Asystolic donor warm ischemia time is associated with development of postreperfusion syndrome in donation after circulatory death liver transplant.

BACKGROUND: Individual events during donation after circulatory death (DCD) procurement, such as hypotensive or hypoxic warm ischemia, or circulatory arrest are all a part of donor warm ischemia time (dWIT), and may have differing effects on the outcome of the liver graft. This study aimed to identify risk factors for postreperfusion syndrome (PRS), a state of severe hemodynamic derangement following graft reperfusion, and its impact on DCD liver transplantation (LT) outcomes. METHODS: This was a retrospective analysis using 106 DCD LT. Detailed information for events during procurement (withdrawal of life support; systolic blood pressure < 80 mmHg; oxygen saturation < 80%; circulatory arrest; aortic cold perfusion) and their association with the development of PRS were examined using logistic regression. RESULTS: The overall incidence of PRS was 26.4%, occurring in 28 patients. Independent risk factors for PRS were asystolic dWIT (odds ratio (OR) 3.65, 95% confidence interval (CI) 1.38-9.66) and MELD score (OR 1.06, 95% CI 1.01-1.10). Total bilirubin was significantly higher in the PRS group at postoperative day (POD) 1 (p = .02; 5.2 mg/dL vs. 3.4 mg/dL), POD 3 (p = .049; 4.5 mg/dL vs. 2.8 mg/dL), and POD 7 (p = .04; 3.1 mg/dL vs. 1.9 mg/dL). Renal replacement therapy after LT was more likely to be required in the PRS group (p = .01; 48.2% vs. 23.1%). CONCLUSION: Asystolic dWIT is a risk factor for the development of PRS in DCD LT. Our results suggest that asystolic dWIT should be considered when selecting DCD liver donors.

Unveiling the evolving landscape of stroke care costs: A time-driven analysis.

INTRODUCTION: Stroke is a common cause of mortality in the United States. However, the economic burden of stroke on the healthcare system is not well known. In this study, we aim to calculate the annual cumulative and per-patient cost of stroke. METHODS: We conducted a retrospective analysis of Nationwide Emergency Department Sample (NEDS). We calculate annual trends in cost for stroke patients from 2006 to 2019. A multivariate linear regression with patient characteristics (e.g. age, sex, Charlson Comorbidity Index) as covariates was used to identify factors for higher costs. RESULTS: In this study time-period, 2,998,237 stroke patients presented to the ED and 2,481,171 (83 %) were admitted. From 2006 to 2019, the cumulative ED cost increased by a factor of 7.0 from 0.49 ± 0.03 to 3.91 ± 0.16 billion dollars (p < 0.001). The cumulative inpatient (IP) cost increased by a factor of 2.7 from 14.42 ± 0.78 to 37.06 ± 2.26 billion dollars (p < 0.001. Per-patient ED charges increased by a factor of 3.0 from 1950 ± 64 to 7818 ± 260 dollars (p < 0.001). Per-patient IP charges increased by 89 % from 40.22 +/- 1.12 to 76.06 ± 3.18 thousand dollars (p < 0.001). CONCLUSION: Strokes place an increasing financial burden on the US healthcare system. Certain patient demographics including age, male gender, more comorbidities, and insurance type were significantly associated with increased cost of care.

Dimensions of Uncertainty: A spatiotemporal review of five COVID-19 datasets.

COVID-19 surveillance across the U.S. is essential to tracking and mitigating the pandemic, but data representing cases and deaths may be impacted by attribute, spatial, and temporal uncertainties. COVID-19 case and death data are essential to understanding the pandemic and serve as key inputs for prediction models that inform policy-decisions; consistent information across datasets is critical to ensuring coherent findings. We implement an exploratory data analytic approach to characterize, synthesize, and visualize spatial-temporal dimensions of uncertainty across commonly used datasets for case and death metrics (Johns Hopkins University, the New York Times, USAFacts, and 1Point3Acres). We scrutinize data consistency to assess where and when disagreements occur, potentially indicating underlying uncertainty. We observe differences in cumulative case and death rates to highlight discrepancies and identify spatial patterns. Data are assessed using pairwise agreement (Cohen's kappa) and agreement across all datasets (Fleiss' kappa) to summarize changes over time. Findings suggest highest agreements between CDC, JHU, and NYT datasets. We find nine discrete type-components of information uncertainty for COVID-19 datasets reflecting various complex processes. Understanding processes and indicators of uncertainty in COVID-19 data reporting is especially relevant to public health professionals and policymakers to accurately understand and communicate information about the pandemic.

Parkinson's disease - current treatment.

