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The introduction of the hospitalist co-management model represents an opportunity to improve care by changing the system as it applies to a small group of patients. Eighty-six consecutive patients with multiple comorbidities were selectively enrolled in an academic medical center hospitalist-orthopedic surgery co-management patient care program. Patients were stratified by all patient refined diagnosis-related groups, severity of illness, and risk of mortality. Hospital length of stay, cost of care, in-hospital mortality, complications, and intensive care unit admissions were compared with a retrospectively constructed control group of 54 patients undergoing similar surgery during the period immediately preceding initiation of the program. The University HealthSystem Consortium observed-to-expected ratio for hospital length of stay was 0.693 compared to 0.862 for the control group. The severity of illness and risk of mortality scores represented a relatively higher risk stratification in the study group. While the overall observed-to-expected cost of care remained virtually unchanged, the positive impact of the study model revealed an increased positive effect on the more severely affected severity of illness and risk of mortality patients. The results of this study suggest that a proactive, cooperative, co-management model for the perioperative management of high-risk patients undergoing complex surgery can improve the quality and efficiency metrics associated with the delivery of service to patients. [ABSTRACT FROM AUTHOR]

Objectives: Pathological forms of neural activity, such as epileptic seizures, modify the expression pattern of multiple proteins, leading to persistent changes in brain function. One such protein is activity-regulated cytoskeleton-associated protein (Arc), which is critically involved in protein-synthesis-dependent synaptic plasticity underlying learning and memory. In the present study, we have investigated how the expression of ArcKR, a form of Arc in which the ubiquitination sites have been mutated, resulting in slowed Arc degradation, modifies group I metabotropic glutamate receptor-mediated long-term depression (G1-mGluR-LTD) following seizures., Methods: We used a knock-in mice line that express ArcKR and two hyperexcitation models: an in vitro model, where hippocampal slices were exposed to zero Mg 2+ , 6 mM K + ; and an in vivo model, where kainic acid was injected unilaterally into the hippocampus. In both models, field excitatory postsynaptic potentials (fEPSPs) were recorded from the CA1 region of hippocampal slices in response to Schaffer collateral stimulation and G1-mGluR-LTD was induced chemically with the group 1 mGluR agonist DHPG., Results: In the in vitro model, ArcKR expression enhanced the effects of seizure activity and increased the magnitude of G1-mGluR LTD, an effect that could be blocked with the mGluR5 antagonist MTEP. In the in vivo model, fEPSPs were significantly smaller in slices from ArcKR mice and were less contaminated by population spikes. In this model, the amount of G1-mGluR-LTD was significantly less in epileptic slices from ArcKR mice as compared to wildtype (WT) mice., Significance: We have shown that expression of ArcKR, a form of Arc in which degradation is reduced, significantly modulates the magnitude of G1-mGluR-LTD following epileptic seizures. However, the effect of ArcKR on LTD depends on the epileptic model used, with enhancement of LTD in an in vitro model and a reduction in the kainate mouse model., (© 2024 International League Against Epilepsy.)

Case Series Summary: Four confirmed cases of xanthinuria in cats, and one suspected case based on pedigree analysis, were identified. Clinical presentations varied and included haematuria, pollakiuria, dysuria, and urethral and ureteral obstruction. All cats had upper urinary tract uroliths. Diagnosis was obtained through infrared mass spectrometry of uroliths or urine. Clinical signs commenced at 3-8 months of age and reduced in all cats in the medium to long term after the introduction of a protein-restricted diet. Four cats were castrated males and one was a spayed female. Cases consisted of four Munchkin pedigree cats and one unrelated domestic shorthair cat. All four affected Munchkin pedigree cats were related, with three cases full siblings and the fourth case a half-sibling. No connection to the Munchkin pedigree could be established for the domestic shorthair cat. A candidate causative genetic variant ( XDH p.A681V) proposed for this cat was excluded in the Munchkin family., Relevance and Novel Information: All affected cats presented diagnostic challenges and routine urinalysis was insufficient to obtain a diagnosis. Cases of feline xanthinuria may be underdiagnosed due to situations where uroliths cannot be retrieved for analysis and there is an inability to make a diagnosis using crystal morphology alone on routine urinalysis. Metabolic screening of urine may provide an effective mechanism to confirm xanthinuria in suspected cases where uroliths are inaccessible or absent. In this case series, male cats were more common. Their anatomy may increase the risk of lower urinary tract signs and urethral obstruction developing secondary to xanthine urolithiasis. A protein-restricted diet appears to reduce clinical signs as part of long-term management., Plain Language Summary: Four closely related Munchkin cats and one domestic shorthair cat were found with a suspected genetic disease causing high levels of xanthine in their urine. The case series looks at similarities and differences in their clinical signs, as well as difficulties experienced in obtaining a correct diagnosis. All cats had upper urinary tract stones and required metabolic testing of the stones or urine to diagnose. All cats were young when their clinical signs started and were on a high-protein diet. Four cats were desexed males and one was a desexed female. A genetic variant that may have caused the disease in the domestic shorthair cat was ruled out in the Munchkin family. Cases of high xanthine levels in feline urine may be underdiagnosed as the stones may not be accessed for testing. In this case series, male cats were more common. Their anatomy may increase the risk of lower urinary tract signs. A protein-restricted diet appears to reduce clinical signs as part of long-term management., Competing Interests: Conflict of interestThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Technical skill is essential for good outcomes in cardiac surgery. However, no objective methods exist to measure dexterity while performing surgery. The purpose of this study was to validate sensor-based hand motion analysis (HMA) of technical dexterity while performing a graft anastomosis within a validated simulator., Methods: Surgeons at various training levels performed an anastomosis while wearing flexible sensors (BioStamp nPoint, MC10 Inc) with integrated accelerometers and gyroscopes on each hand to quantify HMA kinematics. Groups were stratified as experts (n = 8) or novices (n = 18). The quality of the completed anastomosis was scored using the 10 Point Microsurgical Anastomosis Rating Scale (MARS10). HMA parameters were compared between groups and correlated with quality. Logistic regression was used to develop a predictive model from HMA parameters to distinguish experts from novices., Results: Experts were faster (11 ± 6 minutes vs 21 ± 9 minutes; P = .012) and used fewer movements in both dominant (340 ± 166 moves vs 699 ± 284 moves; P = .003) and nondominant (359 ± 188 moves vs 567 ± 201 moves; P = .02) hands compared with novices. Experts' anastomoses were of higher quality compared with novices (9.0 ± 1.2 MARS10 vs 4.9 ± 3.2 MARS10; P = .002). Higher anastomosis quality correlated with 9 of 10 HMA parameters, including fewer and shorter movements of both hands (dominant, r = -0.65, r = -0.46; nondominant, r = -0.58, r = -0.39, respectively)., Conclusions: Sensor-based HMA can distinguish technical dexterity differences between experts and novices, and correlates with quality. Objective quantification of hand dexterity may be a valuable adjunct to training and education in cardiac surgery training programs., (Copyright © 2024 The Society of Thoracic Surgeons. All rights reserved.)

