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Abstract Wolverine distribution contracted along the southern periphery of its range in North America during the 19th and 20th centuries due primarily to human influences. This history, along with low densities, sensitivity to climate change, and concerns about connectivity among fragmented habitats spurred the recent US federal listing of threatened status and special concern status in Canada. To help inform large scale landscape connectivity, we collected 882 genetic samples genotyped at 19 microsatellite loci. We employed multiple statistical models to assess the landscape factors (terrain complexity, human disturbance, forest configuration, and climate) associated with wolverine genetic connectivity across 2.2 million km2 of southwestern Canada and the northwestern contiguous United States. Genetic similarity (positive spatial autocorrelation) of wolverines was detected up to 555 km and a high-to-low gradient of genetic diversity occurred from north-to-south. Landscape genetics analyses confirmed that wolverine genetic connectivity has been negatively influenced by human disturbance at broad scales and positively influenced by forest cover and snow persistence at fine- and broad–scales, respectively. This information applied across large landscapes can be used to guide management actions with the goal of maintaining or restoring population connectivity.

Abstract In this paper, we study the physical properties of black holes in the framework of the recently proposed Einstien-Bel-Robinson gravity. We show that interestingly the theory propagates a transverse and massless graviton on a maximally symmetric background with positive energy. There is also a single ghost-free branch that returns to the Einstein case when β → 0. We find new black hole solutions to the equations, both approximate and exact, the latter being a constant curvature black hole solution, and discuss inconsistencies with metrics that were previously claimed to be approximate solutions to the equations. We obtain the conserved charges of the theory and briefly study the thermodynamics of the black hole solutions.

Madariaga virus (MADV) and Venezuelan equine encephalitis virus (VEEV) are emerging arboviruses affecting rural and remote areas of Latin America. However, clinical and epidemiologic reports are limited, and outbreaks are occurring at an increasing frequency. We addressed the data gap by analyzing all available clinical and epidemiologic data of MADV and VEEV infections recorded since 1961 in Panama. A total of 168 human alphavirus encephalitis cases were detected in Panama during 1961‒2023. We described the clinical signs and symptoms and epidemiologic characteristics of those cases, and also explored signs and symptoms as potential predictors of encephalitic alphavirus infection compared with those of other arbovirus infections occurring in the region. Our results highlight the challenges for the clinical diagnosis of alphavirus disease in endemic regions with overlapping circulation of multiple arboviruses.

Abstract Circulating cell-free DNA (cfDNA) assays for monitoring individuals with cancer typically rely on prior identification of tumor-specific mutations. Here, we develop a tumor-independent and mutation-independent approach (DELFI-tumor fraction, DELFI-TF) using low-coverage whole genome sequencing to determine the cfDNA tumor fraction and validate the method in two independent cohorts of patients with colorectal or lung cancer. DELFI-TF scores strongly correlate with circulating tumor DNA levels (ctDNA) (r = 0.90, p

Abstract Parkinson’s disease (PD) and Dementia with Lewy Bodies (DLB) are neurodegenerative disorders characterized by the accumulation of α-synuclein aggregates. α-synuclein forms droplets via liquid-liquid phase separation (LLPS), followed by liquid-solid phase separation (LSPS) to form amyloids, how this process is physiologically-regulated remains unclear. β-synuclein colocalizes with α-synuclein in presynaptic terminals. Here, we report that β-synuclein partitions into α-synuclein condensates promotes the LLPS, and slows down LSPS of α-synuclein, while disease-associated β-synuclein mutations lose these capacities. Exogenous β-synuclein improves the movement defects and prolongs the lifespan of an α-synuclein-expressing NL5901 Caenorhabditis elegans strain, while disease-associated β-synuclein mutants aggravate the symptoms. Decapeptides targeted at the α-/β-synuclein interaction sites are rationally designed, which suppress the LSPS of α-synuclein, rescue the movement defects, and prolong the lifespan of C. elegans NL5901. Together, we unveil a Yin-Yang balance between α- and β-synuclein underlying the normal and disease states of PD and DLB with therapeutical potentials.

Abstract We explore the generalized holographic complexity of odd-dimensional Myers-Perry asymptotically Anti-de Sitter (MP-AdS) black holes with equal angular momenta within the “complexity equals anything” proposal. We begin by determining the codimension-one generalized volume complexity by finding the extremum of the generally covariant volume functional. Locally, we show that its late-time growth rate aligns with the critical momenta associated with the extremal hypersurfaces. Globally, we discover diverse phase transitions for the complexity at early times, including first-order, second-order, and multicritical transitions. An area law and a phase diagram are proposed to adapt to these phase behaviours, highlighting the effects of the black hole’s angular momentum. At zero time, we define the generalized holographic complexity of formation and examine its scaling relations for both large near-extremal MP-AdS black holes and static charged black holes. We find that the scaling behaviours of the generalized volume complexity of formation maintain uniformity with those of the original holographic complexity formulations, except in cases where the scalar functional defining the generalized holographic complexity is infinite in the vacuum limit or at spatial infinity. Additionally, we show that these findings can be applied to codimension-zero observables.

Abstract Background Cannabinoids such as cannabidiol (CBD) exhibit anti-inflammatory properties and have the potential to act as a therapeutic following mild traumatic brain injury. There is limited evidence available on the pharmacological, physiological and psychological effects of escalating CBD dosages in a healthy, male, university athlete population. Furthermore, no dosing regimen for CBD is available with implications of improving physiological function. This study will develop an optimal CBD dose based on the pharmacokinetic data in contact-sport athletes. The physiological and psychological data will be correlated to the pharmacokinetic data to understand the mechanism(s) associated with an escalating CBD dose. Methods/design Forty participants will receive escalating doses of CBD ranging from 5 mg CBD/kg/day to 30 mg CBD/kg/day. The CBD dose is escalated every two weeks in increments of 5 mg CBD/kg/day. Participants will provide blood for pharmacological assessments at each of the 10 visits. Participants will complete a physiological assessment at each of the visits, including assessments of cerebral hemodynamics, blood pressure, electrocardiogram, seismocardiogram, transcranial magnetic stimulation, and salivary analysis for genomic sequencing. Finally, participants will complete a psychological assessment consisting of sleep, anxiety, and pain-related questionnaires. Discussion This study will develop of an optimal CBD dose based on pharmacological, physiological, and psychological properties for future use during contact sport seasons to understand if CBD can help to reduce the frequency of mild traumatic injuries and enhance recovery. Trial registration Clinicaltrials.gov: NCT06204003.