PURPOSE OF REVIEW: The purpose is to review the results and impact of recent studies for current and future treatment of both motor and non-motor symptoms in Parkinson's disease (PD). RECENT FINDINGS: New formulations of levodopa further optimize motor fluctuations, allowing for more on-time and less dyskinesia. On demand apomorphine continues to showcase itself as an effective and tolerable tool for treating motor off-periods. Though there are no clear treatment guidelines for PD-related constipation and sleep related disorders, several new agents for these non-motor symptoms show promising preliminary data. Expiratory muscle strength training may represent a useful and cost-effective strategy to alleviate oropharyngeal dysphagia associated with PD. There is evidence to suggest that the use of shorter pulse width and directional deep brain stimulation leads can results in a greater therapeutic window. SUMMARY: Though no interventions currently exist to significantly modify the disease progression of PD, new studies continue to give insight into optimal symptomatic management. Clinicians should be familiar with expanding the repertoire of tools available to treat the diverse range of symptoms and challenges associated with PD.

Robust Biomass-Derived Carbon Frameworks as High-Performance Anodes in Potassium-Ion Batteries.

Potassium-ion batteries (PIBs) have become one of the promising candidates for electrochemical energy storage that can provide low-cost and high-performance advantages. The poor cyclability and rate capability of PIBs are due to the intensive structural change of electrode materials during battery operation. Carbon-based materials as anodes have been successfully commercialized in lithium- and sodium-ion batteries but is still struggling in potassium-ion battery field. This work conducts structural engineering strategy to induce anionic defects within the carbon structures to boost the kinetics of PIBs anodes. The carbon framework provides a strong and stable structure to accommodate the volume variation of materials during cycling, and the further phosphorus doping modification is shown to enhance the rate capability. This is found due to the change of the pore size distribution, electronic structures, and hence charge storage mechanism. The optimized electrode in this work shows a high capacity of 175 mAh g-1 at a current density of 0.2 A g-1 and the enhancement of rate performance as the PIB anode (60% capacity retention with the current density increase of 50 times). This work, therefore provides a rational design for guiding future research on carbon-based anodes for PIBs.

Intraoperative intracardiac thrombus in liver transplantation: A 9-year retrospective review focusing on treatment and outcomes.

This study characterizes incidence and outcomes surrounding intracardiac thrombosis (ICT) during liver transplantation over 9 years at a single center before and after the routine use of transesophageal echocardiography (TEE). Adult liver transplantation patients from 2011 to 2020 were divided into eras based on routine TEE use. ICTs were identified by querying anesthetic records for search terms. Descriptive statistics included counts and proportions for baseline recipient, donor, intraoperative, and postoperative characteristics. Outcome data were based on date of hospital discharge and date of death. The incidence of ICT increased in the TEE era (2016-2020) compared with the pre-TEE era (2011-2015; 3.7% [25/685] vs. 1.9% [9/491]; p < 0.001). Patients with ICT had significantly higher Model for End-Stage Liver Disease-sodium (MELD-Na) scores, pretransplant hospitalization, malignancy, drug-induced liver injury, hypertension, deep vein thrombosis, reperfusion syndrome, transfused platelets and cryoprecipitate, and use of hemostatic medications. A higher proportion of patients in the ICT group underwent simultaneous liver-kidney transplantation. The patients with ICT were similar, except patients in the pre-TEE era had higher MELD-Na scores and incidences of hepatitis C virus and lower incidences of encephalopathy. In the pre-TEE era, all ICTs presented as intraoperative cardiac arrest, and the 30-day mortality in the setting of ICT was 66.7% (6/9). During the TEE era, 80% of ICTs were diagnosed incidentally or attributed to hemodynamic instability (p = 0.002). The 30-day mortality rate was 36% (9/25) in the TEE era (p = 0.25). ICT incidence increased in the TEE era, yet the mortality rate was lower, suggesting that routine intraoperative TEE may lead to the early detection of ICT prior to hemodynamic collapse.

Abnormal paraoxonase-1 (PON1) enzyme activity in idiopathic inflammatory myopathies.

OBJECTIVES: Patients with idiopathic inflammatory myopathies (IIM) have severe vascular involvement, which contributes to disease morbidity and mortality. Paraoxonase-1 (PON1) is a high-density lipoprotein (HDL) associated protein that protects the vascular endothelium from oxidative injury and damage. The current work assessed the functional and genetic determinants of PON1 activity in IIM patients. METHODS: A total of 184 IIM patients and 112 healthy controls (HC) were included. PON1 enzyme activity was assessed by paraoxonase, arylesterase and lactonase assays, and the Q192R PON1 single nucleotide polymorphism (SNP) was analysed. Multivariate regression models examined associations of PON1 activity with IIM diagnosis and myositis disease outcomes. RESULTS: The arylesterase and lactonase activities of PON1 were significantly lower in IIM patients compared with HC. Higher myositis disease activity, the presence of severe IIM-associated interstitial lung disease (ILD), and the presence of MDA5 or anti-synthetase antibodies were significantly associated with lower PON1 activity. The PON1 Q192R polymorphism was strongly linked to the paraoxonase activity of PON1 in IIM, and patients with the PON1 QQ genotype had better IIM disease outcomes compared with patients with the QR or RR genotypes. CONCLUSIONS: The arylesterase and lactonase activities of PON1 are significantly impaired in IIM patients compared with HC, and inversely associate with IIM disease activity and the presence of severe ILD. The PON1 QQ genotype associates with more favourable disease outcomes in IIM patients. Large prospective studies are needed to further evaluate the role of PON1 and PON1 genetic polymorphisms in the development and propagation of IIM and IIM-ILD.