Background: Choosing between a bioprosthetic and a mechanical mitral valve is an important decision for both patients and surgeons. We compared patient outcomes and readmission rates after bioprosthetic mitral valve replacement (Bio-MVR) vs mechanical mitral valve replacement (Mech-MVR)., Methods: The Nationwide Readmissions Database was queried to identify 31 474 patients who underwent isolated MVR (22 998 Bio-MVR, 8476 Mech-MVR) between January 1, 2016, and December 31, 2018. Propensity score matching by age, sex, elective status, and comorbidities was used to compare outcomes between matched cohorts by prosthesis type. Freedom from readmission within the first calendar year was estimated by Kaplan-Meier analysis and compared between matched cohorts., Results: Bio-MVR patients were older (median age, 69 vs 57 years; P < .001) and had more comorbidities (median Elixhauser score, 14 vs 11; P < .001) compared with Mech-MVR patients. After propensity score matching (n = 15 549), Bio-MVR patients had similar operative mortality (3.5% vs 3.4%; P = .97) and costs ($50 958 vs $49 782; P = .16) but shorter lengths of stay (8 vs 9 days; P < .001) and fewer 30-day (16.0% vs 18.1%; P = .04) and 90-day (23.8% vs 26.8%; P = .01) readmissions compared with Mech-MVR patients. The difference in readmissions persisted at 1 year (P = .045). Readmission for bleeding or coagulopathy complications was less common with Bio-MVR (5.7% vs 10.1%; P < .001)., Conclusions: Readmission was more common after Mech-MVR than after Bio-MVR. Identifying and closely observing patients at high risk for bleeding complications may bridge the readmissions gap between Bio-MVR and Mech-MVR., (Copyright © 2024 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Objective: In patients who underwent mitral valve replacement for infectious endocarditis, we evaluated the association of prosthesis choice with readmission rates and causes (the primary outcomes), as well as with in-hospital mortality, cost, and length of stay (the secondary outcomes)., Methods: Patients with infectious endocarditis who underwent isolated mitral valve replacement from January 2016 to December 2018 were identified in the United States Nationwide Readmissions Database and stratified by valve type. Propensity score matching was used to compare adjusted outcomes., Results: A weighted total of 4206 patients with infectious endocarditis underwent bioprosthetic mitral valve replacement (n = 3132) and mechanical mitral valve replacement (n = 1074) during the study period. Patients in the bioprosthetic mitral valve replacement group were older than those in the mechanical mitral valve replacement group (median 57 vs 46 y, P  < .001). After propensity matching, the bioprosthetic mitral valve replacement group (n = 1068) had similar in-hospital mortality, length of stay, and costs compared with the mechanical mitral valve replacement group (n = 1056). Overall, 90-day readmission rates were high (28.9%) and comparable for bioprosthetic mitral valve replacement (30.5%) and mechanical mitral valve replacement (27.5%, P  = .4). Likewise, there was no difference in readmissions over a calendar year by prosthesis type. Readmissions for infection and bleeding were common for both bioprosthetic mitral valve replacement and mechanical mitral valve replacement groups., Conclusions: Outcomes and readmission rates were similar for mechanical mitral valve replacement and bioprosthetic mitral valve replacement in infectious endocarditis, suggesting that valve choice should not be determined by endocarditis status. Additionally, strategies to mitigate readmission for infection and bleeding are needed for both groups., Competing Interests: Dr Coselli participates in clinical studies with and consults for Terumo Aortic, Medtronic, WL Gore & Associates, CytoSorbents, Edwards Lifesciences, and Abbott Laboratories, and receives royalties and grant support from Terumo Aortic. Dr Moon serves on the advisory board for Medtronic. Dr Chatterjee has served on advisory boards for Edwards Lifesciences, La Jolla Pharmaceutical Company, Eagle Pharmaceuticals, and Baxter Pharmaceuticals. All other authors reported no conflicts of interest. The Journal policy requires editors and reviewers to disclose conflicts of interest and to decline handling or reviewing manuscripts for which they may have a conflict of interest. The editors and reviewers of this article have no conflicts of interest.

