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Objectives: The optimal treatment strategy for symptomatic young infants with tetralogy of Fallot (TOF) is unclear. We sought to compare the outcomes of staged repair (SR) (shunt palliation followed by second-stage complete repair) versus primary repair (PR) at 2 institutions that have exclusively adopted each strategy. Methods: We performed propensity score-matched comparison of 143 infants under 4 months of age who underwent shunt palliation at one institution between 1993 and 2021 with 122 infants who underwent PR between 2004 and 2018 at another institution. The primary outcome was mortality. Secondary outcomes were postoperative complications, durations of perioperative support and hospital stays, and reinterventions. Median follow-up was 8.3 years (interquartile range, 8.1-13.4 years). Results: After the initial procedure, hospital mortality (shunt, 2.8% vs PR, 2.5%; P = .86) and 10-year survival (shunt, 95%; 95% confidence interval [CI], 90%-98% vs PR, 90%; 95% CI, 81%-95%; P = .65) were similar. The SR group had a greater risk of early reinterventions but similar rates of late reinterventions. Propensity score matching yielded 57 well-balanced pairs. In the matched cohort, the SR group had similar freedom from reintervention (55%; 95% CI, 39%-68% vs 59%; 95% CI, 43%-71%; P = .85) and greater survival (98%; 95% CI, 88%-99.8% vs 85%; 95% CI, 69%-93%; P = .02) at 10 years, as the result of more noncardiac-related mortalities in the PR group. Conclusions: In symptomatic young infants with TOF operated at 2 institutions with exclusive treatment protocols, the SR strategy was associated with similar cardiac-related mortality and reinterventions as the PR strategy at medium-term follow-up.

In orthopedic research, many studies have applied vitamin E as a protective antioxidant or used tert-butyl hydroperoxide to induce oxidative injury to chondrocytes. These studies often support the hypothesis that joint pathology causes oxidative stress and increased lipid peroxidation that might be prevented with lipid antioxidants to improve cell survival or function and joint health; however, lipid antioxidant supplementation was ineffective against osteoarthritis in clinical trials and animal data have been equivocal. Moreover, increased circulating vitamin E is associated with increased rates of osteoarthritis. This disconnect between benchtop and clinical results led us to hypothesize that oxidative stress-driven paradigms of chondrocyte redox function do not capture the metabolic and physiologic effects of lipid antioxidants and prooxidants on articular chondrocytes. We used ex vivo and in vivo cartilage models to investigate the effect of lipid antioxidants on healthy, primary, articular chondrocytes and applied immuno-spin trapping techniques to provide a broad indicator of high levels of oxidative stress independent of specific reactive oxygen species. Key findings demonstrate lipid antioxidants were pro-mitochondrial while lipid prooxidants decreased mitochondrial measures. In the absence of injury, radical formation was increased by lipid antioxidants; however, in the presence of injury, radical formation was decreased. In unstressed conditions, this relationship between chondrocyte mitochondria and redox regulation was reproduced in vivo with overexpression of glutathione peroxidase 4. In mice aged 18 months or more, overexpression of glutathione peroxidase 4 significantly decreased the presence of pro-mitochondrial peroxisome proliferation activated receptor gamma and deranged the relationship between mitochondria and the redox environment. This complex interaction suggests strategies targeting articular cartilage may benefit from adopting more nuanced paradigms of articular chondrocyte redox metabolism.

Objective: The best approach to minimize the observed higher mortality of newborn infants with low birth weight who require congenital heart surgery is unclear. This retrospective study was designed to review outcomes of newborn infants weighing 3500 g at surgery were excluded. Results: Median age was 24 days and weight at the time of surgery was 1920 g. Twenty-six (25%) operative mortalities were recorded. Median follow-up period was 2.7 years. The 1- and 3-year overall Kaplan-Meier survival estimate was 72.4% ± 4.5% and 69.1% ± 4.6%. The 1-year survival of patients who had a weight increase >300 g from birth to surgery was far superior to the survival of those who did not achieve such a weight gain (81.4% ± 5.6% vs 64.0% ± 6.7%; log-rank P = .04). By multivariable Cox-hazard regression analysis, the independent predictor of 1-year mortality was genetic syndrome (hazard ratio, 3.54; 95% CI, 1.67-7.82; P

Abstract Land trusts have historically selected many project sites opportunistically, awaiting communication from willing sellers or donors interested in conserving their land. However, in light of the multiple ecological crises faced by land trusts, including climate change, biodiversity loss, and habitat destruction, there is a growing awareness of the need to practice land conservation with an increased pace, scale, and efficacy. In answer to that challenge, we provide one example of how a land trust can adopt methodology for the strategic selection of land protection project sites. Strategic land conservation, as demonstrated in this paper, involves thoughtful prioritization of the attributes of future conservation project sites. Following prioritization, spatial analysis of the region is conducted to identify sites that meet the prioritized attributes, in this case, resilience to climate change. The case study explored in this paper is the 2020 Strategic Land Conservation Plan created by Southwest Michigan Land Conservancy and its partners.

The expansive field of drug discovery is continually seeking innovative approaches to identify and develop novel peptide-based therapeutics. With the advent of artificial intelligence (AI), there has been a transformative shift in the generation of new peptide drugs. AI offers a range of computational tools and algorithms that enables researchers to accelerate the therapeutic peptide pipeline. This review explores the current landscape of AI applications in peptide drug discovery, highlighting its potential, challenges, and ethical considerations. Additionally, it presents case studies and future prospectives that demonstrate the impact of AI on the generation of new peptide drugs.

