Search

Abstract Fetal microchimerism, the presence of fetal cells in maternal tissues, has garnered interest for its potential role in maternal physiology. In this study, we aimed to explore the impact of fetal microchimeric cells on maternal lung health following term and preterm delivery, particularly in the context of infection-induced preterm birth and subsequent allergic challenges. We characterized the immune cells in maternal lungs using a transgenic mouse model (mT+ Ve, Td Tomato) and high dimensional mass cytometry (CyTOF) techniques. We evaluated their influence on lung function and inflammation. Our findings revealed distinct differences in the immune cell composition of maternal lungs between term and preterm deliveries. Mice delivered preterm significantly increased in fetal-specific cells, such as activated macrophages and Tbet + Ve memory B-cells, compared to term-delivered mice. Conversely, term deliveries showed elevated levels of CD4 cells. Furthermore, preterm-delivered dams demonstrated heightened airway hyperresponsiveness, pro-inflammatory cytokine expression, cellular infiltration, and lung mucous production compared to term-delivered dams. Co-culture experiments demonstrated that microchimeric cells from preterm births stimulated the production of inflammatory cytokines IL-6 and TNF-α in lung epithelial cells. These findings shed light on the complex immune dynamics postpartum and their role in lung complications after preterm birth. Understanding these mechanisms could provide insights for targeted interventions to improve maternal lung health in at-risk populations.

Abstract Emerging evidence from neurophysiological brain vital sign studies show repeatable sensitivity to cumulative subconcussive impairments over a season of contact sports. The current study addressed the need for research comparing a low-contact control group to high-contact group. Importantly, the study also expanded the scope of neurophysiological changes related to repetitive head impacts to include female athletes in addition to male athletes. In total, 89 high school student athletes underwent 231 brain vital sign scans over a full calendar year. The results replicated prior subconcussive cognitive impairments (N400 delays) and sensory impairments (N100 amplitude reductions) in male athletes and demonstrated similar subconcussive impairments for the first time in female athletes. While there was no significant subconcussive difference between female and male athletes, female athletes show overall larger responses in general. The findings demonstrated that subconcussive impairments are detectable in a controlled experimental comparison for both female and male high school athletes. The study highlights the opportunity to monitor subconcussive changes in cognitive processing for both female and male athletes to help advance prevention, mitigation and management efforts aimed at reducing athletes’ risk of potential long-term negative health outcomes related to cumulative exposure to repetitive head impacts.

Chronic pancreatitis (CP) is a progressive benign fibroinflammatory condition involving repeated episodes of pancreatic inflammation, which lead to fibrotic tissue replacement and subsequent pancreatic insufficiency. A lifetime risk of developing pancreatic ductal adenocarcinoma (PDAC) in patients with chronic pancreatitis is reported to be 1.5%-4%. However, diagnosis of PDAC in patients with CP can be challenging, in part due to overlapping imaging features. In rare instances, pancreatic parenchymal calcifications that are typically associated with chronic pancreatitis may diminish in the case of a developing PDAC. In this article, we present a patient with chronic pancreatitis in whom calcifications decreased at the time of pancreatic ductal adenocarcinoma diagnosis, as compared to prior CT imaging. The unique imaging features of “diminishing calcifications” associated with a hypoattenuating lesion can potentially be a useful sign of pancreatic ductal adenocarcinoma and may aid in early diagnosis and prompt treatment intervention.

Abstract Background Progression of chronic lung disease may lead to the requirement for lung transplant (LTx). Despite improvements in short-term survival after LTx, chronic lung allograft dysfunction (CLAD) remains a critical challenge for long-term survival. This study investigates the molecular and microbial relationships between underlying lung disease and the development of CLAD in bronchoalveolar lavage fluid (BALF) from subjects post-LTx, which is crucial for tailoring treatment strategies specific to allograft dysfunctions. Methods Paired 16S rRNA gene amplicon sequencing and untargeted LC–MS/MS metabolomics were performed on 856 BALF samples collected over 10 years from LTx recipients (n = 195) with alpha-1-antitrypsin disease (AATD, n = 23), cystic fibrosis (CF, n = 47), chronic obstructive pulmonary disease (COPD, n = 78), or pulmonary fibrosis (PF, n = 47). Data were analyzed using random forest (RF) machine learning and multivariate statistics for associations with underlying disease and CLAD development. Results The BALF microbiome and metabolome after LTx differed significantly according to the underlying disease state (PERMANOVA, p = 0.001), with CF and AATD demonstrating distinct microbiome and metabolome profiles, respectively. Uniqueness in CF was mainly driven by Pseudomonas abundance and its metabolites, whereas AATD had elevated levels of phenylalanine and a lack of shared metabolites with the other underlying diseases. BALF microbiome and metabolome composition were also distinct between those who did or did not develop CLAD during the sample collection period (PERMANOVA, p = 0.001). An increase in the average abundance of Veillonella (AATD, COPD) and Streptococcus (CF, PF) was associated with CLAD development, and decreases in the abundance of phenylalanine-derivative alkaloids (CF, COPD) and glycerophosphorylcholines (CF, COPD, PF) were signatures of the CLAD metabolome. Although the relative abundance of Pseudomonas was not associated with CLAD, the abundance of its virulence metabolites, including siderophores, quorum-sensing quinolones, and phenazines, were elevated in those with CF who developed CLAD. There was a positive correlation between the abundance of these molecules and the abundance of Pseudomonas in the microbiome, but there was no correlation between their abundance and the time in which BALF samples were collected post-LTx. Conclusions The BALF microbiome and metabolome after LTx are particularly distinct in those with underlying CF and AATD. These data reflect those who developed CLAD, with increased virulence metabolite production from Pseudomonas, an aspect of CF CLAD cases. These findings shed light on disease-specific microbial and metabolic signatures in LTx recipients, offering valuable insights into the underlying causes of allograft rejection. Video Abstract

Abstract Therapy targeting the BRAF-MEK cascade created a treatment revolution for patients with BRAF mutant advanced melanoma. Unfortunately, 80% patients treated will progress by 5 years follow-up. Thus, it is imperative we study mechanisms of melanoma progression and therapeutic resistance. We created a scRNA (single cell RNA) atlas of 128,230 cells from 18 tumors across the treatment spectrum, discovering melanoma cells clustered strongly by transcriptome profiles of patients of origins. Our cell-level investigation revealed gains of 1q and 7q as likely early clonal events in metastatic melanomas. By comparing patient tumors and their derivative cell lines, we observed that PD1 responsive tumor fraction disappears when cells are propagated in vitro. We further established three anti-BRAF-MEK treatment resistant cell lines using three BRAF mutant tumors. ALDOA and PGK1 were found to be highly expressed in treatment resistant cell populations and metformin was effective in targeting the resistant cells. Our study suggests that the investigation of patient tumors and their derivative lines is essential for understanding disease progression, treatment response and resistance.