Objective: Acute kidney injury after cardiac surgery increases morbidity and mortality. Diagnosis relies on oliguria or increased serum creatinine, which develop 48 to 72 hours after injury. We hypothesized machine learning incorporating preoperative, operative, and intensive care unit data could dynamically predict acute kidney injury before conventional identification., Methods: Cardiac surgery patients at a tertiary hospital (2008-2019) were identified using electronic medical records in the Medical Information Mart for Intensive Care IV database. Preoperative and intraoperative parameters included demographics, Charlson Comorbidity subcategories, and operative details. Intensive care unit data included hemodynamics, medications, fluid intake/output, and laboratory results. Kidney Disease: Improving Global Outcomes creatinine criteria were used for acute kidney injury diagnosis. An ensemble machine learning model was trained for hourly predictions of future acute kidney injury within 48 hours. Performance was evaluated by area under the receiver operating characteristic curve and balanced accuracy., Results: Within the cohort (n = 4267), there were approximately 7 million data points. Median baseline creatinine was 1.0 g/dL (interquartile range, 0.8-1.2), with 17% (735/4267) of patients having chronic kidney disease. Postoperative stage 1 acute kidney injury occurred in 50% (2129/4267), stage 2 occurred in 8% (324/4267), and stage 3 occurred in 4% (183/4267). For hourly prediction of any acute kidney injury over the next 48 hours, area under the receiver operating characteristic curve was 0.82, and balanced accuracy was 75%. For hourly prediction of stage 2 or greater acute kidney injury over the next 48 hours, area under the receiver operating characteristic curve was 0.95 and balanced accuracy was 86%. The model predicted acute kidney injury before clinical detection in 89% of cases., Conclusions: Ensemble machine learning models using electronic medical records data can dynamically predict acute kidney injury risk after cardiac surgery. Continuous postoperative risk assessment could facilitate interventions to limit or prevent renal injury., (Copyright © 2022 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.)

Expression of the immediate early gene Arc/Arg3.1 (Arc), a key mediator of synaptic plasticity, is enhanced by neural activity and then reduced by proteasome-dependent degradation. We have previously shown that the disruption of Arc degradation, in an Arc knock-in mouse (ArcKR), where the predominant Arc ubiquitination sites were mutated, reduced the threshold to induce, and also enhanced, the strength of Group I metabotropic glutamate receptor-mediated long-term depression (DHPG-LTD). Here, we have investigated if ArcKR expression changes long-term potentiation (LTP) in CA1 area of the hippocampus. As previously reported, there was no change in basal synaptic transmission at Schaffer collateral/commissural-CA1 (SC-CA1) synapses in ArcKR versus wild-type (WT) mice. There was, however, a significant increase in the amplitude of synaptically induced (with low frequency paired-pulse stimulation) LTD in ArcKR mice. Theta burst stimulation (TBS)-evoked LTP at SC-CA1 synapses was significantly reduced in ArcKR versus WT mice (after 2 h). Group 1 mGluR priming of LTP was abolished in ArcKR mice, which could also potentially contribute to a depression of LTP. Although high frequency stimulation (HFS)-induced LTP was not significantly different in ArcKR compared with WT mice (after 1 h), there was a phenotype in environmentally enriched mice, with the ratio of LTP to short-term potentiation (STP) significantly reduced in ArcKR mice. These findings support the hypothesis that Arc ubiquitination supports the induction and expression of LTP, likely via limiting Arc-dependent removal of AMPA receptors at synapses., (© 2023 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

Objective: Studies have noted racial/ethnic disparities in coronary artery disease intervention strategies. We investigated trends and outcomes of coronary artery disease treatment choice (coronary artery bypass grafting or percutaneous coronary intervention) stratified by race/ethnicity., Methods: We queried the National Inpatient Sample for patients who underwent isolated coronary artery bypass grafting or percutaneous coronary intervention (2002-2017). Outcomes were stratified by race/ethnicity (White, African American, Hispanic, Asian). Multivariable logistic regression evaluated associations between race/ethnicity and receiving coronary artery bypass grafting versus percutaneous coronary intervention, in-hospital mortality, and costs., Results: Over the 15-year period, 2,426,917 isolated coronary artery bypass grafting surgeries and 7,184,515 percutaneous coronary interventions were performed. Compared with White patients, African American patients were younger (62 [interquartile range, 53-70] vs 66 [interquartile range, 57-75] years), were more likely to have Medicaid insurance (12.2% vs 4.4%), and had more comorbidities (Charlson-Deyo index, 1.9 ± 1.6 vs 1.7 ± 1.6) (all P < .01). After adjustment for patient comorbidities, presence of acute myocardial infarction, insurance status, and geography, African Americans were the least likely of all racial/ethnic groups to undergo coronary artery bypass grafting (odds ratio, 0.76; P < .01), a consistent trend throughout the study. African American patients had higher risk-adjusted mortality after coronary artery bypass grafting (odds ratio, 1.09; P < .01). Race/ethnicity was not associated with increased mortality after percutaneous coronary intervention. African American patients had higher hospitalization costs for coronary artery bypass grafting (+$5816; P < .01) and percutaneous coronary intervention (+$856; P < .01) after controlling for confounders., Conclusions: In this contemporary national analysis, risk-adjusted frequency of coronary artery bypass grafting versus percutaneous coronary intervention for coronary artery disease differed by race/ethnicity. African American patients had lower odds of undergoing coronary artery bypass grafting and worse outcomes. Reasons for these differences merit further investigation to identify opportunities to reduce potential disparities., (Copyright © 2022 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.)