Abstract Recent advances in high-resolution mapping of spatial interactions among regulatory elements support the existence of complex topological assemblies of enhancers and promoters known as enhancer-promoter hubs or cliques. Yet, organization principles of these multi-interacting enhancer-promoter hubs and their potential role in regulating gene expression in cancer remain unclear. Here, we systematically identify enhancer-promoter hubs in breast cancer, lymphoma, and leukemia. We find that highly interacting enhancer-promoter hubs form at key oncogenes and lineage-associated transcription factors potentially promoting oncogenesis of these diverse cancer types. Genomic and optical mapping of interactions among enhancer and promoter elements further show that topological alterations in hubs coincide with transcriptional changes underlying acquired resistance to targeted therapy in T cell leukemia and B cell lymphoma. Together, our findings suggest that enhancer-promoter hubs are dynamic and heterogeneous topological assemblies with the potential to control gene expression circuits promoting oncogenesis and drug resistance.

Abstract Advances in cancer biology have highlighted metabolic reprogramming as an essential aspect of tumorigenesis and progression. However, recent efforts to study tumor metabolism in vivo have identified some disconnects between in vitro and in vivo biology. This is due, at least in part, to the simplified nature of cell culture models and highlights a growing need to utilize more physiologically relevant approaches to more accurately assess tumor metabolism. In this review, we outline the evolution of our understanding of cancer metabolism and discuss some discrepancies between in vitro and in vivo conditions. We describe how the development of physiological media, in combination with advanced culturing methods, can bridge the gap between in vitro and in vivo metabolism.

Abstract Background Ductal carcinoma in situ (DCIS) is a non-obligate precursor to invasive breast cancer (IBC). Studies have indicated differences in DCIS outcome based on race or ethnicity, but molecular differences have not been investigated. Methods We examined the molecular profile of DCIS by self-reported race (SRR) and outcome groups in Black (n = 99) and White (n = 191) women in a large DCIS case-control cohort study with longitudinal follow up. Results Gene expression and pathway analyses suggested that different genes and pathways are involved in diagnosis and ipsilateral breast outcome (DCIS or IBC) after DCIS treatment in White versus Black women. We identified differences in ER and HER2 expression, tumor microenvironment composition, and copy number variations by SRR and outcome groups. Conclusions Our results suggest that different molecular mechanisms drive initiation and subsequent ipsilateral breast events in Black versus White women.

Abstract Chemotherapy induced ovarian failure and infertility is an important concern in female cancer patients of reproductive age or younger, and non-invasive, pharmacological approaches to maintain ovarian function are urgently needed. Given the role of reduced nicotinamide adenine dinucleotide phosphate (NADPH) as an essential cofactor for drug detoxification, we sought to test whether boosting the NAD(P)+ metabolome could protect ovarian function. We show that pharmacological or transgenic strategies to replenish the NAD+ metabolome ameliorates chemotherapy induced female infertility in mice, as measured by oocyte yield, follicle health, and functional breeding trials. Importantly, treatment of a triple-negative breast cancer mouse model with the NAD+ precursor nicotinamide mononucleotide (NMN) reduced tumour growth and did not impair the efficacy of chemotherapy drugs in vivo or in diverse cancer cell lines. Overall, these findings raise the possibility that NAD+ precursors could be a non-invasive strategy for maintaining ovarian function in cancer patients, with potential benefits in cancer therapy.

Abstract Introduction Psoriatic arthritis (PsA) is a chronic inflammatory disease requiring long-term treatment. Bimekizumab, a monoclonal IgG1 antibody that selectively inhibits interleukin (IL)-17F in addition to IL-17A, has demonstrated tolerability and sustained clinical efficacy for up to 1 year for patients with PsA. Here, we report the longer-‍term safety and efficacy of bimekizumab up to 2 years. Methods BE OPTIMAL (biologic disease-modifying antirheumatic drug [bDMARD]-naïve) and BE COMPLETE (prior inadequate response/intolerance to tumor necrosis factor inhibitors [TNFi-IR]) assessed subcutaneous bimekizumab 160 mg every 4 weeks in patients with PsA. BE OPTIMAL included a reference arm (adalimumab 40 mg every 2 weeks); patients switched to bimekizumab at week 52 with no washout between treatments. BE OPTIMAL week 52 and BE COMPLETE week 16 completers were eligible for the BE VITAL open-label extension. Efficacy outcomes are reported to week 104/100 (BE OPTIMAL/BE COMPLETE). Results A total of 710/852 (83.3%) bDMARD-naïve and 322/400 (80.5%) TNFi-IR patients completed week 104/100. Up to 104 weeks, patients treated with bimekizumab in BE OPTIMAL and BE COMPLETE had treatment-emergent adverse event incidence rates (exposure-adjusted incidence rate/100 patient-years) of 179.9 (95% CI 166.9, 193.7) and 100.3 (89.2, ‍112.4), respectively. The proportion of patients achieving efficacy outcomes (≥ 50% improvement from baseline in American College of Rheumatology [ACR] response criteria, 100% improvement from baseline in Psorisis Area and Severity Index [PASI], minimal disease activity [MDA]) was sustained in all patients from week 52 to week 104/100. Conclusions Bimekizumab was well tolerated for up to 2 years of treatment and no new safety signals were observed. Sustained clinical efficacy was observed up to 2 years in bDMARD-naïve and TNFi-IR patients with active PsA. Patients switching from adalimumab to bimekizumab demonstrated further improvement in skin and nail symptoms, and sustained efficacy in joint symptoms. Trial Registration BE OPTIMAL (NCT03895203), BE COMPLETE (NCT03896581), BE VITAL (NCT04009499).

Abstract Within the framework of braneworld holography, we construct a quantum charged black hole localized on a three-dimensional anti-de Sitter (AdS) brane that intersects the asymptotic boundary of the four-dimensional AdS spacetime at the conformal defects and incorporates quantum backreaction effects from the conformal field theory (CFT) on the brane. This quantum charged black hole is an exact solution of the semiclassical gravitational equation corresponding to a theory with higher curvature gravity and nonminimally coupled nonlinear gauge field. In the framework of double holography, we investigate the thermodynamics of the quantum charged black hole from three perspectives: a pure bulk perspective, in which four-dimensional classical Einstein gravity couples to Maxwell electrodynamics and a codimension-one tensional brane; a brane perspective, where semiclassical higher curvature gravity is subject to quantum backreaction from the holographic CFT on the brane, yielding a quantum charged black hole; and a boundary perspective, where the defect CFT is coupled to a boundary CFT at the asymptotic boundary and the degrees of freedom for defect quantum conformal matter is considered. In so doing, we obtain doubly holographic formulations of both the first law of thermodynamics and the Smarr (energy) relations for the quantum charged black holes.