Abstract Mouse (Mus musculus) models have been heavily utilized in developmental biology research to understand mammalian embryonic development, as mice share many genetic, physiological, and developmental characteristics with humans. New explorations into the integration of temporal (stage-specific) and transcriptional (tissue-specific) data have expanded our knowledge of mouse embryo tissue-specific gene functions. To better understand the substantial impact of synonymous mutational variations in the cell-state-specific transcriptome on a tissue’s codon and codon pair usage landscape, we have established a novel resource—Mouse Embryo Codon and Codon Pair Usage Tables (Mouse Embryo CoCoPUTs). This webpage not only offers codon and codon pair usage, but also GC, dinucleotide, and junction dinucleotide usage, encompassing four strains, 15 murine embryonic tissue groups, 18 Theiler stages, and 26 embryonic days. Here, we leverage Mouse Embryo CoCoPUTs and employ the use of heatmaps to depict usage changes over time and a comparison to human usage for each strain and embryonic time point, highlighting unique differences and similarities. The usage similarities found between mouse and human central nervous system data highlight the translation for projects leveraging mouse models. Data for this analysis can be directly retrieved from Mouse Embryo CoCoPUTs. This cutting-edge resource plays a crucial role in deciphering the complex interplay between usage patterns and embryonic development, offering valuable insights into variation across diverse tissues, strains, and stages. Its applications extend across multiple domains, with notable advantages for biotherapeutic development, where optimizing codon usage can enhance protein expression; one can compare strains, tissues, and mouse embryonic stages in one query. Additionally, Mouse Embryo CoCoPUTs holds great potential in the field of tissue-specific genetic engineering, providing insights for tailoring gene expression to specific tissues for targeted interventions. Furthermore, this resource may enhance our understanding of the nuanced connections between usage biases and tissue-specific gene function, contributing to the development of more accurate predictive models for genetic disorders.

Endometriosis is a chronic disease characterized by the presence and growth of endometrial glands and stroma outside of the uterine cavity. The pathogenesis is unclear, but a common theory attributes the condition to retrograde menstruation into the peritoneal cavity via the fallopian tubes. Hormonal influence causes these ectopic tissues to undergo cyclical bleeding, resulting in subsequent inflammation and scar tissue formation; however, it can affect postmenopausal women. In rare instances, endometriotic lesions can obstruct the ureter and result in hydroureteronephrosis and subsequent loss of renal function. This condition presents with nonspecific symptoms and is known as an often-silent disease, resulting in challenging and delayed preoperative diagnosis. In this article, we report the case of an asymptomatic 65-year old female who was diagnosed with deep pelvic endometriosis, which obstructed the right distal ureter. We focus on optimizing diagnosis and management through the application of radiological imaging modalities, specifically computed tomography (CT) and magnetic resonance imaging (MRI).

Abstract Objectives (1) To plot the trajectory of humoral and cellular immune responses to the primary (two‐dose) COVID‐19 mRNA series and the third/booster dose in B‐cell‐depleted multiple sclerosis (MS) patients up to 2 years post‐vaccination; (2) to identify predictors of immune responses to vaccination; and (3) to assess the impact of intercurrent COVID‐19 infections on SARS CoV‐2‐specific immunity. Methods Sixty ocrelizumab‐treated MS patients were enrolled from NYU (New York) and University of Colorado (Anschutz) MS Centers. Samples were collected pre‐vaccination, and then 4, 12, 24, and 48 weeks post‐primary series, and 4, 12, 24, and 48 weeks post‐booster. Binding anti‐Spike antibody responses were assessed with multiplex bead‐based immunoassay (MBI) and electrochemiluminescence (Elecsys®, Roche Diagnostics), and neutralizing antibody responses with live‐virus immunofluorescence‐based microneutralization assay. Spike‐specific cellular responses were assessed with IFNγ/IL‐2 ELISpot (Invitrogen) and, in a subset, by sequencing complementarity determining regions (CDR)‐3 within T‐cell receptors (Adaptive Biotechnologies). A linear mixed‐effect model was used to compare antibody and cytokine levels across time points. Multivariate analyses identified predictors of immune responses. Results The primary vaccination induced an 11‐ to 208‐fold increase in binding and neutralizing antibody levels and a 3‐ to 4‐fold increase in IFNγ/IL‐2 responses, followed by a modest decline in antibody but not cytokine responses. Booster dose induced a further 3‐ to 5‐fold increase in binding antibodies and 4‐ to 5‐fold increase in IFNγ/IL‐2, which were maintained for up to 1 year. Infections had a variable impact on immunity. Interpretation Humoral and cellular benefits of COVID‐19 vaccination in B‐cell‐depleted MS patients were sustained for up to 2 years when booster doses were administered.

Abstract Chorion trophoblasts (CTCs) and immune cell-enriched decidua (DECs) comprise the maternal-fetal membrane interface called the chorio-decidual interface (CDi) which constantly gets exposed to maternal stressors without leading to labor activation. This study explored how CTCs act as a barrier at CDi. The roles of human leukocyte antigen (HLA)-G and progesterone receptor membrane component 2 (PGRMC2) in mediating immune homeostasis were also investigated. The CDi was recreated in a two-chamber microfluidic device (CDi-on-chip) with an outer chamber of primary DECs and immune cell line-derived innate immune cells and an inner chamber of wild-type or PGRMC2 or HLA-G knockout immortalized CTCs. To mimic maternal insults, DECs were treated with lipopolysaccharide, poly(I:C), or oxidative stress inducer cigarette smoke extract. Expression levels of inflammation and immunity genes via targeted RNA sequencing, production of soluble mediators, and immune cell migration into CTCs were determined. In CDi-on-chip, decidua and immune cells became inflammatory in response to insults while CTCs were refractory, highlighting their barrier function. HLA-G and PGRMC2 are found to be vital to immune homeostasis at the CDi, with PGRMC2 serving as an upstream regulator of inflammation, HLA-G expression, and mesenchymal-epithelial transition, and HLA-G serving as a frontline immunomodulatory molecule, thus preventing fetal membrane compromise.

Abstract Fluxes in human copper levels recently garnered attention for roles in cellular signaling, including affecting levels of the signaling molecule cyclic adenosine monophosphate. We herein apply an unbiased temporal evaluation of the signaling and whole genome transcriptional activities modulated by copper level fluctuations to identify potential copper sensor proteins responsible for driving these activities. We find that fluctuations in physiologically relevant copper levels modulate EGFR signal transduction and activation of the transcription factor CREB. Both intracellular and extracellular assays support Cu1+ inhibition of the EGFR phosphatase PTPN2 (and potentially PTPN1)–via ligation to the PTPN2 active site cysteine side chain–as the underlying mechanism. We additionally show i) copper supplementation drives weak transcriptional repression of the copper importer CTR1 and ii) CREB activity is inversely correlated with CTR1 expression. In summary, our study reveals PTPN2 as a physiological copper sensor and defines a regulatory mechanism linking feedback control of copper stimulated EGFR/CREB signaling and CTR1 expression.

Adrenal schwannoma is a rare tumor of Schwann cell origin that represents less than 0.2% of all adrenal tumors. These typically benign tumors are most often found in the head, neck, and limbs. However, schwannomas can also rarely occur rarely in the adrenal gland within the retroperitoneal cavity. In the adrenal gland, these tumors arise from the medulla and are difficult to diagnose, often misdiagnosed as other benign or malignant entities. In this article, we report the case of a 43-year-old female with a large left adrenal mass revealed by biopsy to be a schwannoma. We focus on the use of radiological imaging modalities and immunohistochemical analysis to optimize diagnosis and treatment intervention of this rare tumor.