Introduction: Prosthesis choice during aortic valve replacement (AVR) weighs lifelong anticoagulation with mechanical valves (M-AVR) against structural valve degeneration in bioprosthetic valves (B-AVR)., Methods: The Nationwide Readmissions Database was queried to identify patients who underwent isolated surgical AVR between January 1, 2016 and December 31, 2018, stratifying by prothesis type. Propensity score matching was used to compare risk-adjusted outcomes. Readmission at 1 y was estimated with Kaplan-Meier (KM) analysis., Results: Patients (n = 109,744) who underwent AVR (90,574 B-AVR and 19,170 M-AVR) were included. B-AVR patients were older (median 68 versus 57 y; P < 0.001) and had more comorbidities (mean Elixhauser score: 11.8 versus 10.7; P < 0.001) compared to M-AVR patients. After matching (n = 36,951), there was no difference in age (58 versus 57 y; P = 0.6) and Elixhauser score (11.0 versus 10.8; P = 0.3). B-AVR patients had similar in-hospital mortality (2.3% versus 2.3%; P = 0.9) and cost (mean: $50,958 versus $51,200; P = 0.4) compared with M-AVR patients. However, B-AVR patients had shorter length of stay (8.3 versus 8.7 d; P < 0.001) and fewer readmissions at 30 d (10.3% versus 12.6%; P < 0.001) and 90 d (14.8% versus 17.8%; P < 0.001), and 1 y (P < 0.001, KM analysis). Patients undergoing B-AVR were less likely to be readmitted for bleeding or coagulopathy (5.7% versus 9.9%; P < 0.001) and effusions (9.1% versus 11.9%; P < 0.001)., Conclusions: B-AVR patients had similar early outcomes compared to M-AVR patients, but lower rates of readmission. Bleeding, coagulopathy, and effusions are drivers of excess readmissions in M-AVR patients. Readmission reduction strategies targeting bleeding and improved anticoagulation management are warranted in the first year following AVR., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Machine learning (ML) algorithms may enhance outcomes prediction and help guide clinical decision making. This study aimed to develop and validate a ML model that predicts postoperative outcomes and costs after cardiac surgery., Methods: The Society of Thoracic Surgeons registry data from 4874 patients who underwent cardiac surgery (56% coronary artery bypass grafting, 42% valve surgery, 19% aortic surgery) at our institution were divided into training (80%) and testing (20%) datasets. The Extreme Gradient Boosting decision-tree ML algorithms were trained to predict three outcomes: operative mortality, major morbidity or mortality, and Medicare outlier high hospitalization cost. Algorithm performance was determined using accuracy, F1 score, and area under the precision-recall curve (AUC-PR). The ML algorithms were validated in index surgery cases with The Society of Thoracic Surgeons risk scores for mortality and major morbidities and with logistic regression and were then applied to nonindex cases., Results: The ML algorithms with 25 input parameters predicted operative mortality (accuracy 95%; F1 0.31; AUC-PR 0.21), major morbidity or mortality (accuracy 71%, F1 0.47; AUC-PR 0.47), and high cost (accuracy 84%; F1 0.62; AUC-PR 0.65). Preoperative creatinine, complete blood count, patient height and weight, ventricular function, and liver dysfunction were important predictors for all outcomes. For patients undergoing nonindex cardiac operations, the ML model achieved an AUC-PR of 0.15 (95% CI, 0.05-0.32) for mortality and 0.59 (95% CI, 0.51-0.68) for major morbidity or mortality., Conclusions: The extreme gradient boosting ML algorithms can predict mortality, major morbidity, and high cost after cardiac surgery, including operations without established risk models. These ML algorithms may refine risk prediction after cardiac surgery for a wide range of procedures., (Copyright © 2023 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Campylobacter is one of the most common foodborne bacterial pathogens causing illness, known as campylobacteriosis, in the United States. More than 70% of the campylobacteriosis cases have direct or indirect relation with poultry/poultry products. Currently, both conventional and organic/pasture poultry farmers are searching for sustainable alternative to antibiotics which can reduce colonization and cross-contamination of poultry products with Campylobacter and promote poultry health and growth. Probiotic and their nutritional supplement, known as prebiotic, have become consumers' preferences as alternatives to antibiotics/chemicals. In this study, we evaluated the combined effect of plant-derived prebiotic and probiotic-derived metabolites in reducing growth of Campylobacter in cecum contents, a simulated chicken gut condition. Cecum contents were collected from chickens pre-inoculated with kanamycin-resistant Campylobacter (CJRMKm), were incubated over 48 h time period, while being supplemented with either berry phenolic extract (BPE), cell free cultural supernatant from an engineered probiotic, Lactobacillus casei, or their combination. It was found that combine treatments were able to reduce both inoculated and naturally colonized Campylobacter more effectively. Microbiome analysis using 16S rRNA sequencing also revealed that combine treatments were capable to alter natural microflora positively within chicken cecum contents. Differences were observed in bacterial abundance at both phylum and genus level but did not show significant alteration in alpha diversity due to this treatment. PRACTICAL APPLICATION: The results of this study provide critical information for understanding the potential of synbiotic as an alternative in sustainable poultry farming. The outcomes of this study will lead future direction of using combination of probiotic-derived metabolites and BPE in poultry farming., (© 2023 Institute of Food Technologists.)