Abstract Methane emissions from the oil and gas sector are a large contributor to climate change. Robust emission quantification and source attribution are needed for mitigating methane emissions, requiring a transparent, comprehensive, and accurate geospatial database of oil and gas infrastructure. Realizing such a database is hindered by data gaps nationally and globally. To fill these gaps, we present a deep learning approach on freely available, high-resolution satellite imagery for automatically mapping well pads and storage tanks. We validate the results in the Permian and Denver-Julesburg basins, two high-producing basins in the United States. Our approach achieves high performance on expert-curated datasets of well pads (Precision = 0.955, Recall = 0.904) and storage tanks (Precision = 0.962, Recall = 0.968). When deployed across the entire basins, the approach captures a majority of well pads in existing datasets (79.5%) and detects a substantial number (>70,000) of well pads not present in those datasets. Furthermore, we detect storage tanks (>169,000) on well pads, which were not mapped in existing datasets. We identify remaining challenges with the approach, which, when solved, should enable a globally scalable and public framework for mapping well pads, storage tanks, and other oil and gas infrastructure.

Abstract The type 1 cannabinoid receptor (CB1R) mediates neurotransmitter release and synaptic plasticity in the central nervous system. Endogenous, plant-derived, synthetic cannabinoids bind to CB1R, initiating the inhibitory G-protein (Gi) and the β-arrestin signaling pathways. Within the Gi signaling pathway, CB1R activates G protein-gated, inwardly-rectifying potassium (GIRK) channels. The β-arrestin pathway reduces CB1R expression on the cell surface through receptor internalization. Because of their association with analgesia and drug tolerance, GIRK channels and receptor internalization are of interest to the development of pharmaceuticals. This research used immortalized mouse pituitary gland cells transduced with a pH-sensitive, fluorescently-tagged human CB1R (AtT20-SEPCB1) to measure GIRK channel activity and CB1R internalization. Cannabinoid-induced GIRK channel activity is measured by using a fluorescent membrane-potential sensitive dye. We developed a kinetic imaging assay that visualizes and measures CB1R internalization. All cannabinoids stimulated a GIRK channel response with a rank order potency of WIN55,212-2 > (±)CP55,940 > Δ9-THC > AEA. Efficacy was expressed relative to (±)CP55,940 with a rank order efficacy of (±)CP55,940 > WIN55, 212-2 > AEA > Δ9-THC. All cannabinoids stimulated CB1R internalization with a rank order potency of (±)CP55,940 > WIN55, 212-2 > AEA > Δ9-THC. Internalization efficacy was normalized to (±)CP55,940 with a rank order efficacy of WIN55,212-2 > AEA > (±)CP55,940 > Δ9-THC. (±)CP55,940 was significantly more potent and efficacious than AEA and Δ9-THC at stimulating a GIRK channel response; no significant differences between potency and efficacy were observed with CB1R internalization. No significant differences were found when comparing a cannabinoid’s GIRK channel and CB1R internalization response. In conclusion, AtT20-SEPCB1 cells can be used to assess cannabinoid-induced CB1R internalization. While cannabinoids display differential Gi signaling when compared to each other, this did not extend to CB1R internalization.

Abstract Circulating cell-free DNA (cfDNA) is emerging as an avenue for cancer detection, but the characteristics of cfDNA fragmentation in the blood are poorly understood. We evaluate the effect of DNA methylation and gene expression on genome-wide cfDNA fragmentation through analysis of 969 individuals. cfDNA fragment ends more frequently contained CCs or CGs, and fragments ending with CGs or CCGs are enriched or depleted, respectively, at methylated CpG positions. Higher levels and larger sizes of cfDNA fragments are associated with CpG methylation and reduced gene expression. These effects are validated in mice with isogenic tumors with or without the mutant IDH1, and are associated with genome-wide changes in cfDNA fragmentation in patients with cancer. Tumor-related hypomethylation and increased gene expression are associated with decrease in cfDNA fragment size that may explain smaller cfDNA fragments in human cancers. These results provide a connection between epigenetic changes and cfDNA fragmentation with implications for disease detection.

Abstract Background Dysferlinopathies are a clinically heterogeneous group of muscular dystrophies caused by gene mutations resulting in deficiency of the membrane-associated protein dysferlin. They manifest post-growth and are characterised by muscle wasting (primarily in the limb and limb-gridle muscles), inflammation, and replacement of myofibres with adipose tissue. The precise pathomechanism for dysferlinopathy is currently unclear; as such there are no treatments currently available. Glucocorticoids (GCs) are widely used to reduce inflammation and treat muscular dystrophies, but when administered to patients with dysferlinopathy, they have unexpected adverse effects, with accelerated loss of muscle strength. Methods To investigate the mechanistic basis for the adverse effects of GCs in dysferlinopathy, the potent GC dexamethasone (Dex) was administered for 4–5 weeks (0.5–0.75 µg/mL in drinking water) to dysferlin-deficient BLA/J and normal wild-type (WT) male mice, sampled at 5 (Study 1) or 10 months (Study 2) of age. A wide range of analyses were conducted. Metabolism- and immune-related gene expression was assessed in psoas muscles at both ages and in quadriceps at 10 months of age. For the 10-month-old mice, quadriceps and psoas muscle histology was assessed. Additionally, we investigated the impact of Dex on the predominantly slow and fast-twitch soleus and extensor digitorum longus (EDL) muscles (respectively) in terms of contractile function, myofibre-type composition, and levels of proteins related to contractile function and metabolism, plus glycogen. Results At both ages, many complement-related genes were highly expressed in BLA/J muscles, and WT mice were generally more responsive to Dex than BLA/J. The effects of Dex on BLA/J mice included (i) increased expression of inflammasome-related genes in muscles (at 5 months) and (ii) exacerbated histopathology of quadriceps and psoas muscles at 10 months. A novel observation was pronounced staining for glycogen in many myofibres of the damaged quadriceps muscles, with large pale vacuolated myofibres, suggesting possible myofibre death by oncosis. Conclusion These pilot studies provide a new focus for further investigation into the adverse effects of GCs on dysferlinopathic muscles.

Objective: Cardiac surgeons experience unpredictable overnight operative responsibilities, with variable rest before same-day, first-start scheduled cases. This study evaluated the frequency and associated impact of a surgeon's overnight operative workload on the outcomes of their same-day, first-start operations. Methods: A statewide cardiac surgery quality database was queried for adult cardiac surgical operations between July 1, 2011, and March 1, 2021. Nonemergency, first-start, Society of Thoracic Surgeons predicted risk of mortality operations were stratified by whether or not the surgeon performed an overnight operation that ended after midnight. A generalized mixed effect model was used to evaluate the effect of overnight operations on a Society of Thoracic Surgeons composite outcome (5 major morbidities or operative mortality) of the first-start operation. Results: Of all first-start operations, 0.4% (239/56,272) had a preceding operation ending after midnight. The Society of Thoracic Surgeons predicted risk of morbidity and mortality was similar for first-start operations whether preceded by an overnight operation or not (overnight operation: 11.3%; no overnight operation: 11.7%, P = .42). Unadjusted rates of the primary outcome were not significantly different after an overnight operation (overnight operation: 13.4%; no overnight operation: 12.3%, P = .59). After adjustment, overnight operations did not significantly impact the risk of major morbidity or mortality for first-start operations (adjusted odds ratio, 1.1, P = .70). Conclusions: First-start cardiac operations performed after an overnight operation represent a small subset of all first-start Society of Thoracic Surgeons predicted risk operations. Overnight operations do not significantly influence the risk of major morbidity or mortality of first-start operations, which suggests that surgeons exercise proper judgment in determining appropriate workloads.