Abstract Adenosine-to-inosine (A-to-I) editing is a prevalent post-transcriptional RNA modification within the brain. Yet, most research has relied on postmortem samples, assuming it is an accurate representation of RNA biology in the living brain. We challenge this assumption by comparing A-to-I editing between postmortem and living prefrontal cortical tissues. Major differences were found, with over 70,000 A-to-I sites showing higher editing levels in postmortem tissues. Increased A-to-I editing in postmortem tissues is linked to higher ADAR and ADARB1 expression, is more pronounced in non-neuronal cells, and indicative of postmortem activation of inflammation and hypoxia. Higher A-to-I editing in living tissues marks sites that are evolutionarily preserved, synaptic, developmentally timed, and disrupted in neurological conditions. Common genetic variants were also found to differentially affect A-to-I editing levels in living versus postmortem tissues. Collectively, these discoveries offer more nuanced and accurate insights into the regulatory mechanisms of RNA editing in the human brain.

Abstract In recent years, the concept of global symmetry has generalized considerably. Two dramatic examples of this generalization are the exotic symmetries that govern theories with fractons and non-invertible symmetries, which do not fuse according to a group law. Only recently has the interplay between these two been examined. In this paper, we provide further examples of the interplay in the XY plaquette model, XY cube model, 1+1 d theory with global dipole symmetry, and the 2+1 d Lifshitz theory. They are analogs of the duality symmetries in 2d CTFs and are constructed by first gauging a finite subgroup of the momentum symmetry on half of spacetime and then performing a duality transformation. We analyze the fusion rules of the symmetries and find that they are condensation defects from an analog of higher gauging exotic symmetries. We also address their dependence on the UV cutoff when relevant.

Abstract Intra-abdominal infections (IAIs) are an important cause of morbidity and mortality in hospital settings worldwide. The cornerstones of IAI management include rapid, accurate diagnostics; timely, adequate source control; appropriate, short-duration antimicrobial therapy administered according to the principles of pharmacokinetics/pharmacodynamics and antimicrobial stewardship; and hemodynamic and organ functional support with intravenous fluid and adjunctive vasopressor agents for critical illness (sepsis/organ dysfunction or septic shock after correction of hypovolemia). In patients with IAIs, a personalized approach is crucial to optimize outcomes and should be based on multiple aspects that require careful clinical assessment. The anatomic extent of infection, the presumed pathogens involved and risk factors for antimicrobial resistance, the origin and extent of the infection, the patient’s clinical condition, and the host’s immune status should be assessed continuously to optimize the management of patients with complicated IAIs.

# Background Dry needling (DN) has emerged as a popular therapeutic intervention for managing musculoskeletal pain. While major adverse events are generally rare, those that have been reported in vulnerable areas such as the spine and thorax can be serious and warrant further investigation regarding safe techniques in and around these areas. # Purpose The purpose of this study was to reproduce the methods employed by Williams et al. but with an inferior-medial multifidus DN technique to determine if a dry needle can penetrate the ligamentum flavum (LF) and breach the spinal canal at the thoracolumbar junction. # Study Design Descriptive Cadaveric study. # Methods The procedure was performed on a cadaver in the prone position. The needle was advanced under ultrasound guidance to determine if a 0.30 x 40 mm dry needle inserted lateral to the spinous process of T12 and directed inferior-medially could penetrate the LF and enter the spinal canal. # Results A 0.30 x 40 mm dry needle inserted 1.9 cm lateral to the spinous process of T12 was able to traverse the space between the vertebral laminae of T12 and L1, penetrate the LF, and enter the spinal canal with an inferior-medial needle angulation of 33-degrees medial and 18-degrees inferior. # Conclusion The results of this study demonstrate the feasibility of a dry needle entering the spinal canal at the thoracolumbar junction using an inferior-medial technique. These findings support the potential role of ultrasound guidance in the training and clinical practice of DN, especially in regions where safety issues have been documented. # Level of Evidence Level IV.

Grant writing is a time-consuming and labor-intensive process that is the essential mechanism by which most academic researchers fund their scientific investigations. To support this effort, we present a software application with corresponding source code that provides draft sections of a typical NIH-style grant to expedite the time to a first draft. The software provides draft grant text, affording researchers extra time to optimize the content and improve the probability of an award. There are three main components to the software: 1) a search and compare tool that compares the proposed research to previously funded NIH applications, 2) a specific aims page drafter, and 3) a research strategy section that incorporates significance, innovation, approach, rigor, and preliminary data. Our initial internal software deployment has been well received, and researchers indicate significant perceived time savings when using this tool.

Understanding the relationship between multi-scale processes driving community- and population-level diversity can guide conservation efforts. While the importance of population-level genetic diversity is widely recognized, it is not always assessed for conservation planning, and positive correlations with community-level diversity are sometimes assumed, such that only the latter is measured. We surveyed species richness and cumulative multispecies abundance of crayfishes in impounded and unimpounded streams in the southern Appalachian Mountains (Alabama, USA). We simultaneously assessed levels of population genetic diversity within two focal crayfishes (Faxonius validus and F. erichsonianus) using nuclear (nDNA; inter-simple sequence repeat (ISSR)) and mitochondrial DNA (mtDNA; mitochondrial DNA cytochrome oxidase subunit I (mtCOI)) markers. We then tested for species-genetic diversity correlations (SGDCs), species diversity-abundance correlations (i.e., more individuals hypothesis, MIH), and abundance-genetic diversity correlations (AGDCs) across sites. We also examined the relationship between each of the three different types of correlation (i.e., species richness, cumulative multispecies abundance, and population genetic diversity) and stream habitat characteristics and fragmentation. Surprisingly, based on F. validus mtDNA data, sites with the greatest multispecies abundance had the lowest genetic diversity, indicating a negative AGDC. However, no AGDC was evident from nDNA. There was no evidence of SGDCs for F. validus based on either of the two genetic data types. For F. erichsonianus, there was no evidence for SGDC or AGDC. When considering the community-level data only, there was no support for the MIH. Stream width was positively correlated with F. validus genetic diversity, but negatively correlated with multispecies abundance. Similarly, species richness was positively correlated with stream width in unimpounded streams but negatively correlated with width in impounded streams. These findings indicate that community-level diversity cannot be indiscriminately used as a proxy for population-level diversity without empirically testing this correlation on the focal group. As such, community- and population-level assessments for multiple crayfish species are needed to better understand drivers of diversity and eco-evolutionary processes which will aid in the conservation of this vulnerable taxonomic group.

One of the most abundant Al-containing molecules detected in the interstellar medium (ISM) is AlOH. Over the past several years, there have been various pathways proposed for the formation of AlOH in the ISM, including reactions between AlO and H2 or H2O. However, these pathways include an energetic barrier from a transition state that likely prevents the reaction from progressing efficiently in the low temperature/low pressure environment of the ISM. Recently, a barrierless pathway for formation of AlOH from AlO and AlH has been proposed for the formation of AlOH. Even so, only one of these species really needs to contain an aluminum atom. To account for this, alternative but related pathways reacting the known interstellar molecule AlO with XH and AlH with XO (X = Mg, Si, P, or S) to form AlOH are explored with high accuracy quantum chemical calculations via CCSD(T)-F12b/cc-pVTZ-F12. Each third row element has at least one pair of reactants that lead to exothermic formation of AlOH. These reactions can go on to form other aluminum oxides and aluminum oxide clusters that may, in part, lead to the formation of interstellar dust grains.