Key Clinical Message Although endometriosis is a common condition, both extrapelvic endometriosis and endometriosis associated malignancy (EAM) are rare. We describe the first reported case of a patient with Müllerian‐type carcinosarcoma arising in gastric endometriosis.

Matthew M Mirsky,1 Carley Mitchell,1 Augustine Hong,1 Shufen Cao,2 Pingfu Fu,2 Seunghee Margevicius,2 Sulin Wu,1 Afshin Dowlati,1 Ariel Nelson,1 J Eva Selfridge,1 Nikhil Ramaiya,1 Christopher Hoimes,1 Asrar Alahmadi,1,&ast; Debora S Bruno1,&ast; 1University Hospitals Cleveland Medical Center, Case Western Reserve University School of Medicine, Cleveland, OH, USA; 2Department of Population and Quantitative Health Sciences, Case Western Reserve University School of Medicine, Cleveland, OH, USA&ast;These authors contributed equally to this workCorrespondence: Debora S Bruno, University Hospitals Cleveland Medical Center, Case Western Reserve University School of Medicine, 11100 Euclid Avenue, Cleveland, OH, 44106, USA, Tel +1 216 844-3951, Email Debora.Bruno@uhhospitals.orgPurpose: Disparities in cancer care delivery remain a pressing health-care crisis within the United States (US). The use of immune checkpoint inhibitors (ICIs) and their management may be a disparity generator that impacts survival. This retrospective study assessed disparities in a cohort of patients with a variety of solid tumors treated with ICIs within a single health-care organization focusing on the impact of race, socioeconomic status (SES) and site of care delivery on survival and the development of severe immune-related adverse events (irAEs).Patients and Methods: Manual chart review was performed on all patients with solid tumors treated with ICIs within a health-care organization from 2012 to 2018. Care delivery was dichotomized as DOP (disease-oriented provider at academic center) and COP (community oncology provider). Primary and secondary outcomes were overall survival (OS) and rates of grade 3– 4 irAEs, respectively. Relationships with covariates of interest, including race, socioeconomic status and type of care delivery, were assessed among both outcomes.Results: A total of 1070 eligible patients were identified. Of those, 11.4% were of Black race, 59.7% had either non-small cell lung cancer (NSCLC) or melanoma and 82.8% had stage IV disease. Patients of Black race and lower SES were more likely to be treated by DOPs (p< 0.0001). A superior OS was associated with care delivered by DOPs when compared to COPs (HR 0.68; 95% CI 0.56– 0.84; p=0.0002), which was durable after accounting for race, SES, histopathologic diagnosis and disease stage. Melanoma patients experienced higher rates of severe irAEs (HR 2.37; 95% CI 1.42– 3.97; p=0.001). Race, SES and site of care delivery were not related to rates of severe irAEs.Conclusion: In a large health-care organization, patients treated with checkpoint inhibitors by DOPs benefited from a significant OS advantage that was durable after controlling for racial and socioeconomic factors, providing evidence that disease-oriented care has the potential to mitigate racial and socioeconomic disparities.Keywords: disparities, healthcare delivery, immunotherapy outcomes

Insights from JWST observations suggest that active galactic nuclei feedback evolved from a short-lived, high-redshift phase in which radiatively cooled turbulence and/or momentum-conserving outflows stimulated vigorous early star formation (“positive” feedback), to late, energy-conserving outflows that depleted halo gas reservoirs and quenched star formation. The transition between these two regimes occurred at z ∼ 6, independently of galaxy mass, for simple assumptions about the outflows and star formation process. Observational predictions provide circumstantial evidence for the prevalence of massive black holes at the highest redshifts hitherto observed, and we discuss their origins.

Objective: Energy-intensive kidney reabsorption processes essential for normal whole-body function are maintained by tubular epithelial cell metabolism. Although tubular metabolism changes markedly following acute kidney injury (AKI), it remains unclear which metabolic alterations are beneficial or detrimental. By analyzing large-scale, publicly available datasets, we observed that AKI consistently leads to downregulation of the mitochondrial pyruvate carrier (MPC). This investigation aimed to understand the contribution of the tubular MPC to kidney function, metabolism, and acute injury severity. Methods: We generated tubular epithelial cell-specific Mpc1 knockout (MPC TubKO) mice and employed renal function tests, in vivo renal 13C-glucose tracing, mechanistic enzyme activity assays, and tests of injury and survival in an established rhabdomyolysis model of AKI. Results: MPC TubKO mice retained normal kidney function, displayed unchanged markers of kidney injury, but exhibited coordinately increased enzyme activities of the pentose phosphate pathway and the glutathione and thioredoxin oxidant defense systems. Following rhabdomyolysis-induced AKI, compared to WT control mice, MPC TubKO mice showed increased glycolysis, decreased kidney injury and oxidative stress markers, and strikingly increased survival. Conclusions: Our findings suggest that decreased renal tubular mitochondrial pyruvate uptake hormetically upregulates oxidant defense systems before AKI and is a beneficial adaptive response after rhabdomyolysis-induced AKI. This raises the possibility of therapeutically modulating the MPC to attenuate AKI severity.