The Palaearctic species of Aphodius Hellwig, 1798, subgenus Liothorax Motschulsky, 1860 are revised using a combination of chromosome analysis, molecular phylogenetics and morphological statistical analysis. Sixteen species are recognised, one of which is shown to comprise two subspecies. Based mainly on the morphology of the aedeagal endophallus and the phylogenetic analysis, they are placed in two groups: the. niger group, apparently monophyletic, comprising Aphodius (Liothorax) niger Illiger, 1798, A. (L.) muscorum (Ádám, 1994), stat. rest., A. (L.) felix sp. nov., A. (L.) bellumgerens sp. nov., A. (L.) bameuli sp. nov., A. (L.) krelli sp. nov., A. (L.) isikdagensis (Balthasar, 1953), A. (L.) alberti sp. nov. and A. (L.) wilsonae Maté et Angus, 2005, stat. rest.; and the plagiatus group, almost certainly paraphyletic, comprising A. (L.) plagiatus (Linnaeus, 1767), including A. (L.) p. plagiatus and A. (L.) p. sinoplagiatus subsp. nov., A. (L.) rodrigoi sp. nov., A. (L.) discoides A. Schmidt, 1916, stat. rest., A. (L.) rutilipennis (Baudi di Selve, 1870), stat. rest., A. (L.) chellala sp. nov., A. (L.) kraatzi Harold, 1868, and A. (L.) rusakovi Gusakov, 2004. A key to the species is given as well as details of their morphology, distributions, and habitats.

Neogale africana (Desmarest, 1818), Amazon Weasel, is a poorly known South American carnivore, with records from north-central Brazil to Ecuador and south to central Peru and central Brazil. Based on two videographic records, we report the presence of this species in Bolivia and document a new elevational record. Furthermore, our new record extends the species’ distribution by 900 km from the nearest locality in Peru, and by 1500 km from the nearest Brazilian locality. Current gaps in its distribution are attributable to the low detectability and rarity of this mustelid.

Biochar, formed through the pyrolysis or burning of organic wastes, has a complex chemical composition influenced by feedstock, pyrolysis temperature, and reaction conditions. Water-soluble, dissolved black carbon species released from biochar comprise one of the most photoreactive organic matter fractions. Photodegradation of these water-soluble species from wheat straw biochar, produced at different pyrolysis temperatures in laboratory microcosms, resulted in noticeable compositional differences. This study characterized water-soluble transformation products formed through the photodegradation of wheat straw biochar pyrolyzed at 300, 400, 500, or 600°C by electrospray ionization 21 ​T Fourier transform ion cyclotron resonance mass spectrometry (21T FT-ICR MS). We also evaluated global trends in the toxicity of these water-soluble fractions using MicroTox™ to assess the impacts of pyrolysis temperature. Additionally, we examined biochar surface morphology after photodegradation and observed minimal change after irradiation for 48 ​h, though the total yield of water-soluble biochar species varied with pyrolysis temperature. Trends in toxicity observed from MicroTox® analysis reveal that water-soluble photoproducts from biochar produced at 300°C and 900°C are nearly three times as toxic compared to dark controls. The ultrahigh resolving power of 21T FT-ICR MS allows for the separation of tens of thousands of highly oxidized, low-molecular-weight (

We contribute to the literature on new mobilities by measuring spatial disparities in travel times for accessing essential non-work destinations via ridehailing. We focused on healthcare, restaurants, and grocery destinations in Chicago. Data from Chicago ridehailing providers, which included detailed information about all realized ridehailing trips in Chicago, were used to derive mean travel times by ridehailing for each census tract. Inspired by the gravity-based model, we calculated an inverse travel time index based on cumulative travel times for each census tract where ridehailing trips occurred. To understand the disparities in travel times, we compared the inverse travel time index for ridehailing and transit in the same census tracts. Then, we applied spatial autoregressive regression to examine the effects of various sociodemographic factors. The results suggested that the inverse travel time index was preferable in tracts with a higher household income and a lower percentage of minority populations. Also, disparities in travel times tended to be greater via ridehailing than transit. This study sheds light on disparities related to ridehailing and how we could improve access to essential destinations for underserved and underrepresented populations and communities. Policy implications include subsidizing disadvantaged users who lack reliable transportation options, regulating ridehailing prices, increasing the provision of essential destinations for underserved areas, and maintaining the quality of public transit services.

Objectives Early treatment of individuals at risk of developing rheumatoid arthritis (RA-risk) in the preclinical phase has the potential to positively impact both patients and society by preventing disease onset and improving patients’ quality of life. The PRAIRI study was a randomised, double-blind, placebo-controlled trial with the B-cell depleting agent rituximab (RTX), which resulted in a significant delay of arthritis development of up to 12 months in seropositive RA-risk individuals. Here, we report our findings on patient-reported outcomes (PROs) in this study population.Methods Seventy-eight RA-risk individuals were treated with one single dose of either placebo (PBO) or 1000 mg RTX plus 100 mg methylprednisolone (MP) and anti-histamines, regardless of treatment allocation, as co-medication. Data on quality of life were collected at baseline and 1, 4, 6, 12 and 24 months using established PRO questionnaires (visual analogue scale (VAS) pain, health assessment questionnaire disability index (HAQ-DI) score, EuroQol five dimension (EQ-5D) and both physical and mental component score of the 36-item short-form heath survey (SF-36)).Results No significant changes in quality of life over a 2 year follow-up were observed in at-risk individuals treated with RTX compared to PBO given the PRO scores at 24 months (mean difference±SEM: HAQ score=0.07±0.16; EQ-5D=−0.02±0.05; VAS pain=11.11±7.40). Furthermore, no significant effect of treatment on perceived arthritis severity at the time of clinically manifest disease (arthritis) was found.Conclusion One single dose of RTX plus MP administered to RA-risk individuals does not have a meaningful and measurable positive effect on PROs after 2 years of follow-up and/or perceived disease severity at the time of arthritis development.Trial registration number Trial registered at EU Clinical Trial Register, EudraCT Number: 2009-010955-29 (https://www.clinicaltrialsregister.eu/ctr-search/search?query=Prevention+of+RA+by+B+cell+directed+therapy).