Background: All patients starting dialysis should be informed of kidney transplant as a renal replacement therapy option. Prior research has shown disparities in provision of this information. In this study, we aimed to identify patient sociodemographic and dialysis facility characteristics associated with not receiving transplant information at the time of dialysis initiation. We additionally sought to determine the association of receiving transplant information with waitlist and transplant outcomes. Methods: We retrospectively analyzed CMS-2728 forms filed from 2007 to 2019. The primary outcome was report of provision of information about transplant on the Centers for Medicare and Medicaid Services Form CMS-2728. For patients not informed at the time of dialysis, we collected the reported reason for not being informed (medically unfit, declined information, unsuitable due to age, psychologically unfit, not assessed, or other). Cox proportional-hazards model estimates were used to study determinants of addition to the waitlist and transplant (secondary outcomes). Results: Fifteen percent of patients did not receive information about transplant (N = 133,414). Non-informed patients were more likely to be older, female, white, and on Medicare. Patients informed about transplant had a shorter time between end-stage renal disease onset and addition to the waitlist; they also spent a shorter time on the waitlist before receiving a transplant. Patients at chain dialysis facilities were more likely to receive information, but this did not translate into higher waitlist or transplant rates. Patients at independent facilities acquired by chains were more likely to be informed but less likely to be added to the waitlist post acquisition. Conclusions: Disparities continue to persist in providing information about transplant at initiation of dialysis. Patients who are not informed have reduced access to the transplant waitlist and transplant. Maximizing the number of patients informed could increase the number of patients referred to transplant centers, and ultimately transplanted. However, policy actions should account for differences in protocols stemming from facility ownership.

Genetic resources are the foundation of American agriculture’s ongoing success—the diversity, security, health, and genetic integrity of these resources must be safeguarded. However, in contrast to other crops, protecting, managing, and using collections of woody landscape plant genetic resources present significant challenges. These include conservation of at-risk populations that have high genetic diversity, evaluation of taxa with an unknown potential to invade, and management of large specimens that have long generation times and often recalcitrant or difficult-to-store seeds. The wide diversity of taxa and the limited number of specialist curators and scholars present further challenges. Thus, effective collection, preservation, evaluation, and distribution of woody landscape plant germplasm require substantial and specialized resources. The most fundamental challenge is simple: too many built landscapes have low taxonomic diversity and are often dominated by a single taxon, or monoculture. In turn, these taxonomically and genetically depauperate landscapes are vulnerable to a host of biotic and abiotic threats and are less likely to provide ecosystem and societal services for which they were designed. To develop more resilient landscapes, there is an urgent need to expand taxonomic diversity, which requires the horticultural community to effectively acquire, curate, evaluate, distribute, and use diverse woody landscape plant genetic resources. The role of the US Department of Agriculture-Agricultural Research Service (USDA-ARS) National Plant Germplasm System (NPGS) Woody Landscape Plant Crop Germplasm Committee (WLPCGC) is to identify vulnerabilities and threats that compromise WLP crops in the United States and make recommendations for prioritization of germplasm acquisition, evaluation, research, and management priorities through regular interaction with stakeholders. Due to the breadth of genera and shifting plant genetic resource needs of the nursery industry, it is impractical to list specific threatened or priority genera in a broadly applicable crop vulnerability statement. Instead, the WLPCGC has identified themes of threats and vulnerabilities providing a foundation upon which to support prioritization as threats to specific genera emerge.

We investigated objective brain vital signs derived from event-related potentials (ERPs) for mixed martial arts (MMA) athletes and matched controls (N = 24). Brain vital sign scans were acquired from 9 MMA athletes and 15 age-and sex-matched controls. Our analysis specifically compared differences in brain vital signs between MMA athletes and controls at baseline. We predicted that MMA athletes would show significant differences relative to controls due to their ongoing exposure to repetitive head impacts. Participants were scanned to extract three well-established ERPs: N100 for auditory sensation; P300 for basic attention; and N400 for cognitive processing. Scans were verified using automated reports, with N100, P300, and N400 amplitudes and latencies manually identified by a blinded reviewer. Brain vital signs were compared across groups with a Kruskal-Wallis H-test for independent samples, with FDR correction for multiple comparisons. We identified significant differences between MMA athletes and controls. Specifically, there were significant N400 amplitude reductions, indicating that exposure to repetitive head impacts in MMA may be associated with changes in brain function.

Summary: Etomoxir has been used for decades as a popular small molecule inhibitor of carnitine palmitoyltransferase I, Cpt1, to block mitochondrial fatty acid β-oxidation. To test the specificity of etomoxir, we generated click chemistry–enabled reagents to label etomoxir binding proteins in situ. Etomoxir bound to Cpt1, but also bound to a large array of diverse proteins that metabolize and transport fatty acids in the cytoplasm, peroxisome, and mitochondria. Many of the most abundant proteins identified in primary hepatocytes were peroxisomal proteins. The loss of Pex5, required for the import of peroxisomal matrix proteins, eliminated many of these etomoxir-labeled proteins. By utilizing the promiscuous, covalent, and fatty acid mimetic properties of etomoxir, etomoxir targets of fatty acid ω-oxidation were revealed following the loss of Pex5. These data demonstrate that etomoxir is not specific for Cpt1 and is not appropriate as a tool to distinguish the biological effects of fatty acid oxidation.

Background: Early laparoscopic fundoplication (LF) has been shown to slow lung function decline in chronic lung disease (CLD) patients and lung transplant (LTx) recipients. Magnetic sphincter augmentation (MSA) has emerged as an effective minimally invasive alternative to LF for the treatment of GERD. We evaluate the safety and efficacy of MSA compared to LF for GERD in CLD and LTx. Methods: A retrospective review identified CLD and LTx patients undergoing LF or MSA for GERD. Primary outcome was change in percent predicted FEV1. Secondary outcomes were 30d morbidity, mortality, operative time, and length of stay (LOS). Results: 77 patients met inclusion criteria, 45 (58.5 %) were LTx recipients. 35 (45.5 %) underwent Nissen, 23 (29.9 %) underwent Toupet, and 19 (24.7 %) underwent MSA. Average age was 54.2 years, 54.5 % were female, and average BMI at ARS was 24.9 kg/m2. Median FEV1 % change between pre-ARS and post-ARS was 0 % with no significant differences between groups. MSA had faster operative times at 50.5 min than Nissen (83.5 min, p = 0.002) and Toupet (72.6 min, p = 0.003) and shorter LOS at 0.8 days than Nissen (3.7 days, p = 0.002) and Toupet (2.1 days, p = 0.0008). MSA and Nissen had higher reintervention rates than Toupet, though this was not statistically significant. There were no differences in 30-day morbidities or 30-day ED visits between groups. There were no mortalities. Conclusion: MSA is an advantageous alternative to LF in the CLD and LTx population with stabilization of percent predicted FEV1, equivalent safety profile, shorter operative times, and shorter length of hospital stay.