Embryo culture with and without human serum supplementation, previously common practice in assisted reproductive technologies (ARTs), have been associated with increased heart weight in early and late gestation in the sheep fetus. The present study aimed to determine whether the effects of embryo culture and transfer on cardiac growth and associated signalling pathways persist after birth. Embryos were either transferred to an intermediate ewe (ET) or cultured in vitro in the absence (IVC) or presence of human serum (IVCHS) and with methionine supplementation (IVCHS+M) for 6 days after mating. Naturally mated (NM) ewes were used as controls. There was an increase in the number of cardiomyocytes in the left ventricle of IVC and IVCHS+M compared to IVCHS lambs, but only in males. There were no differences in birth weight, body weight, relative heart weight, left ventricular weight, signalling molecules involved in hypertrophy, apoptosis or fibrosis at 6 months of age between the treatment groups. However, there was increased protein abundance of signalling molecules involved in ribosomal biogenesis, in male offspring from the IVC and IVCHS+M groups compared to the IVCHS group. In conclusion, the composition of the culture media used for in vitro embryo culture altered the abundance of proteins involved in ribosomal biogenesis as well as cardiomyocyte endowment in a sex specific manner. Our data suggest that male embryos cultured in the presence of human serum leads to molecular and structural changes that may detrimentally impact cardiovascular health across the life-course.

Abstract Synovium is critical for maintaining joint homeostasis and may contribute to mechanobiological responses during joint movement. We investigated mechanobiological responses of whole synovium from patients with late-stage knee osteoarthritis (OA). Synovium samples were collected during total knee arthroplasty and assigned to histopathology or cyclic 10% tensile strain loading, including (1) static (control); (2) low-frequency (0.3 Hz); and iii) high-frequency (1.0 Hz) for 30-min. After 6-h incubation, tissues were bisected for RNA isolation and immunostaining (3-nitrotyrosine; 3-NT). RNA sequencing was analyzed for differentially expressed genes and pathway enrichment. Cytokines and lactate were measured in conditioned media. Compared to controls, low-frequency strain induced enrichment of pathways related to interferon response, Fc-receptor signaling, and cell metabolism. High-frequency strain induced enrichment of pathways related to NOD-like receptor signaling, high metabolic demand, and redox signaling/stress. Metabolic and redox cell stress was confirmed by increased release of lactate into conditioned media and increased 3-NT formation in the synovial lining. Late-stage OA synovial tissue responses to tensile strain include frequency-dependent increases in inflammatory signaling, metabolism, and redox biology. Based on these findings, we speculate that some synovial mechanobiological responses to strain may be beneficial, but OA likely disturbs synovial homeostasis leading to aberrant responses to mechanical stimuli, which requires further validation.

Abstract Personalized treatment approaches for patients with limited liver metastases from colorectal cancer are critically needed. By leveraging three large, independent cohorts of patients with colorectal liver metastases (n = 336), we found that a proliferative subtype associated with elevated CIN70 scores is linked to immune exclusion, increased metastatic proclivity, and inferior overall survival in colorectal liver metastases; however, high CIN70 scores generate a therapeutic vulnerability to DNA-damaging therapies leading to improved treatment responses. We propose CIN70 as a candidate biomarker to personalize systemic treatment options for patients with metastatic colorectal cancer. These findings are potentially broadly applicable to other human cancers.

JWST observations demonstrate that supermassive black holes (SMBHs) exist by redshifts z ≳ 10, providing further evidence for “direct collapse” black hole (BH) formation, whereby massive (∼10 ^3–5 M _⊙ ) SMBH seeds are generated within a few million years as a byproduct of the rapid inflow of gas into the centers of protogalaxies. Here we analyze the intermediate “quasi-star” phase that accompanies some direct-collapse models, during which a natal BH accretes mass from and energetically sustains (through accretion) an overlying gaseous envelope. We argue that previous estimates of the maximum BH mass that can be reached during this stage, ∼1% of the total quasi-star mass, are unphysical, and arise from underestimating the efficiency with which energy can be transported outward from regions close to the BH. We construct new quasi-star models that consist of an inner, “saturated convection” region (which conforms to a convection-dominated accretion flow near the BH) matched to an outer, adiabatic envelope. These solutions exist up to a BH mass of ∼60% of the total quasi-star mass, at which point the adiabatic envelope contains only 2% of the mass (with the remaining ∼38% in the saturated-convection region), and this upper limit is reached within a time of 20–40 Myr. We conclude that quasi-stars remain a viable route for producing SMBHs at large redshifts, which is consistent with recent JWST observations.

Background:. Surgeon productivity is measured in relative value units (RVUs). The feasibility of attaining RVU productivity targets requires surgeons to have enough allocated block time to generate RVUs. However, it is unknown how much block time is required for surgeons to attain specific RVU targets. We aimed to estimate the effect of surgeon and practice environment characteristics (SPECs) on block time needed to attain fixed RVU targets. Methods:. We computationally simulated individual surgeons’ annual caseloads under a variety of SPECs in the following way. First, empirical case data were sampled from ACS NSQIP in accordance with surgeon specialty, case-mix complexity, and RVU target. Surgeons’ operating schedules were then constructed according to the block length, turnover time, and scheduling flexibility of the practice environment. These 6 SPECs were concurrently varied over their ranges for a 6-way sensitivity analysis. Results:. Annual operating schedules for 60,000,000 surgeons were simulated. The number of blocks required to attain RVU targets varied significantly with surgeon specialty and increased with increased case-mix complexity, increased turnover time, and decreased scheduling flexibility. Intraspecialty variation in block requirement with variation in environmental characteristics exceeded interspecialty variation with fixed environmental characteristics. Multivariate linear models predicted block utilization across surgical specialties with consideration for the stated factors. An online tool is shared with which to apply these results to one’s particular practice. Conclusions:. Block time required to attain RVU targets varies widely with SPECs; intraspecialty variation exceeds interspecialty variation. The feasibility of attaining RVU targets requires alignment between targets and allocated operating time with consideration for surgical specialty and other practice conditions.

Mitochondrial complex I deficiency is frequent in congenital, neurologic and cardiovascular disease. Here the authors demonstrate that Complex I stimulates the turnover of a mitochondrial calcium channel, which becomes stabilized during Complex I deficiency, preserving energetic homeostasis.