Postreperfusion syndrome in liver transplantation: Outcomes, predictors, and application for recipient selection.

BACKGROUND: This study aimed to identify risk factors for postreperfusion syndrome (PRS) and its impact on LT outcomes. METHODS: Data analysis was performed in 1021 adult patients undergoing donation after brain death (DBD) LT to identify PRS incidence, the risk factors for PRS development, and its impact on LT outcomes. RESULTS: The overall incidence of PRS was 16.1%. Independent risk factors for PRS included donor age (odds ratio (OR) 1.01, P = .02), donor body mass index (BMI) (OR 1.04, P = .003), moderate macrosteatosis (OR 2.48, P = .02), and cold ischemia time (CIT) (OR 1.06, P = .02). On multivariable analysis for 30-day graft failure, PRS (hazard ratio (HR) 3.49; P < .001) and Model for End-stage Liver Disease (MELD) score (HR 1.01; P = .05) were independent risk factors. Patients were categorized into four distinct groups based on PRS risk groups and MELD groups, which showed different 1-year graft survival (P < .001). There were comparable outcomes between low PRS risk - high MELD and high PRS risk - low MELD group (P = .33). CONCLUSIONS: Donor age, donor BMI, moderate macrosteatosis, and CIT were identified as risk factors for the development of PRS in LT using DBD grafts. PRS risk evaluation may improve donor-to-recipient matching based on their MELD scores.

Validation of a Crisis Standards of Care Model for Prioritization of Limited Resources During the Coronavirus Disease 2019 Crisis in an Urban, Safety-Net, Academic Medical Center.

OBJECTIVES: The coronavirus disease 2019 pandemic has overwhelmed healthcare resources even in wealthy nations, necessitating rationing of limited resources without previously established crisis standards of care protocols. In Massachusetts, triage guidelines were designed based on acute illness and chronic life-limiting conditions. In this study, we sought to retrospectively validate this protocol to cohorts of critically ill patients from our hospital. DESIGN: We applied our hospital-adopted guidelines, which defined severe and major chronic conditions as those associated with a greater than 50% likelihood of 1- and 5-year mortality, respectively, to a critically ill patient population. We investigated mortality for the same intervals. SETTING: An urban safety-net hospital ICU. PATIENTS: All adults hospitalized during April of 2015 and April 2019 identified through a clinical database search. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Of 365 admitted patients, 15.89% had one or more defined chronic life-limiting conditions. These patients had higher 1-year (46.55% vs 13.68%; p < 0.01) and 5-year (50.00% vs 17.22%; p < 0.01) mortality rates than those without underlying conditions. Irrespective of classification of disease severity, patients with metastatic cancer, congestive heart failure, end-stage renal disease, and neurodegenerative disease had greater than 50% 1-year mortality, whereas patients with chronic lung disease and cirrhosis had less than 50% 1-year mortality. Observed 1- and 5-year mortality for cirrhosis, heart failure, and metastatic cancer were more variable when subdivided into severe and major categories. CONCLUSIONS: Patients with major and severe chronic medical conditions overall had 46.55% and 50.00% mortality at 1 and 5 years, respectively. However, mortality varied between conditions. Our findings appear to support a crisis standards protocol which focuses on acute illness severity and only considers underlying conditions carrying a greater than 50% predicted likelihood of 1-year mortality. Modifications to the chronic lung disease, congestive heart failure, and cirrhosis criteria should be refined if they are to be included in future models.

Reduction in Stroke After Transient Ischemic Attack in a Province-Wide Cohort Between 2003 and 2015.