Sclerosing epithelioid fibrosarcoma is a rare fibrosarcoma variant in which more than half of patients experience local recurrence or metastatic spread. In the current literature, there is limited and nonspecific imaging data, contributing to frequent misdiagnosis and delays in treatment intervention. Given the poor prognosis associated with this malignancy and the high probability of metastases, accurate and prompt diagnoses are critical. In this article, we report the case of a 27-year-old female diagnosed with metastatic sclerosing epithelioid fibrosarcoma following the discovery of a growing palpable mass on her right gluteus maximus muscle. We focus on the use of radiological imaging modalities in optimizing diagnosis and correlate our imaging and pathological findings.

A plasmacytoma is a cancerous growth of abnormal plasma cells that arise within osseous or soft tissue structures. In soft tissue structures, plasmacytomas can present as solitary or multiple masses in the absence of systemic involvement. Solitary plasmacytomas can be subcategorized as extramedullary plasmacytoma (derived from plasma cells located in soft tissues) or osseous plasmacytoma (derived from plasma cells located in the bone marrow). Infrequently, these tumors can arise as extramedullary lesions from the pancreas and present similarly to other tumors, such as pancreatic neuroendocrine tumors (PNETs). In this article, we report the case of a 62-year-old male with a diagnosis of solitary plasmacytoma of the pancreas. We focus on optimizing diagnosis and management through the application of radiological imaging modalities, specifically computed tomography (CT) scans and positron emission tomography-computed tomography (PET-CT) scans.

Liposarcomas are infrequent malignant tumors of mesenchymal origin most commonly seen in the extremities. Although infrequent, these can develop as primary lesions in the soft tissue of the kidney, making them difficult to diagnose through imaging modalities alone. Primary renal liposarcomas are associated with poor prognoses, increasing the importance of timely and accurate diagnosis. In extremely rare instances, the tumor can arise directly from the fat in the epicenter of the kidney, disguised as an angiomyolipoma. In this article, we report the case of a 54-year-old female who was diagnosed with a well-differentiated liposarcoma of the kidney and underwent radical nephrectomy. Our objective is to evaluate unique radiological imaging findings and correlate with histopathological analysis to optimize diagnosis

Abstract Targeting the mitogen-activated protein kinase (MAPK) cascade in pancreatic ductal adenocarcinoma (PDAC) remains clinically unsuccessful. We aim to develop a MAPK inhibitor-based therapeutic combination with strong preclinical efficacy. Utilizing a reverse-phase protein array, we observe rapid phospho-activation of human epidermal growth factor receptor 2 (HER2) in PDAC cells upon pharmacological MAPK inhibition. Mechanistically, MAPK inhibitors lead to swift proteasomal degradation of dual-specificity phosphatase 6 (DUSP6). The carboxy terminus of HER2, containing a TEY motif also present in extracellular signal-regulated kinase 1/2 (ERK1/2), facilitates binding with DUSP6, enhancing its phosphatase activity to dephosphorylate HER2. In the presence of MAPK inhibitors, DUSP6 dissociates from the protective effect of the RING E3 ligase tripartite motif containing 21, resulting in its degradation. In PDAC patient-derived xenograft (PDX) models, combining ERK and HER inhibitors slows tumour growth and requires cytotoxic chemotherapy to achieve tumour regression. Alternatively, MAPK inhibitors with trastuzumab deruxtecan, an anti-HER2 antibody conjugated with cytotoxic chemotherapy, lead to sustained tumour regression in most tested PDXs without causing noticeable toxicity. Additionally, KRAS inhibitors also activate HER2, supporting testing the combination of KRAS inhibitors and trastuzumab deruxtecan in PDAC. This study identifies a rational and promising therapeutic combination for clinical testing in PDAC patients.

Abstract Magnetic resonance imaging (MRI) has increasingly been used to characterize structure–function relationships during white matter neuroplasticity. Biological sex differences may be an important factor that affects patterns of neuroplasticity, and therefore impacts learning and rehabilitation. The current study examined a participant cohort before and after visuo-motor training to characterize sex differences in microstructural measures. The participants (N = 27) completed a 10-session (4 week) complex visuo-motor training task with their non-dominant hand. All participants significantly improved movement speed and their movement speed variability over the training period. White matter neuroplasticity in females and males was examined using fractional anisotropy (FA) and myelin water fraction (MWF) along the cortico-spinal tract (CST) and the corpus callosum (CC). FA values showed significant differences in the middle portion of the CST tract (nodes 38–51) across the training period. MWF showed a similar cluster in the inferior portion of the tract (nodes 18–29) but did not reach significance. Additionally, at baseline, males showed significantly higher levels of MWF measures in the middle body of the CC. Combining data from females and males would have resulted in reduced sensitivity, making it harder to detect differences in neuroplasticity. These findings offer initial insights into possible female versus male differences in white matter neuroplasticity during motor learning. This warrants investigations into specific patterns of white matter neuroplasticity for females versus males across the lifespan. Understanding biological sex-specific differences in white matter neuroplasticity may have significant implications for the interpretation of change associated with learning or rehabilitation.

Gastrointestinal basidiobolomycosis is an unusual fungal infection caused by Basidiobolus ranarum, a saprophytic fungus primarily found in soil and decaying vegetables. Basidiobolomycosis typically presents as a chronic subcutaneous swelling and rarely infects the gastrointestinal tract. Thus, the infrequency of gastrointestinal infections, along with nonspecific clinical symptoms, often results in misdiagnosed cases and delays in treatment. In this article, we report the case of a 68-year-old male with gastrointestinal basidiobolomycosis masquerading as metastatic cancer. We focus on the use of radiological imaging modalities and histopathological analysis to optimize the diagnosis and treatment of this rare gastrointestinal infection.

When found in the cecum or rectosigmoid junction, primary colorectal B-cell lymphoma is a rare malignant non-Hodgkin's lymphoma often associated with an unfavorable prognosis. Due to the nonspecific clinical symptoms, these uncommon tumors are often left undefined or misdiagnosed, resulting in delays in treatment and adverse patient outcomes. Contrast-enhanced computed tomography is the most commonly used medical imaging process for primary colorectal lymphoma, but due to the rarity of this disorder, accurate imaging diagnosis remains a clinical challenge. In this article, we report the case of a 70-year-old male who was diagnosed with primary B-cell lymphoma of the cecum. We focus on improving diagnosis through the utilization of radiological imaging modalities, particularly computed tomography (CT) and fluorine-18-fluorodeoxyglucose positron emission tomography/computed tomography (18-F-FDG PET/CT). While imaging modalities are important in recognizing colonic lymphomas, there are no pathognomonic imaging features for lymphoma; therefore, biopsy remains necessary for diagnostic confirmation.