Background: Few studies of the relationship between residential proximity to agricultural pesticide applications and pesticide levels in the home have incorporated crop location or wind direction. We evaluated the relationship between agricultural pesticide applications using the California Pesticide Use Reporting (CPUR) database and pesticide concentrations in carpet dust accounting for land use and wind direction. Methods: We measured concentrations (ng/g) of seven herbicides and two fungicides in carpet dust samples from 578 California homes (2001–2007). We created three metrics by computing the density (kg/km2) of use of each pesticide reported in CPUR within 0.5-, 1-, 2-, and 4-km buffers around homes 180- and 365-days before sampling (CPUR metric). We apportioned applications to the crop area within the buffers (CROP-A metric) and weighted CPUR applications by the proportion of days that the home was within ±45° of the downwind direction (W-CPUR metric). We modeled natural-log concentrations (Tobit regression) and dust detections (logistic regression) adjusting for season/year, occupation, and home/garden use. Results: Detections were >90 % for glyphosate, 2,4-D, and simazine. Detection rates and dust concentrations increased with increasing CPUR densities for all herbicides and one fungicide. Compared to homes without applications within 4 km, the highest tertile of 365-day glyphosate use was associated with ∼100 % higher concentrations (CPURT3>9.2kg/km2 %change = 110, 95 %CI = 55, 183; CROP-AT3>13.4kg/km2 %change = 144, 95 %CI = 81, 229; and W-CPURT3>2.1kg/km2 %change = 102, 95 %CI = 50, 171). The highest density tertiles of 2,4-D, simazine, and trifluralin were associated with 2- to 6-times higher concentrations, respectively; that was similar across metrics. Across all metrics, agricultural use of dacthal, dicamba, and iprodione were associated with 5- to 10-times higher odds of dust detections. Associations were unclear for 2-methyl-4-chlorophenoxyacetic acid and null for chlorothalonil. Conclusions: Agricultural herbicide and fungicide use was an important determinant of indoor contamination within 4 km of homes. Accounting for crops and wind direction did not substantially change these relationships.

Epithelial-to-mesenchymal transition (EMT) contributes significantly to chemotherapy resistance and remains a critical challenge in treating advanced breast cancer. The complexity of EMT, involving redundant pro-EMT signaling pathways and its paradox reversal process, mesenchymal-to-epithelial transition (MET), has hindered the development of effective treatments. In this study, we utilized a Tri-PyMT EMT lineage-tracing model in mice and single-cell RNA sequencing (scRNA-seq) to comprehensively analyze the EMT status of tumor cells. Our findings revealed elevated ribosome biogenesis (RiBi) during the transitioning phases of both EMT and MET processes. RiBi and its subsequent nascent protein synthesis mediated by ERK and mTOR signalings are essential for EMT/MET completion. Importantly, inhibiting excessive RiBi genetically or pharmacologically impaired the EMT/MET capability of tumor cells. Combining RiBi inhibition with chemotherapy drugs synergistically reduced metastatic outgrowth of epithelial and mesenchymal tumor cells under chemotherapies. Our study suggests that targeting the RiBi pathway presents a promising strategy for treating patients with advanced breast cancer.

Study objectives: Patients frequently present to the emergency department (ED) with chest pain requiring further risk stratification. Traditional cardiac diagnostics such as stress testing may expose patients to ionizing radiation, may not be readily available, may take significant time for testing and interpretation, and adds cost to the workup. Magnetocardiography (MCG) is an alternative approach to assess candidates more quickly and efficiently than routine downstream testing. Design: We created and ran 1000 trials of a Monte Carlo simulation. Using this simulation, we modeled the national annual impact by averting further cardiac diagnostics. Setting: All EDs in the United States. Participants: All ED adult patients with chest pain. Interventions: Simulated use of MCG to reduce avoidable downstream cardiac diagnostics. Main outcome measures: Our primary outcome was to estimate the impact of an MCG-first strategy on the annual national cost savings among eligible patients in the ED. Our secondary outcomes were the estimated reduction in short-stay hospitalizations, cancer cases, and cancer deaths due to radiation exposure. Results: An MCG-first strategy was estimated to save a mean (±SD) of $574 million (±$175 million) by avoiding 555,000 (±93,000) downstream cardiac diagnostic tests. This resulted in a national annual cumulative decrease of 500,000 (±84,000) hospitalizations, 7,600,000 (±1,500,000) bed hours, 409 (±110) new cancer diagnoses, and 210 (±56) new cancer deaths due to radiation exposure from avoidable cardiac diagnostics. Conclusions: If adopted widely and used consistently, an MCG-first strategy among eligible patients could yield substantial benefits by averting avoidable cardiac diagnostic testing.

Abstract Evolution results from the interaction of stochastic and deterministic processes that create a web of historical contingency, shaping gene content and organismal function. To understand the scope of this interaction, we examine the relative contributions of stochasticity, determinism, and contingency in shaping gene inactivation in 34 lineages of endosymbiotic bacteria, Sodalis, found in parasitic lice, Columbicola, that are independently undergoing genome degeneration. Here we show that the process of genome degeneration in this system is largely deterministic: genes involved in amino acid biosynthesis are lost while those involved in providing B-vitamins to the host are retained. In contrast, many genes encoding redundant functions, including components of the respiratory chain and DNA repair pathways, are subject to stochastic loss, yielding historical contingencies that constrain subsequent losses. Thus, while selection results in functional convergence between symbiont lineages, stochastic mutations initiate distinct evolutionary trajectories, generating diverse gene inventories that lack the functional redundancy typically found in free-living relatives.

Abstract Therapeutic approaches targeting proteins on the surface of cancer cells have emerged as an important strategy for precision oncology. To capitalize on the potential impact of drugs targeting surface proteins, detailed knowledge about the expression patterns of the target proteins in tumor tissues is required. In castration-resistant prostate cancer (CRPC), agents targeting prostate-specific membrane antigen (PSMA) have demonstrated clinical activity. However, PSMA expression is lost in a significant number of CRPC tumors. The identification of additional cell surface targets is necessary to develop new therapeutic approaches. Here, we performed a comprehensive analysis of the expression heterogeneity and co-expression patterns of trophoblast cell-surface antigen 2 (TROP2), delta-like ligand 3 (DLL3), and carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5) in CRPC samples from a rapid autopsy cohort. We show that DLL3 and CEACAM5 exhibit the highest expression in neuroendocrine prostate cancer (NEPC), while TROP2 is expressed across different CRPC molecular subtypes, except for NEPC. We further demonstrated that AR alterations were associated with higher expression of PSMA and TROP2. Conversely, PSMA and TROP2 expression was lower in RB1-altered tumors. In addition to genomic alterations, we show a tight correlation between epigenetic states, particularly histone H3 lysine 27 methylation (H3K27me3) at the transcriptional start site and gene body of TACSTD2 (encoding TROP2), DLL3, and CEACAM5, and their respective protein expression in CRPC patient-derived xenografts. Collectively, these findings provide insights into patterns and determinants of expression of TROP2, DLL3, and CEACAM5 with implications for the clinical development of cell surface targeting agents in CRPC.