The cognitive deficits of schizophrenia are linked to imbalanced excitatory and inhibitory signalling in the prefrontal cortex (PFC), disrupting gamma oscillations. We previously demonstrated that two mGlu5 receptor-positive allosteric modulators (PAMs), VU0409551 and VU0360172, restore cognitive deficits in the sub-chronic PCP (scPCP) rodent model for schizophrenia via distinct changes in PFC intracellular signalling molecules. Here, we have assessed ex vivo gamma oscillatory activity in PFC slices from scPCP rats and investigated the effects of VU0409551 and VU0360172 upon oscillatory power. mGlu5 receptor, protein kinase C (PKC), and phospholipase C (PLC) inhibition were also used to examine 'modulation bias' in PAM activity. The amplitude and area power of gamma oscillations were significantly diminished in the scPCP model. Slice incubation with either VU0409551 or VU0360172 rescued scPCP-induced oscillatory deficits in a concentration-dependent manner. MTEP blocked the PAM-induced restoration of oscillatory power, confirming the requirement of mGlu5 receptor modulation. Whilst PLC inhibition prevented the power increase mediated by both PAMs, PKC inhibition diminished the effects of VU0360172 but not VU0409551. This aligns with previous reports that VU0409551 exhibits preferential activation of the phosphatidylinositol-3-kinase (PI3K) signalling pathway over the PKC cascade. Restoration of the excitatory/inhibitory signalling balance and gamma oscillations may therefore underlie the mGluR5 PAM-mediated correction of scPCP-induced cognitive deficits.

Background and Objective: Penetrating cardiac trauma is rare but can cause life-threatening complications. Survival is dependent on prompt diagnosis and treatment. Given the low incidence and life-threatening implications, it is difficult to study in large prospective studies. The current literature regarding penetrating cardiac trauma comes primarily from large, experienced trauma centers and military sources. Understanding the history, current literature and even expert opinion can help with effectively treating injury promptly to maximize survival after penetrating cardiac trauma. We aimed to review the etiology and history of penetrating cardiac trauma. We review the prehospital treatment and initial diagnostic modalities. We review the incisional approaches to treatment including anterolateral thoracotomy, median sternotomy and subxiphoid window. The repair of atrial, ventricular and coronary injuries are also addressed in our review. The purpose of this paper is to perform a narrative review to better describe the history, etiology, presentation, and management of penetrating cardiac trauma., Methods: A narrative review was preformed synthesizing literature from MEDLINE and bibliographic review from identified publications. Studies were included based on relevance without exclusion to time of publication or original publication language., Key Content and Findings: Sonographic identification of pericardial fluid can aid in diagnosis of patients too unstable for CT. Anterolateral thoracotomy should be used for emergent repairs and initial stabilization. A median sternotomy can be used for more stable patients with known injuries. Carefully placed mattress sutures can be useful for repair of injuries surrounding coronary vessels to avoid devascularization., Conclusions: Penetrating cardiac trauma is life threatening and requires prompt workup and treatment. Trauma algorithms should continue to refine and be clear on which patients should undergo an emergency department (ED) thoracotomy, median sternotomy and further imaging., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://med.amegroups.com/article/view/10.21037/med-22-18/coif). The series “Traumatic Injuries of the Mediastinum” was commissioned by the editorial office without any funding or sponsorship. The authors have no other conflicts of interest to declare., (2023 Mediastinum. All rights reserved.)

Objectives: Safety-net hospitals (SNHs) provide essential services to predominantly underserved patients regardless of their ability to pay. We hypothesized that patients who underwent coronary artery bypass grafting (CABG) would have inferior observed outcomes at SNHs compared with non-SNHs but that matched cohorts would have comparable outcomes., Methods: We queried the Nationwide Readmissions Database for patients who underwent isolated CABG from 2016 to 2018. We ranked hospitals by the percentage of all admissions in which the patient was uninsured or insured with Medicaid; hospitals in the top quartile were designated as SNHs. We used propensity-score matching to mitigate the effect of confounding factors and compare outcomes between SNHs and non-SNHs., Results: A total of 525,179 patients underwent CABG, including 96,133 (18.3%) at SNHs, who had a greater burden of baseline comorbidities (median Elixhauser score 8 vs 7; P  = .04) and more frequently required urgent surgery (57.1% vs 52.8%; P  < .001). Observed in-hospital mortality (2.1% vs 1.8%; P  = .004) and major morbidity, length of stay (9 vs 8 days; P  < .001), cost ($46,999 vs $38,417; P  < .001), and readmission rate at 30 (12.4% vs 11.3%) and 90 days (19.0% vs 17.7%) were greater at SNHs (both P  < .001). After matching, none of these differences persisted except length of stay (9 vs 8 days) and cost ($46,977 vs $39,343) (both P  < .001)., Conclusions: After matching, early outcomes after CABG were comparable at SNHs and non-SNHs. Improved discharge resources could reduce length of stay and curtail cost, improving the value of CABG at SNHs., (© 2023 The Author(s).)