Background:. Closed, unstable AO/OTA 44B2 ankle fractures are common injuries with similar distributions by age, sex, and race. The purpose of this study was to identify disparities in access to and utilization of surgical care for these injuries. Methods:. Ambulatory patients ≥18 years of age with capitated Medicaid health insurance who presented from January 2016 to February 2020 with an isolated, closed AO/OTA 44B2 ankle fracture with radiographic evidence of instability were retrospectively identified at 1 Level-I safety-net trauma center. Associations between patient characteristics (age, sex, preferred language, race, ethnicity, housing status, employment, and substance use) and measures of access to and utilization of ankle fracture surgery (days from injury to evaluation, being offered surgery, undergoing surgery, and days from evaluation to surgery) were investigated on bivariable and multivariable analysis. Results:. Of the 1,116 patients who were screened, 323 met the inclusion criteria. The included patients had a median age of 41 years; 207 patients (64%) were male and 255 (79%) were Hispanic. Patients presented at a mean of 4.6 ± 7.0 days from injury. Delayed presentation was associated with self-identification as Hispanic (rate ratio [RR], 1.93; 95% confidence interval [CI]: 1.17, 3.12]) and with marijuana use (RR, 1.59; 95% CI: 1.08, 2.36), whereas significantly earlier presentation was associated with a non-English language preference (RR, 0.64; 95% CI: 0.46, 0.89), alcohol abuse (RR, 0.74; 95% CI: 0.55, 0.99), and illicit drug use (RR, 0.30; 95% CI: 0.14, 0.67). Ankle fracture surgery was offered to 274 patients (85%). Experiencing homelessness was associated with a decreased likelihood of being offered surgery (odds ratio [OR], 0.15; 95% CI: 0.03, 0.69). Of patients who were offered surgery, 216 (79%) underwent surgery. Black patients underwent surgery significantly less frequently than patients who identified as White (OR, 0.14; 95% CI: 0.01, 0.77). The median time from evaluation to surgery was 11 days (interquartile range, 7 to 14 days). Patients who used illicit drugs experienced a mean delay to surgery of 6.0 days relative to those who did not use illicit drugs (mean time to surgery, 16.8 ± 7.1 and 10.8 ± 5.1 days, respectively). Conclusions:. We identified disparities in access to and utilization of surgical care for unstable AO/OTA 44B2 ankle fractures that negatively affected patients with Medicaid insurance who identified as Hispanic or Black, were experiencing homelessness, or used illicit drugs. These disparities may negatively affect outcomes for patients receiving care in similar environments, such as capitated health-care networks and public safety-net health systems. Level of Evidence:. Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.

ABSTRACTMetastatic (m) colorectal cancer (CRC) is an incurable disease with a poor prognosis and thus remains an unmet clinical need. Immune checkpoint blockade (ICB)-based immunotherapy is effective for mismatch repair-deficient (dMMR)/microsatellite instability-high (MSI-H) mCRC patients, but it does not benefit the majority of mCRC patients. NK cells are innate lymphoid cells with potent effector responses against a variety of tumor cells but are frequently dysfunctional in cancer patients. Memory-like (ML) NK cells differentiated after IL-12/IL-15/IL-18 activation overcome many challenges to effective NK cell anti-tumor responses, exhibiting enhanced recognition, function, and in vivo persistence. We hypothesized that ML differentiation enhances the NK cell responses to CRC. Compared to conventional (c) NK cells, ML NK cells displayed increased IFN-γ production against both CRC cell lines and primary patient-derived CRC spheroids. ML NK cells also exhibited improved killing of CRC target cells in vitro in short-term and sustained cytotoxicity assays, as well as in vivo in NSG mice. Mechanistically, enhanced ML NK cell responses were dependent on the activating receptor NKG2D as its blockade significantly decreased ML NK cell functions. Compared to cNK cells, ML NK cells exhibited greater antibody-dependent cytotoxicity when targeted against CRC by cetuximab. ML NK cells from healthy donors and mCRC patients exhibited increased anti-CRC responses. Collectively, our findings demonstrate that ML NK cells exhibit enhanced responses against CRC targets, warranting further investigation in clinical trials for mCRC patients, including those who have failed ICB.

ABSTRACTTo date, an affordable, effective treatment for an HIV-1 cure remains only a concept with most “latency reversal” agents (LRAs) lacking specificity for the latent HIV-1 reservoir and failing in early clinical trials. We assessed HIV-1 latency reversal using a multivalent HIV-1-derived virus-like particle (HLP) to treat samples from 32 people living with HIV-1 (PLWH) in Uganda, US and Canada who initiated combined antiretroviral therapy (cART) during chronic infection. Even after 5–20 years on stable cART, HLP could target CD4+ T cells harbouring latent HIV-1 reservoir resulting in 100-fold more HIV-1 release into culture supernatant than by common recall antigens, and 1000-fold more than by chemotherapeutic LRAs. HLP induced release of a divergent and replication-competent HIV-1 population from PLWH on cART. These findings suggest HLP provides a targeted approach to reactivate the majority of latent HIV-1 proviruses among individuals infected with HIV-1.

ABSTRACTPancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy that is refractory to immune checkpoint inhibitor therapy. However, intratumoral T-cell infiltration correlates with improved overall survival (OS). Herein, we characterized the diversity and antigen specificity of the PDAC T-cell receptor (TCR) repertoire to identify novel immune-relevant biomarkers. Demographic, clinical, and TCR-beta sequencing data were collated from 353 patients across three cohorts that underwent surgical resection for PDAC. TCR diversity was calculated using Shannon Wiener index, Inverse Simpson index, and “True entropy.” Patients were clustered by shared repertoire specificity. TCRs predictive of OS were identified and their associated transcriptional states were characterized by single-cell RNAseq. In multivariate Cox regression models controlling for relevant covariates, high intratumoral TCR diversity predicted OS across multiple cohorts. Conversely, in peripheral blood, high abundance of T-cells, but not high diversity, predicted OS. Clustering patients based on TCR specificity revealed a subset of TCRs that predicts OS. Interestingly, these TCR sequences were more likely to encode CD8+ effector memory and CD4+ T-regulatory (Tregs) T-cells, all with the capacity to recognize beta islet-derived autoantigens. As opposed to T-cell abundance, intratumoral TCR diversity was predictive of OS in multiple PDAC cohorts, and a subset of TCRs enriched in high-diversity patients independently correlated with OS. These findings emphasize the importance of evaluating peripheral and intratumoral TCR repertoires as distinct and relevant biomarkers in PDAC.

IntroductionIn past work we demonstrated different patterns of white matter (WM) plasticity in females versus males associated with learning a lab-based unilateral motor skill. However, this work was completed in neurologically intact older adults. The current manuscript sought to replicate and expand upon these WM findings in two ways: (1) we investigated biological sex differences in neurologically intact young adults, and (2) participants learned a dynamic full-body balance task.Methods24 participants (14 female, 10 male) participated in the balance training intervention, and 28 were matched controls (16 female, 12 male). Correlational tractography was used to analyze changes in WM from pre- to post-training.ResultsBoth females and males demonstrated skill acquisition, yet there were significant differences in measures of WM between females and males. These data support a growing body of evidence suggesting that females exhibit increased WM neuroplasticity changes relative to males despite comparable changes in motor behavior (e.g., balance).DiscussionThe biological sex differences reported here may represent an important factor to consider in both basic research (e.g., collapsing across females and males) as well as future clinical studies of neuroplasticity associated with motor function (e.g., tailored rehabilitation approaches).