Purpose: To evaluate the radiographic effect of quadriceps tendon harvest on patellar height and to determine whether closure of a quadriceps graft harvest defect resulted in a significant change in patellar height compared to nonclosure. Methods: We conducted a retrospective review of prospectively enrolled patients. The institutional database was queried and all patients who underwent quadriceps autograft anterior cruciate ligament reconstruction between 2015 and March 2020 were included. Graft harvest length in millimeters and final graft diameter after preparation for implantation were obtained from the operative record and demographic data were obtained from the medical record. Radiographic analysis was performed of eligible patients using standard ratios of patellar height: Insall–Salvati (IS), Blackburn–Peele (BP), and Caton–Deschamps (CD). Measurements were performed using digital calipers on a digital imaging system by 2 postgraduate fellow surgeons. Preoperative and postoperative radiographs were performed at 0° according to a standard protocol. Postoperative radiographs were performed 6 weeks postoperatively in all cases. Preoperative patellar height ratios were compared with postoperative patellar height ratios for all patients using t-tests. Subanalysis was then performed to compare the effect of closure of with nonclosure on patellar height ratios using repeated-measures analysis of variance. Interrater reliability between the 2 reviewers was assessed using an intraclass correlation coefficient calculation. Results: In total, 70 patients met final inclusion criteria. There were no statistically significant changes from pre- to postoperative values for either reviewer for IS (reviewer 1, P = .47; reviewer 2, P = .353), BP (reviewer 1, P = .98; reviewer 2, P = .907), or CD (reviewer 1, P = .107; reviewer, 2 P = .188). The closure and nonclosure groups were adequately powered and no statistically significant demographic differences between the closure and nonclosure groups was identified for sex (P = .066), age (P = .343), weight (P = .881), height (P = .42), laterality (P = 1), meniscal repair (P = .332), graft diameter (P = .068), or graft length (P = .183). According to the repeated measures analysis of variance, closure of the quadriceps defect had no significant impact on any of the knee ratios. However, reviewer identity had a significant influence on the CD ratio. Intraclass correlation coefficient analysis revealed excellent agreement between reviewers for the IS (0.982) and BP (0.954) ratios, but only moderate-to-good agreement for the CD (0.751) ratio. Conclusions: Harvest of quadriceps tendon graft does not result in radiographic changes in patellar height. Furthermore, closure of the quadriceps defect does not appear to result in radiographic changes in patellar height. Level of Evidence: III, retrospective comparative trial.

Though the brain was long characterized as an immune-privileged organ, findings in recent years have shown extensive communications between the brain and peripheral immune cells. We now know that alterations in the peripheral immune system can affect the behavioral outputs of the central nervous system, but we do not know which brain cells are affected by the presence of peripheral immune cells. Glial cells including microglia, astrocytes, oligodendrocytes, and oligodendrocyte precursor cells (OPCs) are critical for the development and function of the central nervous system. In a wide range of neurological and psychiatric diseases, the glial cell state is influenced by infiltrating peripheral lymphocytes. However, it remains largely unclear whether the development of the molecular phenotypes of glial cells in the healthy brain is regulated by lymphocytes. To answer this question, we acutely purified each type of glial cell from immunodeficient Rag2-/- mice. Interestingly, we found that the transcriptomes of microglia, astrocytes, and OPCs developed normally in Rag2-/- mice without reliance on lymphocytes. In contrast, there are modest transcriptome differences between the oligodendrocytes from Rag2-/- and control mice. Furthermore, the subcellular localization of the RNA-binding protein Quaking, is altered in oligodendrocytes. These results demonstrate that the molecular attributes of glial cells develop largely without influence from lymphocytes and highlight potential interactions between lymphocytes and oligodendrocytes.

Opioid use disorder is a well-established and growing problem in the United States. It is responsible for both psychosocial and physical damage to the affected individuals with a significant mortality rate. Given both the medical and non-medical consequences of this epidemic, it is important to understand the current treatments and approaches to opioid use disorder and acute opioid overdose. Naloxone is a competitive mu-opioid receptor antagonist that is used for the reversal of opioid intoxication. When given intravenously, naloxone has an onset of action of approximately 2 min with a duration of action of 60–90 min. Related to its empirical dosing and short duration of action, frequent monitoring of the patient is required so that the effects of opioid toxicity, namely respiratory depression, do not return to wreak havoc. Nalmefene is a pure opioid antagonist structurally similar to naltrexone that can serve as an alternative antidote for reversing respiratory depression associated with acute opioid overdose. Nalmefene is also known as 6-methylene naltrexone. Its main features of interest are its prolonged duration of action that surpasses most opioids and its ability to serve as an antidote for acute opioid overdose. This can be pivotal in reducing healthcare costs, increasing patient satisfaction, and redistributing the time that healthcare staff spend monitoring opioid overdose patients given naloxone.

Wideband beamforming and interference cancellation for phased array antennas requires advances in signal processing algorithms, software, and specialized hardware platforms. A high-throughput array receiver has been developed that enables communication in radio frequency interference-rich environments with field programmable gate array (FPGA)-based frequency channelization and packetization. In this study, a real-time interference mitigation algorithm was implemented on graphics processing units (GPUs) contained in the data pipeline. The key contribution is a hardware and software pipeline for subchannelized wideband array signal processing with 150 MHz instantaneous bandwidth and interference cancellation with a heterogeneous, distributed, and scaleable digital signal processing (DSP) architecture that achieves 30 dB interferer cancellation null depth in real time with a moving interference source.