Abstract The Johns Hopkins Learning Environment Scale (JHLES) was developed by Robert B. Shochet, Jorie M. Colbert and Scott M. Wright of the Johns hopkins university school of medicine and consists of 28 items used to evaluate perception of the academic environment. The objective was to translate and adapt the JHLES to Polish cultural conditions and to validate the Polish version of the tool. The JHLES questionnaire was completed by students of all years (first–fifth) of the faculties of dental medicine at the Medical University of Lublin and the Medical University of Gdańsk. The total surveyed population consisted of 597 students. The overall reliability of the tool was excellent. Confirmatory factor analysis was performed in order to confirm structural consistency with the original JHLES tool. Consequently, all indices had acceptable values (close to 1 or 0, depending on the case), and there was consistency in the results, which shows that the JHLES model is supported by the data. In the present study, the JHLES has been validated in a sample of dental students for the first time in Poland and Europe. Our study provided good evidence for the reliability and validity of the Polish version of the JHLES. In conclusion, the Polish-language version of the JHLES questionnaire is a reliable and valid instrument for analysing the learning environment for students, and its factor structure is supported by the data.

Abstract Background Extracorporeal membrane oxygenation (ECMO) is a rescue therapy in patients with severe acute respiratory distress syndrome (ARDS) secondary to COVID-19. While bleeding and thrombosis complicate ECMO, these events may also occur secondary to COVID-19. Data regarding bleeding and thrombotic events in COVID-19 patients on ECMO are sparse. Methods Using the COVID-19 Critical Care Consortium database, we conducted a retrospective analysis on adult patients with severe COVID-19 requiring ECMO, including centers globally from 01/2020 to 06/2022, to determine the risk of ICU mortality associated with the occurrence of bleeding and clotting disorders. Results Among 1,248 COVID-19 patients receiving ECMO support in the registry, coagulation complications were reported in 469 cases (38%), among whom 252 (54%) experienced hemorrhagic complications, 165 (35%) thrombotic complications, and 52 (11%) both. The hazard ratio (HR) for Intensive Care Unit mortality was higher in those with hemorrhagic-only complications than those with neither complication (adjusted HR = 1.60, 95% CI 1.28–1.99, p

Abstract Lack of rigorous reproducibility and validation are significant hurdles for scientific development across many fields. Materials science, in particular, encompasses a variety of experimental and theoretical approaches that require careful benchmarking. Leaderboard efforts have been developed previously to mitigate these issues. However, a comprehensive comparison and benchmarking on an integrated platform with multiple data modalities with perfect and defect materials data is still lacking. This work introduces JARVIS-Leaderboard, an open-source and community-driven platform that facilitates benchmarking and enhances reproducibility. The platform allows users to set up benchmarks with custom tasks and enables contributions in the form of dataset, code, and meta-data submissions. We cover the following materials design categories: Artificial Intelligence (AI), Electronic Structure (ES), Force-fields (FF), Quantum Computation (QC), and Experiments (EXP). For AI, we cover several types of input data, including atomic structures, atomistic images, spectra, and text. For ES, we consider multiple ES approaches, software packages, pseudopotentials, materials, and properties, comparing results to experiment. For FF, we compare multiple approaches for material property predictions. For QC, we benchmark Hamiltonian simulations using various quantum algorithms and circuits. Finally, for experiments, we use the inter-laboratory approach to establish benchmarks. There are 1281 contributions to 274 benchmarks using 152 methods with more than 8 million data points, and the leaderboard is continuously expanding. The JARVIS-Leaderboard is available at the website: https://pages.nist.gov/jarvis_leaderboard/

Abstract Cellular composition and anatomical organization influence normal and aberrant organ functions. Emerging spatial single-cell proteomic assays such as Image Mass Cytometry (IMC) and Co-Detection by Indexing (CODEX) have facilitated the study of cellular composition and organization by enabling high-throughput measurement of cells and their localization directly in intact tissues. However, annotation of cell types and quantification of their relative localization in tissues remain challenging. To address these unmet needs for atlas-scale datasets like Human Pancreas Analysis Program (HPAP), we develop AnnoSpat (Annotator and Spatial Pattern Finder) that uses neural network and point process algorithms to automatically identify cell types and quantify cell-cell proximity relationships. Our study of data from IMC and CODEX shows the higher performance of AnnoSpat in rapid and accurate annotation of cell types compared to alternative approaches. Moreover, the application of AnnoSpat to type 1 diabetic, non-diabetic autoantibody-positive, and non-diabetic organ donor cohorts recapitulates known islet pathobiology and shows differential dynamics of pancreatic polypeptide (PP) cell abundance and CD8+ T cells infiltration in islets during type 1 diabetes progression.

Abstract Bighead carp (Hypophthalmichthys nobilis), silver carp (H. molitrix), black carp (Mylopharyngodon piceus), and grass carp (Ctenopharyngodon idella), are invasive species in North America. However, they hold significant economic importance as food sources in China. The drifting stage of carp eggs has received great attention because egg survival rate is strongly affected by river hydrodynamics. In this study, we explored egg-drift dynamics using computational fluid dynamics (CFD) models to infer potential egg settling zones based on mechanistic criteria from simulated turbulence in the Lower Missouri River. Using an 8-km reach, we simulated flow characteristics with four different discharges, representing 45–3% daily flow exceedance. The CFD results elucidate the highly heterogeneous spatial distribution of flow velocity, flow depth, turbulence kinetic energy (TKE), and the dissipation rate of TKE. The river hydrodynamics were used to determine potential egg settling zones using criteria based on shear velocity, vertical turbulence intensity, and Rouse number. Importantly, we examined the difference between hydrodynamic-inferred settling zones and settling zones predicted using an egg-drift transport model. The results indicate that hydrodynamic inference is useful in determining the ‘potential’ of egg settling, however, egg drifting paths should be taken into account to improve prediction. Our simulation results also indicate that the river turbulence does not surpass the laboratory-identified threshold to pose a threat to carp eggs.