Abstract Dust dynamics influence planetary atmospheres. However, the settling velocity of dust—and thus its residence time in the atmosphere—is often mispredicted. Challenging, indirect experiments involving few ideal particles revealed that dust settling velocity deviates from Stokes' law under rarefied atmospheres. While useful, such experiments are inadequate to simulate more complex scenarios, including variable particles sizes and shapes. Here, we present direct measurements of settling velocity for spherical particles under Earth‐to‐Mars atmospheric pressures using time‐resolved particle image velocimetry (TR‐PIV), and validate their robustness with existing models. Our results demonstrate that TR‐PIV provides a relatively simple approach to quantifying dust settling velocity from direct observations of over 10,000 particles, enabling systematic investigations of dust settling under realistic scenarios. Such experiments will have significant implications for our understanding of Mars' past, present, and future ‐ from providing a tool to decipher its sedimentary record to enhancing predictive capabilities of atmospheric models.

Abstract Organic electrochemical transistors (OECTs) are of great interest in low‐power bioelectronics and neuromorphic computing, as they utilize organic mixed ionic‐electronic conductors (OMIECs) to transduce ionic signals into electrical signals. However, the poor environmental stability of OMIEC materials significantly restricts the practical application of OECTs. Therefore, the non‐fused planar naphthalenediimide (NDI)‐dialkoxybithiazole (2Tz) copolymers are fine‐tuned through varying ethylene glycol (EG) side chain lengths from tri(ethylene glycol) to hexa(ethylene glycol) (namely P‐XO, X = 3–6) to achieve OECTs with high‐stability and low threshold voltage. As a result, the NDI‐2Tz copolymers exhibit ambipolarity, rapid response (

Abstract DNA barcoding is commonly used for species identification. Despite this, there has not been a comprehensive assessment of the utility of DNA barcoding in crayfishes (Decapoda: Astacidea). Here we examined the extent to which local barcoding gaps (used for species identification) and global barcoding gaps (used for species discovery) exist among crayfishes, and whether global gaps met a previously suggested 10× threshold (mean interspecific difference being 10× larger than mean intra specific difference). We examined barcoding gaps using publicly available mitochondrial COI sequence data from the National Center for Biotechnology Information's nucleotide database. We created two versions of the COI datasets used for downstream analyses: one focused on the number of unique haplotypes (NH) per species, and another that focused on total number of sequences (NS; i.e., including redundant haplotypes) per species. A total of 81 species were included, with 58 species and five genera from the family Cambaridae and 23 species from three genera from the family Parastacidae. Local barcoding gaps were present in only 30 species (20 Cambaridae and 10 Parastacidae species). We detected global barcoding gaps in only four genera (Cambarus, Cherax, Euastacus, and Tenuibranchiurus), which were all below (4.2× to 5.2×) the previously suggested 10× threshold. We propose that a ~5× threshold would be a more appropriate working hypothesis for species discovery. While the NH and NS datasets yielded largely similar results, there were some discrepant inferences. To understand why some species lacked a local barcoding gap, we performed species delimitation analyses for each genus using the NH dataset. These results suggest that current taxonomy in crayfishes may be inadequate for the majority of examined species, and that even species with local barcoding gaps present may be in need of taxonomic revisions. Currently, the utility of DNA barcoding for species identification and discovery in crayfish is quite limited, and caution should be exercised when mitochondrial‐based approaches are used in place of taxonomic expertise. Assessment of the evidence for local and global barcoding gaps is important for understanding the reliability of molecular species identification and discovery, but outcomes are dependent on the current state of taxonomy. As this improves (e.g., via resolving species complexes, possibly elevating some subspecies to the species‐level status, and redressing specimen misidentifications in natural history and other collections), so too will the utility of DNA barcoding.

Abstract Impact craters that form on every planetary body provide a record of planetary surface evolution. On heavily cratered surfaces, new craters that form often overlap antecedent craters, but it is unknown how the presence of antecedent craters alters impact crater formation. We use overlapping complex crater pairs on the lunar surface to constrain this process and find that crater rims are systematically lower where they intersect antecedent crater basins. The rim morphology of the new crater depends on the depth of the antecedent crater and the degree of overlap between the craters. Our observations suggest that new craters do not always obliterate underlying topography and that transient rim collapse is altered by antecedent topography. This study represents the first formalization of the influence of antecedent topography on rim morphology and provides process insight into a common impact scenario relevant to the geology of potential Artemis landing sites.

Growth deficiency is a characteristic feature of both Kabuki syndrome 1 (KS1) and Kabuki syndrome 2 (KS2), Mendelian disorders of the epigenetic machinery with similar phenotypes but distinct genetic etiologies. We previously described skeletal growth deficiency in a mouse model of KS1 and further established that a Kmt2d-/- chondrocyte model of KS1 exhibits precocious differentiation. Here we characterized growth deficiency in a mouse model of KS2, Kdm6atm1d/+. We show that Kdm6atm1d/+ mice have decreased femur and tibia length compared to controls and exhibit abnormalities in cortical and trabecular bone structure. Kdm6atm1d/+ growth plates are also shorter, due to decreases in hypertrophic chondrocyte size and hypertrophic zone height. Given these disturbances in the growth plate, we generated Kdm6a-/- chondrogenic cell lines. Similar to our prior in vitro model of KS1, we found that Kdm6a-/- cells undergo premature, enhanced differentiation towards chondrocytes compared to Kdm6a+/+ controls. RNA-seq showed that Kdm6a-/- cells have a distinct transcriptomic profile that indicates dysregulation of cartilage development. Finally, we performed RNA-seq simultaneously on Kmt2d-/-, Kdm6a-/-, and control lines at Days 7 and 14 of differentiation. This revealed surprising resemblance in gene expression between Kmt2d-/- and Kdm6a-/- at both time points and indicates that the similarity in phenotype between KS1 and KS2 also exists at the transcriptional level.

Abstract Objectives This study aimed to compare the different respiratory rate (RR) monitoring methods used in the emergency department (ED): manual documentation, telemetry, and capnography. Methods This is a retrospective study using recorded patient monitoring data. The study population includes patients who presented to a tertiary care ED between January 2020 and December 2022. Inclusion and exclusion criteria were patients with simultaneous recorded RR data from all three methods and less than 10 min of recording, respectively. Linear regression and Bland–Altman analysis were performed between different methods. Results A total of 351 patient encounters met study criteria. Linear regression yielded an R‐value of 0.06 (95% confidence interval [CI] 0.00–0.12) between manual documentation and telemetry, 0.07 (95% CI 0.01–0.13) between manual documentation and capnography, and 0.82 (95% CI 0.79–0.85) between telemetry and capnography. The Bland–Altman analysis yielded a bias of −0.8 (95% limits of agreement [LOA] −12.2 to 10.6) between manual documentation and telemetry, bias of −0.6 (95% LOA −13.5 to 12.3) between manual documentation and capnography, and bias of 0.2 (95% LOA −6.2 to 6.6) between telemetry and capnography. Conclusion There is a poor correlation between manual documentation and both automated methods, while there is relatively good agreement between the automated methods. This finding highlights the need to further investigate the methodology used by the ED staff in monitoring and documenting RR and ways to improve its reliability given that many important clinical decisions are made based on these assessments.