Aggregated tau protein plays a key role in the pathogenesis of neurodegenerative tauopathies including Alzheimer's disease. Soluble, low-molecular-weight tau oligomers are formed early in disease processes and are thought to have toxic functions that disrupt neuronal function. The dynamic and transient nature of tau oligomers complicates in vitro functional studies to explore the mechanistic links between oligomer formation and neurodegeneration. We have previously described a method of producing stable and structurally characterized oligomers that maintain their oligomeric conformation and prevent further aggregation. This method allows for the flexibility of stabilizing tau oligomers by specifically labelling cysteine residues with fluorescent or colorless maleimide conjugates. Here, we describe the functional applications of these preformed stable tau oligomers in cell biology and electrophysiological studies. These investigations allow real-time insights into the cellular uptake of exogenous tau oligomers and their functional effects in the recipient cells., (© 2023. Springer Science+Business Media, LLC, part of Springer Nature.)

There is growing evidence that tau oligomers are a major pathological species in a number of tauopathies including Alzheimer's disease. However, it is still unclear what exact mechanisms underlie tau oligomer-mediated dysfunction. Studies of tau oligomers in vitro are limited by the high propensity for aggregation and consequent changes in the aggregation state of the produced tau samples over time. In this protocol, we provide a step-by-step description of a validated method for producing stable and structurally characterized oligomers of tau that can be used in biochemical, cellular, and animal model studies to evaluate mechanisms of action of tau in tauopathies., (© 2023. Springer Science+Business Media, LLC, part of Springer Nature.)

A key aim of Alzheimer disease research is to develop efficient therapies to prevent and/or delay the irreversible progression of cognitive impairments. Early deficits in long-term potentiation (LTP) are associated with the accumulation of amyloid beta in rodent models of the disease; however, less is known about how mGluR-mediated long-term depression (mGluR-LTD) is affected. In this study, we have found that mGluR-LTD is enhanced in the APP swe /PS1dE9 mouse at 7 but returns to wild-type levels at 13 months of age. This transient over-activation of mGluR signalling is coupled with impaired LTP and shifts the dynamic range of synapses towards depression. These alterations in synaptic plasticity are associated with an inability to utilize cues in a spatial learning task. The transient dysregulation of plasticity can be prevented by genetic deletion of the MAP kinase-activated protein kinase 2 (MK2), a substrate of p38 MAPK, demonstrating that manipulating the mGluR-p38 MAPK-MK2 cascade at 7 months can prevent the shift in synapse dynamic range. Our work reveals the MK2 cascade as a potential pharmacological target to correct the over-activation of mGluR signalling., (© 2022 The Authors. Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.)

Physiological oscillations in the cortico-thalamo-cortical loop occur during processes such as sleep, but these can become dysfunctional in pathological conditions such as absence epilepsy. The purine neuromodulator adenosine can act as an endogenous anticonvulsant: it is released into the extracellular space during convulsive seizures to activate A 1 receptors suppressing on-going activity and delaying the occurrence of the next seizure. However, the role of adenosine in thalamic physiological and epileptiform oscillations is less clear. Here we have combined immunohistochemistry, electrophysiology, and fixed potential amperometry (FPA) biosensor measurements to characterise the release and actions of adenosine in thalamic oscillations measured in rodent slices. In the thalamus, A 1 receptors are highly expressed particularly in the ventral basal (VB) thalamus and reticular thalamic nucleus (nRT) supporting a role for adenosine signalling in controlling oscillations. In agreement with previous studies, both adenosine and adenosine A 1 receptor agonists inhibited thalamic oscillations in control (spindle-like) and in epileptic conditions. Here we have shown for the first time that both control and epileptiform oscillations are enhanced (i.e., increased number of oscillatory cycles) by blocking A 1 receptors consistent with adenosine release occurring during oscillations. Although increases in extracellular adenosine could not be directly detected during control oscillations, clear increases in adenosine concentration could be detected with a biosensor during epileptiform oscillation activity. Thus, adenosine is released during thalamic oscillations and acts via A 1 receptors to feedback and reduce thalamic oscillatory activity., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Injectable intramyocardial biomaterials have promise to limit adverse ventricular remodeling through mechanical and biologic mechanisms. While some success has been observed by injecting materials to regenerate new tissue, optimal biomaterial stiffness to thicken and stiffen infarcted myocardium to limit adverse remodeling has not been determined. In this work, we present an in-vivo study of the impact of biomaterial stiffness over a wide range of stiffness moduli on ventricular mechanics. We utilized injectable methacrylated polyethylene glycol (PEG) hydrogels fabricated at 3 different mechanical moduli: 5 kPa (low), 25 kPa (medium/myocardium), and 250 kPa (high/supraphysiologic). We demonstrate that the supraphysiological high stiffness favorably alters post-infarct ventricular mechanics and prevents negative tissue remodeling. Lower stiffness materials do not alter mechanics and thus to be effective, must instead target biological reparative mechanisms. These results may influence rationale design criteria for biomaterials developed for infarct reinforcement therapy. STATEMENT OF SIGNIFICANCE: Acellular biomaterials for cardiac application can provide benefit via mechanical and biological mechanisms post myocardial infarction. We study the role of biomaterial mechanical characteristics on ventricular mechanics in myocardial infarcts. Previous studies have not measured the influence of injected biomaterials on ventricular mechanics, and consequently rational design criteria is unknown. By utilizing an in-vivo assessment of ventricular mechanics, we demonstrate that low stiffness biomaterial do not alter pathologic ventricular mechanics. Thus, to be effective, low stiffness biomaterials must target biological reparative mechanisms. Physiologic and supra-physiologic biomaterials favorably alter post-infarct mechanics and prevents adverse ventricular remodeling., Competing Interests: Declaration of Competing Interest The authors report no conflict of interests., (Copyright © 2022. Published by Elsevier Ltd.)