Applying machine learning methods to geographic data provides insights into spatial patterns in the data as well as assists in interpreting and describing environments. This paper investigates the results of k-means clustering applied to 51 geospatial layers, selected and scaled for a model of outdoor acoustic environments, in the continental United States. Silhouette and elbow analyses were performed to identify an appropriate number of clusters (eight). Cluster maps are shown and the clusters are described, using correlations between the geospatial layers and clusters to identify distinguishing characteristics for each cluster. A subclustering analysis is presented in which each of the original eight clusters is further divided into two clusters. Because the clustering analysis used geospatial layers relevant to modeling outdoor acoustics, the geospatially distinct environments corresponding to the clusters may aid in characterizing acoustically distinct environments. Therefore, the clustering analysis can guide data collection for the problem of modeling outdoor acoustic environments by identifying poorly sampled regions of the feature space (i.e., clusters which are not well-represented in the training data).

Cystic fibrosis-related diabetes (CFRD) is one the most common comorbidities in cystic fibrosis (CF). Pancreatic oxidative stress has been postulated in the pathogenesis of CFRD, but no studies have been done to show an association. The main obstacle is the lack of suitable animal models and no immediate availability of pancreas tissue in humans. In the CF porcine model, we found increased pancreatic total glutathione (GSH), glutathione disulfide (GSSG), 3-nitrotyrosine- and 4-hydroxynonenal-modified proteins, and decreased copper zinc superoxide dismutase (CuZnSOD) activity, all indicative of oxidative stress. CF pig pancreas demonstrated increased DHE oxidation (as a surrogate marker of superoxide) in situ compared to non-CF and this was inhibited by a SOD-mimetic (GC4401). Catalase and glutathione peroxidase activities were not different between CF and non-CF pancreas. Isolated CF pig islets had significantly increased DHE oxidation, peroxide production, reduced insulin secretion in response to high glucose and diminished secretory index compared to non-CF islets. Acute treatment with apocynin or an SOD mimetic failed to restore insulin secretion. These results are consistent with the hypothesis that CF pig pancreas is under significant oxidative stress as a result of increased O2●− and peroxides combined with reduced antioxidant defenses against reactive oxygen species (ROS). We speculate that insulin secretory defects in CF may be due to oxidative stress.

1ES1927+654 is a nearby active galactic nucleus (AGN) that has shown an enigmatic outburst in optical/UV followed by X-rays, exhibiting strange variability patterns at timescales of months to years. Here we report the unusual X-ray, UV, and radio variability of the source in its postflare state (2022 January–2023 May). First, we detect an increase in the soft X-ray (0.3–2 keV) flux from 2022 May to 2023 May by almost a factor of 5, which we call the bright soft state. The hard X-ray 2–10 keV flux increased by a factor of 2, while the UV flux density did not show any significant changes (≤30%) in the same period. The integrated energy pumped into the soft and hard X-rays during this period of 11 months is ∼3.57 × 10 ^50 erg and 5.9 × 10 ^49 erg, respectively. From the energetics, it is evident that whatever is producing the soft excess (SE) is pumping out more energy than either the UV or hard X-ray source. Since the energy source presumably is ultimately the accretion of matter onto the supermassive black hole, the SE-emitting region must be receiving the majority of this energy. In addition, the source does not follow the typical disk–corona relation found in AGNs, neither in the initial flare (from 2017 to 2019) nor in the current bright soft state (2022–2023). We found that the core (

The dichotomy between radio-loud (RL) and radio-quiet (RQ) active galactic nuclei (AGNs) is thought to be intrinsically related to radio jet production. This difference may be explained by the presence of a strong magnetic field ( B -field) that enhances, or is the cause of, the accretion activity and the jet power. Here we report the first evidence of an intrinsic difference in the polarized dust emission cores of four RL and five RQ obscured AGNs using 89 μ m polarization with SOFIA/HAWC+. We find that the thermal polarized emission increases with the nuclear radio-loudness, R _20 = L _5GHz / L _20 _μ _m . The dust emission cores of RL AGNs are measured to be polarized, ∼5%–11%, while RQ AGNs are unpolarized,

Abstract The ductus arteriosus (DA) functionally closes during the transition from fetal to postnatal life because of lung aeration and corresponding cardiovascular changes. The thorough and explicit measurement and visualization of the right and left heart output during this transition has not been previously accomplished. We combined 4D flow MRI (dynamic volumetric blood flow measurements) and T2 relaxometry (oxygen delivery quantification) in surgically instrumented newborn piglets to assess the DA. This was performed in Large White‐Landrace‐Duroc piglets (n = 34) spanning four age groups: term‐9 days, term‐3, term+1, and term+5. Subject's DA status was classified using 4D flow: closed DA, forward DA flow, reversed DA flow, and bidirectional DA flow. Over all states, vessel diameters and flows normalized to body weight increased with age (for example in the ascending aorta flow—term‐9: 126.6 ± 45.4; term+5: 260.2 ± 80.0 ml/min per kg; p = 0.0005; ascending aorta diameter—term‐9: 5.2 ± 0.8; term+5: 7.7 ± 0.4 mm; p = 0.0004). In subjects with reversed DA blood flow there was lower common carotid artery blood flow (forward: 37.5 ± 9.0; reversed: 20.0 ± 7.4 ml/min per kg; p = 0.032). Linear regression revealed that as net DA flow decreases, common carotid artery flow decreases (R2 = 0.32, p = 0.004), and left (R2 = 0.33, p = 0.003) and right (R2 = 0.34, p = 0.003) pulmonary artery flow increases. Bidirectional DA blood flow changed oxygen saturation as determined by MRI between the ascending and descending aorta (ascending aorta: 90.1% ± 8.4%; descending aorta: 75.6% ± 14.2%; p