Background: Avascular necrosis (AVN) is a common occurrence following solid organ transplant (SOT) due to chronic steroid use. We report on three shoulders of humeral head hemiarthroplasty (HHA) in the setting of AVN after SOT. This topic is an important issue to study as there is limited literature on AVN requiring shoulder arthroplasty following SOT. As the prevalence of SOT continues to rise, it is important to study this population before making guidelines in the future. Case presentations: In one shoulder, a 51-year-old male presented with AVN of the left shoulder three years after undergoing a lung transplant and taking 5mg oral prednisone daily. In the second and third shoulder, a 61-year-old female presented with AVN of bilateral shoulders two years after undergoing a kidney transplant and taking 7.5mg oral prednisone daily. All three shoulders went on to have HHA with improved outcomes after surgery at a mean follow-up of 4.6 years. Conclusion: Shoulder arthroplasty is safe and effective for patients with avascular necrosis after a SOT.

Ehlers-Danlos syndrome comprises 13 hereditary connective tissue disorders associated with skin hyperelasticity, joint hypermobility, atrophic scarring, and blood vessel fragility. Hypermobile EDS, the most common subtype, has no clear genetic or molecular source. When presented with wide-ranging clinical symptoms, it requires effective clinical diagnosis. A 31-year-old female with hypermobile EDS underwent an abdominal Computed Tomography (CT) scan displaying a 2.9 cm soft-tissue mass possibly arising from the terminal ileum, which was revealed to be a desmoid fibromatosis. It is believed that Gastrointestinal (GI) manifestations may be associated with EDS, specifically the hypermobile subtype. The patient demonstrated manifestations commonly seen throughout the literature on hypermobile EDS, including abdominal pain, nausea, and diarrhoea. With symptoms worsening, a follow-up CT disclosed an enlargement of the ileocecal desmoid tumour, measuring 5.1 cm. Because all the subtypes of EDS share features such as tissue fragility, joint hypermobility, and skin hyperextensibility, and many of the manifestations are insufficient to establish a diagnosis, imaging modalities are essential for proper identification and patient management. Given the patient’s medical history and the involvement of EDS and desmoid tumours with connective tissue, there is a strong linkage between desmoid fibromatosis and the patient’s hypermobile Ehlers-Danlos diagnosis. The available literature does not clearly attribute such a tumour to the syndrome. This patient’s symptoms represent a possible association between hypermobile EDS and desmoid fibromatosis, warranting future research in this area. The patient is now stable and was recently discharged.

Introduction: Numerous studies have demonstrated the accuracy of point-of-care ultrasound (POCUS). Portable, handheld devices have expanded the clinical scope of POCUS at a fraction of the cost of traditional, cart-based models. There is a paucity of data assessing the diagnostic accuracy of portable devices. Our objective in this study was to compare the diagnostic accuracy of a portable device with a cart-based model. Methods: This was an institutional review board-approved, observational, prospective, randomized clinical trial (NCT05196776) of a convenience sample of adult patients who presented to a university-based health system. Patients who required a cardiac, lung, renal, aorta, or biliary POCUS were randomized to a portable device or to a cart-based model. We hypothesized that the cart-based model would have a 90% diagnostic accuracy vs 70% for the handheld device. To detect a 20% difference, the sample size was calculated to be 98, with 49 patients randomized to each arm. We used standard 2x2 tables to calculate test characteristics with 95% confidence intervals (CI). Results: A total of 110 patients were enrolled, with 56 patients randomized to the cart-based model and 54 to the handheld device. The sensitivity, specificity, and diagnostic accuracy of the cart-based vs handheld were 77.8% (40–97.2) vs 92.9% (66.1–99.8), 91.5% (79.6–97.6) vs 92.3% (79.1–98.4%), and 89.3% (78.1–96) vs 92.5% (81.8–97.9), respectively. Conclusion: The diagnostic accuracy of a portable, handheld device is similar to that of a cart-based model.

Background: The UK dairy sheep industry is relatively small but growing, particularly for cheese and yogurt products. Anecdotally, sheep milk (SM) may be better tolerated by humans than cows’ milk and could have environmental as well as health benefits. All milk contains sub-micron particles called extracellular vesicles (EVs) which are mainly derived from the mammary epithelium. Physiologically, milk-derived EVs are thought to aid in the development of infant immunity and the microbiome, but may also have health benefits to adult humans. The purpose of this study was to determine whether EVs could be isolated from raw sheep milk and whether they have any effect on inflammatory responses in THP-1, a human monocyte cell line, in vitro. Methods: Using sequential ultracentrifugation, vesicles of

Abstract When planning for epilepsy surgery, multiple potential sites for resection may be identified through anatomical imaging. Magnetoencephalography (MEG) using optically pumped sensors (OP-MEG) is a non-invasive functional neuroimaging technique which could be used to help identify the epileptogenic zone from these candidate regions. Here we test the utility of a-priori information from anatomical imaging for differentiating potential lesion sites with OP-MEG. We investigate a number of scenarios: whether to use rigid or flexible sensor arrays, with or without a-priori source information and with or without source modelling errors. We simulated OP-MEG recordings for 1309 potential lesion sites identified from anatomical images in the Multi-centre Epilepsy Lesion Detection (MELD) project. To localise the simulated data, we used three source inversion schemes: unconstrained, prior source locations at centre of the candidate sites, and prior source locations within a volume around the lesion location. We found that prior knowledge of the candidate lesion zones made the inversion robust to errors in sensor gain, orientation and even location. When the reconstruction was too highly restricted and the source assumptions were inaccurate, the utility of this a-priori information was undermined. Overall, we found that constraining the reconstruction to the region including and around the participant’s potential lesion sites provided the best compromise of robustness against modelling or measurement error.

Background and Aims: Early biologic therapy treatment has demonstrated better outcomes in Crohn’s disease (CD). We evaluated the impact of CD duration in patients with moderately to severely active CD treated with risankizumab therapy. Methods: This post hoc analysis evaluated clinical, endoscopic, and safety outcomes by baseline CD duration (5–10, and >10 years) in patients from ADVANCE, MOTIVATE, and FORTIFY. Pooled induction analyses included patients who received intravenous 600-mg dose of risankizumab or placebo for 12 weeks. Maintenance analyses included patients who responded to induction risankizumab and received subcutaneous 180-mg or 360-mg dose of risankizumab for 52 weeks. Duration subgroups were compared using Cochrane-Armitage trend tests with nominal P values. Results: Among 527 patients who received risankizumab 600-mg induction therapy, higher outcome rates were observed at week 12 among patients with shorter vs longer baseline disease duration (for 5–10, and >10 years, clinical remission: 42.7%, 46.9%, 43.5%, and 33.2% [P = .046]; endoscopic response: 48.3%, 36.3%, 32.0%, and 33.4% [P = .025]). Among 298 patients receiving risankizumab (180 mg or 360 mg) maintenance therapy, shorter vs longer baseline disease duration was generally associated with numerically higher endoscopic outcome rates at week 52. Higher clinical remission and endoscopic outcome rates were generally observed with shorter disease duration with 180-mg risankizumab dose only. Adverse event rates were generally similar across duration subgroups. Conclusion: Clinical benefits of risankizumab are observed across disease duration subgroups; clinical and endoscopic outcome rates are higher with risankizumab initiation earlier in the disease course (ClinicalTrials.gov numbers: NCT03105128, NCT03104413, and NCT03105102).