Background: Safety-net hospitals provide essential services to vulnerable patients with complex medical and socioeconomic circumstances. We hypothesized that matched patients at safety-net hospitals and non-safety-net hospitals would have comparable outcomes, costs, and readmission rates after isolated surgical aortic valve replacement (AVR) or mitral valve replacement (MVR)., Methods: The National Readmissions Database was queried to identify patients who underwent isolated AVR (n = 109 744) or MVR (n = 31 475) from 2016 to 2018. Safety-net burden was defined as the percentage of patients who were uninsured or insured with Medicaid, with hospitals in the top quartile designated as safety-net hospitals. After propensity score matching, outcomes for AVR and MVR at safety-net hospitals vs non-safety-net hospitals were compared., Results: Overall, 17 925 AVRs (16%) and 5516 MVRs (18%) were performed at safety-net hospitals, and these patients had higher comorbidity rates, had lower socioeconomic status, and more frequently required urgent surgery. Observed inhospital mortality was similar between safety-net hospitals and non-safety-net hospitals (AVR 2.2% vs 2.1%, P = .4; MVR 4.8% vs 4.3%, P = .1). After matching, rates of inhospital mortality, major morbidity, and readmission were similar; however, safety-net hospitals had longer length of stay after AVR (7 vs 6 days, P = .001) and higher total cost after AVR ($49 015 vs $42 473, P < .001) and MVR ($59 253 vs $52 392, P < .001)., Conclusions: Isolated surgical AVR and MVR are both performed at safety-net hospitals with outcomes comparable to those at non-safety-net hospitals, supporting efforts to expand access to these procedures for underserved populations. Investment in care coordination resources to reduce length of stay and curtail cost at safety-net hospitals is warranted., (Copyright © 2022 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: Machine learning may enhance prediction of outcomes after coronary artery bypass grafting (CABG). We sought to develop and validate a dynamic machine learning model to predict CABG outcomes at clinically relevant pre- and postoperative time points., Methods: The Society of Thoracic Surgeons (STS) registry data elements from 2086 isolated CABG patients were divided into training and testing datasets and input into Extreme Gradient Boosting decision-tree machine learning algorithms. Two prediction models were developed based on data from preoperative (80 parameters) and postoperative (125 parameters) phases of care. Outcomes included operative mortality, major morbidity or mortality, high cost, and 30-day readmission. Machine learning and STS model performance were assessed using accuracy and the area under the precision-recall curve (AUC-PR)., Results: Preoperative machine learning models predicted mortality (accuracy, 98%; AUC-PR = 0.16; F1 = 0.24), major morbidity or mortality (accuracy, 75%; AUC-PR = 0.33; F1 = 0.42), high cost (accuracy, 83%; AUC-PR = 0.51; F1 = 0.52), and 30-day readmission (accuracy, 70%; AUC-PR = 0.47; F1 = 0.49) with high accuracy. Preoperative machine learning models performed similarly to the STS for prediction of mortality (STS AUC-PR = 0.11; P = .409) and outperformed STS for prediction of mortality or major morbidity (STS AUC-PR = 0.28; P < .001). Addition of intraoperative parameters further improved machine learning model performance for major morbidity or mortality (AUC-PR = 0.39; P < .01) and high cost (AUC-PR = 0.64; P < .01), with cross-clamp and bypass times emerging as important additive predictive parameters., Conclusions: Machine learning can predict mortality, major morbidity, high cost, and readmission after isolated CABG. Prediction based on the phase of care allows for dynamic risk assessment through the hospital course, which may benefit quality assessment and clinical decision-making., (Copyright © 2022 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

The development of therapeutic agonists for G protein-coupled receptors (GPCRs) is hampered by the propensity of GPCRs to couple to multiple intracellular signalling pathways. This promiscuous coupling leads to numerous downstream cellular effects, some of which are therapeutically undesirable. This is especially the case for adenosine A 1 receptors (A 1 Rs) whose clinical potential is undermined by the sedation and cardiorespiratory depression caused by conventional agonists. We have discovered that the A 1 R-selective agonist, benzyloxy-cyclopentyladenosine (BnOCPA), is a potent and powerful analgesic but does not cause sedation, bradycardia, hypotension or respiratory depression. This unprecedented discrimination between native A 1 Rs arises from BnOCPA's unique and exquisitely selective activation of Gob among the six Gαi/o subtypes, and in the absence of β-arrestin recruitment. BnOCPA thus demonstrates a highly-specific Gα-selective activation of the native A 1 R, sheds new light on GPCR signalling, and reveals new possibilities for the development of novel therapeutics based on the far-reaching concept of selective Gα agonism., (© 2022. The Author(s).)