Severe and recurrent cisplatin-induced acute kidney injury (AKI) as part of standard cancer therapy is a known risk factor for development of chronic kidney disease (CKD). The specific role of superoxide (O2•-)-mediated disruption of mitochondrial oxidative metabolism in CKD after cisplatin treatment is unexplored. Cisplatin is typically administered in weekly or tri-weekly cycles as part of standard cancer therapy. To investigate the role of O2•- in predisposing patients to future renal injury and in CKD, mice were treated with cisplatin and a mitochondrial-specific, superoxide dismutase (SOD) mimetic, GC4419. Renal function, biomarkers of oxidative stress, mitochondrial oxidative metabolism, and kidney injury markers, as well as renal histology, were assessed to evaluate the cellular changes that occur one week and one month (CKD phase) after the cisplatin insult. Cisplatin treatment resulted in persistent upregulation of kidney injury markers, increased steady-state levels of O2•-, increased O2•--mediated renal tubules damage, and upregulation of mitochondrial electron transport chain (ETC) complex I activity both one week and one month following cisplatin treatment. Treatment with a novel, clinically relevant, small-molecule superoxide dismutase (SOD) mimetic, GC4419, restored mitochondrial ETC complex I activity to control levels without affecting complexes II–IV activity, as well as ameliorated cisplatin-induced kidney injury. These data support the hypothesis that increased mitochondrial O2•- following cisplatin administration, as a result of disruptions of mitochondrial metabolism, may be an important contributor to both AKI and CKD progression. Keywords: Cisplatin, Kidney injury, Mitochondrial metabolism, Superoxide, Superoxide dismutase mimetic

Abstract Background To date it has not been possible to obtain a comprehensive 3D assessment of fetal hemodynamics because of the technical challenges inherent in imaging small cardiac structures, movement of the fetus during data acquisition, and the difficulty of fusing data from multiple cardiac cycles when a cardiac gating signal is absent. Here we propose the combination of volumetric velocity-sensitive cardiovascular magnetic resonance imaging (“4D flow” CMR) and a specialized animal preparation (catheters to monitor fetal heart rate, anesthesia to immobilize mother and fetus) to examine fetal sheep cardiac hemodynamics in utero. Methods Ten pregnant Merino sheep underwent surgery to implant arterial catheters in the target fetuses. Anesthetized ewes underwent 4D flow CMR with acquisition at 3 T for fetal whole-heart coverage with 1.2–1.5 mm spatial resolution and 45–62 ms temporal resolution. Flow was measured in the heart and major vessels, and particle traces were used to visualize circulatory patterns in fetal cardiovascular shunts. Conservation of mass was used to test internal 4D flow consistency, and comparison to standard 2D phase contrast (PC) CMR was performed for validation. Results Streaming of blood from the ductus venosus through the foramen ovale was visualized. Flow waveforms in the major thoracic vessels and shunts displayed normal arterial and venous patterns. Combined ventricular output (CVO) was 546 mL/min per kg, and the distribution of flows (%CVO) were comparable to values obtained using other methods. Internal 4D flow consistency across 23 measurement locations was established with differences of 14.2 ± 12.1%. Compared with 2D PC CMR, 4D flow showed a strong correlation (R2 = 0.85) but underestimated flow (bias = − 21.88 mL/min per kg, p

This dataset supports the research paper “Cover crop effects on maize drought stress and yield” by Hunter et al. [1]. Data is provided on ecophysiological and yield measurements of maize grown following five functionally diverse cover crop treatments. The experiment was conducted in Pennsylvania, USA from 2013–2015 with organic management. Cover crops were planted in August after winter wheat harvest. Cover crops were terminated in late May of the following year, manure was applied, and both were incorporated with full inversion tillage prior to planting maize. The five cover crop treatments included a tilled fallow control, medium red clover, cereal rye, forage radish, and a 3-species mixture of medium red clover, cereal rye, and Austrian winter pea. Drought was imposed with rain exclusion shelters starting in early July. Results are provided for two subplots per cover crop treatment representing ambient and drought conditions. The dataset includes: 1) soil moisture in spring and during the maize growing season; 2) maize height, leaf chlorophyll content, leaf area index, stomatal conductance, and pre-dawn leaf xylem water potential; 3) maize yield and yield components including kernel biomass, total biomass, harvest index, number of plants per subplot, ears per plant, kernel mass, and kernel number per ear, per plant, and per subplot; 4) modeled season-long radiation interception and radiation use efficiency of biomass production; and 5) maize rooting density by depth in one year only. Data was collected in the field and lab using ecophysiological instruments (e.g., SPAD meter, ceptometer, porometer, and pressure chamber). Biomass samples were taken to determine yield. Data presented have been averaged to the subplot level (ambient and drought). This dataset can inform future research focused on using cover crops and other cultural practices to improve climate adaptation in cropping systems and also may be useful for meta-analyses.

