African American) in the Birmingham area. Fruit and vegetable costs were obtained from the US Department of Agriculture. We used discrete choice analysis with the dependent variable represented as presence or absence of the fruit or vegetable item. Explanatory variables included fruit and vegetable price per serving; child’s gender, race, and age; and parent’s body mass index and income. Results. Higher cost was inversely related to fruit and vegetable availability. Higher income, African American race, and female gender were positively related to availability. Cost per serving was stratified into 3 categories—low, medium, and high. Relative to low-cost items, only high-cost items decreased the odds of availability significantly. Conclusions. Fruit and vegetable cost does impact availability and has the greatest impact for high-cost items. Although cost was inversely related to availability, African Americans reported higher fruit and vegetable availability than Whites. Additional studies are needed to determine whether food items of lower nutritive value and comparable cost impact availability.

This study examines African American and Caucasian women’s perception of how race affects their weight. Structured focus groups that used the nominal group technique (NGT) were conducted with four groups of African American women (n=30) and four groups of Caucasian women (n=30). Participants generated responses to the question, “How does being a Black/White woman affect your weight?” The African American groups generated 48 unique ideas, including unhealthy food preparation, poor food selection habits, lack of exercise, stress, increased risk of chronic diseases, and associated medical costs; the Caucasian groups produced 32 responses, including distorted expectations of perfect body type, success depended on thinness and beauty, social pressures, media, and men’s preferences. Results suggest that the African American women focused on food choices and health consequences while the Caucasian women emphasized body size and aesthetics. The observed differences support a need for culturally specific interventions that promote good eating patterns and healthy body shapes.

Postoperative cognitive dysfunction (POCD) is a common and persistent complication in aging individuals following surgery, particularly when opioids are used for perioperative pain management. Although opioids are widely administered in the perioperative setting, the mechanisms by which they contribute to long-term cognitive impairment remain poorly understood. Here, we investigated how synaptic, neuroaxonal, and mitochondrial abnormalities contribute to long-lasting memory deficits induced by surgery and morphine, and evaluated therapeutic strategies targeting neuroinflammation and mitochondrial dysfunction. Using an aged rat model of surgery with perioperative morphine administration, we found that persistent hippocampal-dependent memory impairments were not attributable to systemic illness or gross dendritic degeneration. Instead, morphine-treated animals exhibited selective reductions in dendritic spine subtypes associated with synaptic stability, impaired late-phase long-term potentiation, and blunted experience-dependent upregulation of the AMPA receptor subunit GluA1. These synaptic alterations were accompanied by elevated circulating neurofilament light chain (Nf-L), indicating sustained neuroaxonal perturbation. Morphine treatment also produced persistent hippocampal mitochondrial dysfunction, characterized by impaired oxidative phosphorylation, reduced respiratory reserve capacity, and increased oxidative DNA damage, including mitochondrial DNA oxidation. These effects were restricted to the hippocampus and not observed in peripheral tissue. Pharmacological inhibition of TLR4 signaling at the time of surgery, which rescued the memory deficit, attenuated oxidative stress and partially restored mitochondrial function, implicating early neuroinflammatory signaling in the development of long-term mitochondrial impairment. Finally, targeted mitochondrial rejuvenation with SS-31 four weeks post-surgery robustly rescued hippocampal-dependent memory and normalized mitochondrial respiratory function despite persistently elevated DNA oxidation and Nf-L. Together these findings identify sustained hippocampal mitochondrial dysfunction as a key mechanistic substrate underlying long-term cognitive deficits following surgery and morphine exposure in aged rats, and highlight mitochondrial bioenergetics as a promising therapeutic target for POCD.