Abstract Background Double lumen endobronchial tubes (DLTs) are frequently used to employ single lung ventilation strategies during thoracic surgical procedures. Placement of these tubes can be challenging even for experienced clinicians. We hypothesized that airway anatomy, particularly of the glottis and proximal trachea, significantly impacts the ease or difficulty in placement of these tubes. Methods Images from 24 randomly selected Positron Emission Tomography – Computed Tomography (PET-CT) scans were evaluated for several anatomic aspects of the upper airway, including size and angulation of the glottis and proximal tracheal using calibrated CT measurements and an online digital protractor. The anatomic issues identified were confirmed in cadaveric anatomic models. Results Proximal tracheal diameter measurements in PET-CT scans demonstrated a mean ± standard deviation of 20.4 ± 2.5 mm in 12 males and 15.5 ± 0.98 mm in 12 females (p

Abstract Green infrastructure solutions can improve in-stream water quality in lieu of building electricity-consuming gray infrastructure. Permitted under the United States Clean Water Act, these programs allow regulated utilities to trade point-source water quality obligations with non-point source mitigation efforts in the watershed. Carbon financing can provide an incentive for water quality trading. Here we combine data on impaired waters, treatment technologies, and life cycle greenhouse gas emissions in the Contiguous United States, and compare traditional treatment technologies to alternative green infrastructure. We find green infrastructure could save $15.6 billion dollars, 21.2 terawatt-hours of electricity, and 29.8 million tonnes of carbon dioxide equivalent emissions per year while sequestering over 4.2 million tonnes CO2e per year over a 40 year time horizon. Green infrastructure solutions may have the potential to generate $679 million annually in carbon credit revenue (at $20 per credit), which represents a unique opportunity to help accelerate water quality trading.

Abstract Direct air capture has gained traction as a method for carbon dioxide removal. How and whether direct air capture can be deployed requires securing social license to operate, and increasingly demands environmental justice and just transition principles. Here we use a nationally representative survey to evaluate public perceptions of direct air capture, paired with focus groups to assess community perceptions across four communities in the United States: Houston, Texas; Monaca, Pennsylvania; Bakersfield, California; and Rock Springs, Wyoming. We find conditional support for direct air capture deployment among focus group participants, and majority support for direct air capture deployment among national survey respondents. The most important determinants of project support were procedural justice elements—in particular community involvement in planning and implementation—and anticipated community benefits in the forms of local infrastructure and workforce development, supporting the need to center environmental justice and just transition principles into project planning and implementation. Where concerns over environmental and health implications are strong, direct air capture may not gain local social license to operate, especially in communities with previous negative experiences with industry.

Abstract Objectives Peptidoglycan (PG) is an arthritogenic bacterial cell wall component whose role in human osteoarthritis is poorly understood. The purpose of this study was to determine if PG is present in synovial tissue of osteoarthritis patients at the time of primary total knee arthroplasty (TKA), and if its presence is associated with inflammation and patient reported outcomes. Methods Intraoperative synovial tissue and synovial fluid samples were obtained from 56 patients undergoing primary TKA, none of whom had history of infection. PG in synovial tissue was detected by immunohistochemistry (IHC) and immunofluorescence microscopy (IFM). Synovial tissue inflammation and fibrosis were assessed by histopathology and synovial fluid cytokine quantification. Primary human fibroblasts isolated from arthritis synovial tissue were stimulated with PG to determine inflammatory cytokine response. Results A total of 33/56 (59%) of primary TKA synovial tissue samples were positive for PG by IHC, and PG staining colocalized with markers of synovial macrophages and fibroblasts by IFM. Synovial tissue inflammation and elevated IL-6 in synovial fluid positively correlated with PG positivity. Primary human fibroblasts stimulated with PG secreted high levels of IL-6, consistent with ex vivo findings. Interestingly, we observed a significant inverse correlation between PG and age at time of TKA, indicating younger age at time of TKA was associated with higher PG levels. Conclusion Peptidoglycan is commonly found in synovial tissue from patients undergoing TKA. Our data indicate that PG may play an important role in inflammatory synovitis, particularly in patients who undergo TKA at a relatively younger age.

Mormon crickets Anabrus simplex Haldeman, 1852 are a pest of crops and rangeland in the western United States, but little is known about their development in the egg stage. Mormon crickets have multiple states at which they may diapause and thus affect population growth. Consequently, a series of photographs of Mormon cricket embryonic stages was organized using published research on Old World katydids. Earlier stages were more difficult to distinguish without removing the chorion. However, where possible, features that can be seen through the chorion are indicated with the expectation that these will be useful in characterizing development in living embryos. As with other Orthoptera, the timing of development varied greatly among individuals, but at a minimum, embryos filled approximately half the egg in six weeks, whereas they required 12 weeks from oviposition to reach the final stage before their obligate winter diapause.

Abstract Dynamic changes in astrocyte Ca2+ are recognized as contributors to functional hyperemia, a critical response to increased neuronal activity mediated by a process known as neurovascular coupling (NVC). Although the critical role of glutamatergic signaling in this process has been extensively investigated, the impact of behavioral state, and the release of behavior-associated neurotransmitters, such as norepinephrine and serotonin, on astrocyte Ca2+ dynamics and functional hyperemia have received less attention. We used two-photon imaging of the barrel cortex in awake mice to examine the role of noradrenergic and serotonergic projections in NVC. We found that both neurotransmitters facilitated sensory stimulation-induced increases in astrocyte Ca2+. Interestingly, while ablation of serotonergic neurons reduced sensory stimulation-induced functional hyperemia, ablation of noradrenergic neurons caused both attenuation and potentiation of functional hyperemia. Our study demonstrates that norepinephrine and serotonin are involved in modulating sensory stimulation-induced astrocyte Ca2+ elevations and identifies their differential effects in regulating functional hyperemia.

Abstract Förster resonance energy transfer (FRET) is a widely-used and versatile technique for the structural characterization of biomolecules. Here, we introduce FRETpredict, an easy-to-use Python software to predict FRET efficiencies from ensembles of protein conformations. FRETpredict uses a rotamer library approach to describe the FRET probes covalently bound to the protein. The software efficiently and flexibly operates on large conformational ensembles such as those generated by molecular dynamics simulations to facilitate the validation or refinement of molecular models and the interpretation of experimental data. We provide access to rotamer libraries for many commonly used dyes and linkers and describe a general methodology to generate new rotamer libraries for FRET probes. We demonstrate the performance and accuracy of the software for different types of systems: a rigid peptide (polyproline 11), an intrinsically disordered protein (ACTR), and three folded proteins (HiSiaP, SBD2, and MalE). FRETpredict is open source (GPLv3) and is available at github.com/KULL-Centre/FRETpredict and as a Python PyPI package at pypi.org/project/FRETpredict .