Fibrin has been used clinically for wound coverings, surgical glues, and cell delivery because of its affordability, cytocompatibility, and ability to modulate angiogenesis and inflammation. However, its rapid degradation rate has limited its usefulness as a scaffold for 3D cell culture and tissue engineering. Previous studies have sought to slow the degradation rate of fibrin with the addition of proteolysis inhibitors or synthetic crosslinkers that require multiple functionalization or polymerization steps. These strategies are difficult to implement in vivo and introduce increased complexity, both of which hinder the use of fibrin in research and medicine. Previously, we demonstrated that additional crosslinking of fibrin gels using bifunctionalized poly(ethylene glycol)-n-hydroxysuccinimide (PEG-NHS) slows the degradation rate of fibrin. In this study, we aimed to further improve the longevity of these PEG-fibrin gels such that they could be used for tissue engineering in vitro or in situ without the need for proteolysis inhibitors. It is well documented that increasing the salinity of fibrin precursor solutions affects the resulting gel morphology. Here, we investigated whether this altered morphology influences the fibrin degradation rate. Increasing the final sodium chloride (NaCl) concentration from 145 mM (physiologic level) to 250 mM resulted in fine, transparent high-salt (HS) fibrin gels that degrade 2-3 times slower than coarse, opaque physiologic-salt (PS) fibrin gels both in vitro (when treated with proteases and when seeded with amniotic fluid stem cells) and in vivo (when injected subcutaneously into mice). Increased salt concentrations did not affect the viability of encapsulated cells, the ability of encapsulated endothelial cells to form rudimentary capillary networks, or the ability of the gels to maintain induced pluripotent stem cells. Finally, when implanted subcutaneously, PS gels degraded completely within one week while HS gels remained stable and maintained viability of seeded dermal fibroblasts. To our knowledge, this is the simplest method reported for the fabrication of fibrin gels with tunable degradation properties and will be useful for implementing fibrin gels in a wide range of research and clinical applications.

Heart disease is the leading cause of death in the United States among both adults and infants. In adults, 5-year survival after a heart attack is

AimsAnimal models have been used to show that there are critical molecular mechanisms that can be activated to induce myocardial repair at specific times in development. For example, specific miRNAs are critical for regulating the response to myocardial infarction (MI) and improving the response to injury. Manipulating these miRNAs in small animal models provides beneficial effects post-MI; however it is not known if these miRNAs are regulated similarly in large mammals. Studying a large animal where the timing of heart development in relation to birth is similar to humans may provide insights to better understand the capacity to repair a developing mammalian heart and its application to the adult heart.MethodsWe used a sheep model of MI that included permanent ligation of the left anterior descending (LAD) coronary artery. Surgery was performed on fetuses (at 105 days gestation when all cardiomyocytes are mononucleated and proliferative) and adolescent sheep (at 6 months of age when all cardiomyocytes contribute to heart growth by hypertrophy). A microarray was utilized to determine the expression of known miRNAs within the damaged and undamaged tissue regions in fetal and adolescent hearts after MI.Results73 miRNAs were up-regulated and 58 miRNAs were down-regulated significantly within the fetal infarct compared to remote cardiac samples. From adolescent hearts 69 non-redundant miRNAs were up-regulated and 63 miRNAs were down-regulated significantly in the infarct area compared to remote samples. Opposite differential expression profiles of 10 miRNAs within tissue regions (Infarct area, Border zone and Remote area of the left ventricle) occurred between the fetuses and adolescent sheep. These included miR-558 and miR-1538, which when suppressed using LNA anti-miRNAs in cell culture, increased cardiomyoblast proliferation.ConclusionThere were significant differences in miRNA responses in fetal and adolescent sheep hearts following a MI, suggesting that the modulation of novel miRNA expression may have therapeutic potential, by promoting proliferation or repair in a damaged heart.

Background: Treatment of ankle fractures in patients with diabetes is associated with increased complication rates. Ankle arthrodesis is considered a salvage procedure after failed ankle fracture fixation, yet primary ankle arthrodesis has been proposed as a treatment option for patients with significant diabetes-related complications. To date, the characteristics of patients who undergo primary ankle arthrodesis and the associated outcomes have not been described. Methods: A retrospective review was performed of 13 patients with diabetes who underwent primary arthrodesis for traumatic ankle fracture. Patient demographics were characterized in addition to their diabetes complications, Adelaide Fracture in the Diabetic Ankle (AFDA) score, and fracture type. Outcomes assessed included reoperation rates, infection rates, wound complications, nonunion/malunion, amputation, and development of Charcot arthropathy postoperatively. Results: Patients who underwent primary arthrodesis had high rates of diabetes complications, average AFDA scores of 6.4, and high rates of severe injuries, including 38.5% open fractures and 69.2% fracture dislocations. The overall complication rate for primary arthrodesis of ankle fractures in diabetes patients was more than 75% in this cohort. Complications included a 38.5% reoperation rate, 38.5% infection rate, 53.8% wound complication rate, and 23.1% amputation rate. Despite a high nonunion rate at the attempted fusion sites, 89.9% of fractures healed and patients had a stable extremity. Conclusion: This review is the first to characterize the epidemiology and complications of diabetes patients undergoing primary ankle arthrodesis for ankle fractures. In this cohort, patients with multiple diabetic complications and severe injuries underwent primary arthrodesis, which led to an overall high complication rate. Further research is needed to determine the appropriate treatment option for these high-risk patients, and tibiotalocalcaneal stabilization without arthrodesis may be beneficial. Level of Evidence: Level IV, retrospective case series.