Objective: We examined readmissions and resource use during the first postoperative year in patients who underwent thoracic endovascular aortic repair or open surgical repair of Stanford type B aortic dissection., Methods: The Nationwide Readmissions Database (2016-2018) was queried for patients with type B aortic dissection who underwent thoracic endovascular aortic repair or open surgical repair. The primary outcome was readmission during the first postoperative year. Secondary outcomes included 30-day and 90-day readmission rates, in-hospital mortality, length of stay, and cost. A Cox proportional hazards model was used to determine risk factors for readmission., Results: During the study period, type B aortic dissection repair was performed in 6456 patients, of whom 3517 (54.5%) underwent thoracic endovascular aortic repair and 2939 (45.5%) underwent open surgical repair. Patients undergoing thoracic endovascular aortic repair were older (63 vs 59 years; P  < .001) with fewer comorbidities (Elixhauser score of 11 vs 17; P  < .001) than patients undergoing open surgical repair. Thoracic endovascular aortic repair was performed electively more often than open surgical repair (29% vs 20%; P  < .001). In-hospital mortality was 9% overall and lower in the thoracic endovascular aortic repair cohort than in the open surgical repair cohort (5% vs 13%; P  < .001). However, the 90-day readmission rate was comparable between the thoracic endovascular aortic repair and open surgical repair cohorts (28% vs 27%; P  = .7). Freedom from readmission for up to 1 year was also similar between cohorts ( P  = .6). Independent predictors of 1-year readmission included length of stay more than 10 days ( P  = .005) and Elixhauser comorbidity risk index greater than 4 ( P  = .033)., Conclusions: Approximately one-third of all patients with type B aortic dissection were readmitted within 90 days after aortic intervention. Surprisingly, readmission during the first postoperative year was similar in the open surgical repair and thoracic endovascular aortic repair cohorts, despite marked differences in preoperative patient characteristics and interventions., (© 2022 The Author(s).)

Sleep apnoea is a highly prevalent disease that often goes undetected and is associated with poor clinical prognosis, especially as it exacerbates many different disease states. However, most animal models of sleep apnoea (e.g., intermittent hypoxia) have recently been dispelled as physiologically unrealistic and are often unduly severe. Owing to a lack of appropriate models, little is known about the causative link between sleep apnoea and its comorbidities. To overcome these problems, we have created a more realistic animal model of moderate sleep apnoea by reducing the excitability of the respiratory network. This has been achieved through controlled genetically mediated lesions of the preBötzinger complex (preBötC), the inspiratory oscillator. This novel model shows increases in sleep disordered breathing with alterations in breathing during wakefulness (decreased frequency and increased tidal volume) as observed clinically. The increase in dyspnoeic episodes leads to reduction in REM sleep, with all lost active sleep being spent in the awake state. The increase in hypoxic and hypercapnic insults induces both systemic and neural inflammation. Alterations in neurophysiology, an inhibition of hippocampal long-term potentiation (LTP), is reflected in deficits in both long- and short-term spatial memory. This improved model of moderate sleep apnoea may be the key to understanding why this disorder has such far-reaching and often fatal effects on end-organ function., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Roberts, Wall, Braren, Dhillon, Evans, Dunne, Nyakupinda and Huckstepp.)

In schizophrenia, mGlu5 receptor hypofunction has been linked with neuropathology and cognitive deficits, making it an attractive therapeutic target. The cognitive impairment associated with schizophrenia remains an unmet clinical need, with existing antipsychotics primarily targeting positive symptoms, with weaker and more variable effects on cognitive deficits. Using the sub-chronic phencyclidine rat model, widely shown to mimic the cognitive impairment and neuropathology of schizophrenia, we have investigated two mGlu5 receptor positive allosteric modulators (PAMs), VU0409551 and VU0360172. We compared the efficacy of these compounds in restoring cognitive deficits and, since these two PAMs have reportedly distinct signalling mechanisms, changes in mGlu5 receptor signalling molecules AKT and MAPK in the PFC. Although not effective at 0.05 and 1 mg/kg, cognitive deficits were significantly alleviated by both PAMs at 10 and 20 mg/kg. The compounds appeared to have differential effects on the scPCP-induced increases in AKT and MAPK phosphorylation: VU0409551 induced a significant decrease in expression of p-AKT, whereas VU0360172 had this effect on p-MAPK levels. Thus, the beneficial effects of PAMs on scPCP-induced cognitive impairment are accompanied by at least partial reversal of scPCP-induced elevated levels of p-MAPK and p-AKT, whose dysfunction is strongly implicated in schizophrenia pathology. These promising data imply an important role for mGlu5 receptor signalling pathways in improving cognition in the scPCP model and provide support for mGlu5 receptor PAMs as a possible therapeutic intervention for schizophrenia., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Tau protein is involved in maintaining neuronal structure. In Alzheimer's disease, small numbers of tau molecules can aggregate to form oligomers. However, how these oligomers produce changes in neuronal function remains unclear. Previously, oligomers made from full-length human tau were found to have multiple effects on neuronal properties. Here we have cut the tau molecule into two parts: the first 123 amino acids and the remaining 124-441 amino acids. These truncated tau molecules had specific effects on neuronal properties, allowing us to assign the actions of full-length tau to different regions of the molecule. We identified one key target for the effects of tau, the voltage gated sodium channel, which could account for the effects of tau on the action potential. By truncating the tau molecule, we have probed the mechanisms that underlie tau dysfunction, and this increased understanding of tau's pathological actions will build towards developing future tau-targeting therapies., (© 2021. The Author(s).)