People with disabilities (PWD) face elevated mental health concerns and are more likely to utilize mental health services compared to their nondisabled counterparts, yet they also report higher unmet mental health service needs due to myriad attitudinal and environmental barriers to accessing care. Despite these well-documented disparities, little research has examined the nuanced lived experiences of PWD who receive mental health services. Drawing upon semi-structured interviews with 20 U.S. adults with disabilities who were diverse in race/ethnicity, sexual orientation, and gender identity, the present research examined the various structural and interpersonal processes through which ableism undermines the perceived effectiveness and relevance of mental health services. Reflexive thematic analysis identified six themes that characterized participants' ableism experiences in mental healthcare settings, including misplaced assumptions about the impact of disability on mental health, medical trauma and gaslighting, interpersonal ableism, lack of disability knowledge, accessibility challenges, and systematic ableism. These findings highlight the importance of centering PWD's voices in disability-affirmative mental health research and underscore important clinical considerations for fostering accessible and inclusive mental health services.

Introduction:. Unmatched orthopaedic surgery applicants often pursue research fellowships to strengthen their residency applications. The aims of this study were to (1) report the trend of the number of orthopaedic research fellowships offered online between 2019 and 2024, (2) describe the characteristics of research fellowships available to unmatched applicants, and (3) assess the quality of support received by unmatched applicants who complete research fellowships. Methods:. An online orthopaedic forum was retrospectively reviewed to identify job postings for medical student research fellowships in the 2019 to 2020 and 2024 to 2025 academic years. Information regarding expected mentorship and funding described in these postings was collected. Surveys were administered electronically to assess the funding received and perceived levels of mentor advocacy among unmatched orthopaedic applicants who had completed research fellowships between 2022 and 2024. Results:. The number of orthopaedic research fellowships offered online increased by 165% (54-143) between 2019 and 2024, corresponding with a rate of 18 new fellowships offered per year. For the 2024 to 2025 academic year, 80 fellowships (56%) were available to unmatched applicants. The minority of online postings for these positions described support in the match (49%), the specific amount of funding offered (36%), a successful match track record for prior fellows (20%), and contact information of current or prior fellows (11%). The average amount of publicly offered funding was $32,537 (range, $18,000 to $65,000). Among 31 unmatched applicants who responded, the average amount of funding received was $38,180 ± 11,719. Most respondents rated advocacy from research fellowship mentors as high (53%) or moderate (40%), met with their mentors weekly or biweekly (63%), and received feedback on their residency applications (83%). Conclusion:. Over the past 5 years, the number of orthopaedic research fellowships available to unmatched applicants has more than doubled. Although perceived advocacy was rated highly by most unmatched research fellows, fewer than half of the online postings for these positions provided details regarding financial compensation and support during the match cycle. Improvements in transparency related to fellowship characteristics are warranted to assist unmatched orthopaedic applicants in making informed decisions when pursuing research years between match cycles. Level of Evidence:. N/A.

The use of low-cost sensors, with open-source code, facilitates greater spatial resolution and flexibility of environmental monitoring, thus generating more information and overcoming limitations of traditional commercial sensors. Measurement of water turbidity using submerged sensors can be problematic in that rapid biofouling requires frequent site visits to remove, clean, calibrate and replace the sensor. We therefore designed an automated system using low-cost commercially-available sensors that pumps water from the stream, samples it for turbidity and purges remaining water, leaving the turbidity sensor dry between measurements, thus greatly reducing the biofouling problem and minimizing operation costs. Our station was able to estimate suspended sediment concentrations between 0 and 6 g/L with a root mean square error (RMSE) around 5 % of the total range, which meets typical research and operational study requirements. The results showed that the monitoring station is capable of monitoring water level and turbidity for long periods without the need of cleaning the turbidity sensor, due to its purge function. We demonstrated that spatially intense measurement of turbidity within catchments and drainage networks can be achieved at a relatively low cost, which allows a better understanding of the main sources of suspended sediments and their spatial and temporal variability.

It is increasingly understood that the epilepsies are characterized by network pathology that can span multiple spatial and temporal scales. Recent work indicates that infraslow (

BACKGROUND: Preterm birth from intrauterine infection is a leading cause of neonatal neurologic morbidity. Likewise, maternal obesity is associated with intra-amniotic infection and inflammation. Whether maternal obesity is a risk factor for fetal brain injury that occurs with premature birth remains unknown. This study hypothesized that maternal obesity intensifies fetal neuroinflammation in the setting of premature delivery. OBJECTIVE: This study aimed to examine the influence of maternal obesity on perinatal neuroinflammatory responses that arise with preterm birth using a murine model. STUDY DESIGN: Dams with obesity were generated via a high-fat diet that was maintained throughout pregnancy. In parallel, dams without obesity (normal) received a control diet. All dams were paired with males on normal diet. Pregnant dams were randomized to receive an intrauterine administration of bacterial endotoxin (lipopolysaccharide) or the vehicle (phosphate-buffered saline) on embryo day 15.5 of what is typically a 19- to 21-day gestation. Fetal brains were harvested 6 hours after intrauterine administrations, and the expressions of key inflammatory cytokines (Il1b, Il6, and Tnf) and panels of metabolic, immune, and inflammatory genes were analyzed. RESULTS: With the phosphate-buffered saline, there was no difference in gene expression related to maternal obesity. There were substantial differences in Il6 and immune/inflammatory expression profiles in fetal brains from dams with obesity vs normal dams that received lipopolysaccharide. Few differences were observed among the metabolic genes examined under these conditions. The gene expression pattern associated with maternal obesity correlated with pathways related to white matter injury. CONCLUSION: The expression of neuroinflammatory markers instigated by bacterial endotoxin via intrauterine lipopolysaccharide was greater in embryo brains obtained from dams with obesity. Expression profiles suggest that in combination with intrauterine inflammation, maternal obesity may increase the risk of fetal white matter injury. Further investigation is warranted to understand the relationship between maternal health and neurologic outcomes associated with prematurity.

Objectives: To determine the prevalence of diabetic retinopathy and undiagnosed diabetes among Delaware nursing home and assisted care facility residents. Methods: This cross-sectional study involved the statistical analysis of comprehensive eye examination records of 2,063 nursing home residents residing in 18 facilities and 4 assisted living facilities in Delaware from 2005 to 2009. Descriptive statistical analyses were conducted to identify the rates of retinal dot and blot hemorrhages and existing systemic diabetes diagnoses. Results: The mean age of nursing home and assisted care facility residents was 77 years (range 9–104), and 64.4% were over the age of 80. Most residents were female (61.1%) and white (72.5%). 3.6% of the 2,063 nursing home residents had blot or dot hemorrhages in one or both eyes. 32.8% had a type 1 or type 2 diabetes diagnosis. Of the ones with a positive dot and blot hemorrhage finding, 56.8% had a diagnosis of diabetes, and 43.2% did not. Discussion: There was a high prevalence of dot and blot hemorrhages without a systemic diagnosis of diabetes, indicating a need for regular eye care among residents.