Lynda M Cardiff,1 Elaine PM Lum,1 Charles Mitchell,1 Lisa M Nissen,1 Marea P Patounas,1 Liza-Jane McBride2 1Pharmacy Discipline, School of Clinical Sciences, Queensland University of Technology, Brisbane, QLD, Australia; 2Allied Health Professions’ Office of Queensland, Clinical Excellence Division, Queensland Health, Brisbane, QLD, Australia Background: Prescribing medicines is a complex task. A robust prerequisite curriculum that enables the efficient and consistent training of safe and effective prescribers is important. Despite differing prescribing contexts and professional attributes, the core elements of safe and effective prescribing relevant to all prescribers can be identified. This article describes the development process and content of a training program for safe prescribing, which was designed for a mixed cohort of allied health professionals in Queensland, Australia.Methods: The allied health prescribing training program was designed to align with national standards for prescribing and competencies for safe prescribing. International training programs, for nonmedical prescribing, were examined to inform the program development. Content was delivered by experienced prescribers from a range of professions. The inaugural cohort was surveyed before and after training to ascertain their confidence to prescribe.Results: A training program for allied health prescribers was developed and delivered to enable the implementation of a state-sponsored research trial in Queensland public facilities. The program consisted of two modules (the second of which is described in this article) complemented by a mandatory period of supervised workplace learning. Remote blended learning, comprising online prerecorded lectures, self-directed learning, teleconference seminars, and a 2-day on-campus intensive residential, was used to deliver content. A total of 19 allied health professionals (12 physiotherapists and 7 pharmacists) completed the program that equipped them to begin a prescribing trial within their specific practice settings. Post module completion, 90% of the cohort felt confident to prescribe for patients in their practice area.Conclusion: Program development and delivery were challenging, requiring attention to both the needs of each profession and those of the individual practitioner who was required to apply generic prescribing principles to their specific practice setting. Further refinement of content, delivery, assessment, and resource allocation is required for future cohorts.Keywords: allied health, nonmedical prescribing, training, education, curriculum

The oligometastasis hypothesis suggests certain metastases are limited in extent and curable with focal therapies. Here they identify three integrated molecular subtypes of colorectal cancer liver metastasis, which complement clinical risk stratification to distinguish the subset of oligometastatic patients.

Abstract Background Late gadolinium enhancement (LGE) cardiovascular magnetic resonance (CMR) imaging has enabled the accurate assessment of myocardial infarction (MI). However, LGE CMR has not been performed successfully in the fetus, where it could be useful for animal studies of interventions to promote cardiac regeneration. We believe that LGE imaging could allow us to document the presence, extent and effect of MI in utero and would thereby expand our capacity for conducting fetal sheep MI research. We therefore aimed to investigate the feasibility of using LGE to detect MI in sheep fetuses. Methods Six sheep fetuses underwent a thoracotomy and ligation of a left anterior descending (LAD) coronary artery branch; while two fetuses underwent a sham surgery. LGE CMR was performed in a subset of fetuses immediately after the surgery and three days later. Early gadolinium enhancement (EGE) CMR was also performed in a subset of fetuses on both days. Cine imaging of the heart was performed to measure ventricular function. Results The imaging performed immediately after LAD ligation revealed no evidence of infarct on LGE (n=3). Two of four infarcted fetuses (50%) showed hypoenhancement at the infarct site on the EGE images. Three days after the ligation, LGE images revealed a clear, hyper-enhanced infarct zone in four of the five infarcted fetuses (80%). No hyper-enhanced infarct zone was seen on the one sham fetus that underwent LGE CMR. No hypoenhancement could be seen in the EGE images in either the sham (n=1) or the infarcted fetus (n=1). No regional wall motion abnormalities were apparent in two of the five infarcted fetuses. Conclusion LGE CMR detected the MI three days after LAD ligation, but not immediately after. Using available methods, EGE imaging was less useful for detecting deficits in perfusion. Our study provides evidence for the ability of a non-invasive tool to monitor the progression of cardiac repair and damage in fetuses with MI. However, further investigation into the optimal timing of LGE and EGE scans and improvement of the sequences should be pursued with the aim of expanding our capacity to monitor cardiac regeneration after MI in fetal sheep.

Winter cover crops have been proposed as a potential climate mitigation practice, but a recent study concluded that cover crops may increase local temperature by up to 3°C. Here, we present agronomic context and data on cover crop morphology to ground-truth the scenarios simulated in this study. We conclude that the scenario of cover crop morphology on which the study’s headline claim is based is unlikely to be found in contemporary production systems. The most realistic scenario simulated did not result in significant local warming. Therefore, we argue that widespread planting of cover crops is unlikely to substantially increase local winter temperatures.

Aim: Characterizing the response to myocardial infarction (MI) in the regenerative sheep fetus heart compared to the post-natal non-regenerative adolescent heart may reveal key morphological and molecular differences that equate to the response to MI in humans. We hypothesized that the immediate response to injury in (a) infarct compared with sham, and (b) infarct, border, and remote tissue, in the fetal sheep heart would be fundamentally different to the adolescent, allowing for repair after damage.Methods: We used a sheep model of MI induced by ligating the left anterior descending coronary artery. Surgery was performed on fetuses (105 days) and adolescent sheep (6 months). Sheep were randomly separated into MI (n = 5) or Sham (n = 5) surgery groups at both ages. We used magnetic resonance imaging (MRI), histological/immunohistochemical staining, and qRT-PCR to assess the morphological and molecular differences between the different age groups in response to infarction.Results: Magnetic resonance imaging showed no difference in fetuses for key functional parameters; however there was a significant decrease in left ventricular ejection fraction and cardiac output in the adolescent sheep heart at 3 days post-infarction. There was no significant difference in functional parameters between MRI sessions at Day 0 and Day 3 after surgery. Expression of genes involved in glucose transport and fatty acid metabolism, inflammatory cytokines as well as growth factors and cell cycle regulators remained largely unchanged in the infarcted compared to sham ventricular tissue in the fetus, but were significantly dysregulated in the adolescent sheep. Different cardiac tissue region-specific gene expression profiles were observed between the fetal and adolescent sheep.Conclusion: Fetuses demonstrated a resistance to cardiac damage not observed in the adolescent animals. The manipulation of specific gene expression profiles to a fetal-like state may provide a therapeutic strategy to treat patients following an infarction.