BACKGROUND: Improvements in management of transient ischemic attack (TIA) have decreased stroke and mortality post-TIA. Studies examining trends over time on a provincial level are limited. We analyzed whether efforts to improve management have decreased the rate of stroke and mortality after TIA from 2003 to 2015 across an entire province. METHODS: Using administrative data from the Canadian Institute for Health Information's (CIHI) databases from 2003 to 2015, we identified a cohort of patients with a diagnosis of TIA upon discharge from the emergency department (ED). We examined stroke rates at Day 1, 2, 7, 30, 90, 180, and 365 post-TIA and 1-year mortality rates and compared trends over time between 2003 and 2015. RESULTS: From 2003 to 2015 in Ontario, there were 61,710 patients with an ED diagnosis of TIA. Linear regressions of stroke after the index TIA showed a significant decline between 2003 and 2015, decreasing by 25% at Day 180 and 32% at 1 year (p < 0.01). The 1-year stroke rate decreased from 6.0% in 2003 to 3.4% in 2015. Early (within 48 h) stroke after TIA continued to represent approximately half of the 1-year event rates. The 1-year mortality rate after ED discharge following a TIA decreased from 1.3% in 2003 to 0.3% in 2015 (p < 0.001). INTERPRETATION: At a province-wide level, 1-year rates of stroke and mortality after TIA have declined significantly between 2003 and 2015, suggesting that efforts to improve management may have contributed toward the decline in long-term risk of stroke and mortality. Continued efforts are needed to further reduce the immediate risk of stroke following a TIA.

Achieving Nonenzymatic Blood Glucose Sensing by Uprooting Saturation.

The saturation of nonenzymatic blood glucose sensors at lower than normal blood glucose levels has blocked their practical applications. The mechanistic understanding of the saturation, however, has long been under debate. Employing cyclic voltammetry, amperometry, and FTIR with various electrolytes of varying concentrations, we were able to uproot the saturation cause. It was found to be related to the hydroxide ion concentration, which must be 11 times greater than that of the glucose concentration, contrary to the prior understanding. Together with the satisfactory sensitivity at high pH, nonenzymatic blood glucose sensing has finally been achieved, eliminating the usual problem of electrochemical current saturation as well as the need for enzyme found in the present technology.

A mechanism for differential sorting of the planar cell polarity proteins Frizzled6 and Vangl2 at the trans-Golgi network.

In planar cell polarity (PCP), the epithelial cells are polarized along the plane of the cell surface perpendicular to the classical apical-basal axis, a process mediated by several conserved signaling receptors. Two PCP-signaling proteins, VANGL planar cell polarity protein 2 (Vangl2) and Frizzled6 (Fzd6), are located asymmetrically on opposite boundaries of the cell. Examining sorting of these two proteins at the trans-Golgi network (TGN), we demonstrated previously that the GTP-binding protein ADP-ribosylation factor-related protein 1 (Arfrp1) and the clathrin-associated adaptor protein complex 1 (AP-1) are required for Vangl2 transport from the TGN. In contrast, TGN export of Frizzled6 does not depend on Arfrp1 or AP-1. Here, to further investigate the TGN sorting process in mammalian cells, we reconstituted release of Vangl2 and Frizzled6 from the TGN into vesicles in vitro Immunoblotting of released vesicles indicated that Vangl2 and Frizzled6 exit the TGN in separate compartments. Knockdown analysis revealed that a clathrin adaptor, epsinR, regulates TGN export of Frizzled6 but not of Vangl2. Protein interaction analysis suggested that epsinR forms a stable complex with clathrin and that this complex interacts with a conserved polybasic motif in the Frizzled6 cytosolic domain to package Frizzled6 into transport vesicles. Moreover, we found that Frizzled6-epsinR binding dissociates epsinR from AP-1, which may separate these two cargo adaptors from each other to perform distinct cargo-sorting functions. Our results suggest that Vangl2 and Frizzled6 are packaged into separate vesicles that are regulated by different clathrin adaptors at the TGN, which may contribute to their asymmetric localizations.

Novel molecular therapeutic targets in cardiac fibrosis: a brief overview 1.

Cardiac fibrosis, characterized by excessive accumulation of extracellular matrix, abolishes cardiac contractility, impairs cardiac function, and ultimately leads to heart failure. In recent years, significant evidence has emerged that supports the highly dynamic and responsive nature of the cardiac extracellular matrix. Although our knowledge of cardiac fibrosis has advanced tremendously over the past decade, there is still a lack of specific therapies owing to an incomplete understanding of the disease etiology and process. In this review, we attempt to highlight some of the recently investigated molecular determinants of ischemic and non-ischemic fibrotic remodeling of the myocardium that present as promising avenues for development of anti-fibrotic therapies.

Assessing Adherence and Barriers to Long-Term Elimination Diet Therapy in Adults with Eosinophilic Esophagitis.

BACKGROUND: The six-food elimination diet (SFED) is an effective treatment approach for eosinophilic esophagitis (EoE), but it can be challenging and affect patients' quality of life. AIM: Assess patients' long-term adherence to SFED and potential factors influencing adherence. METHODS: EoE patients were recruited online via multiple platforms. Patients were classified as reaching the maintenance stage if they responded to SFED and identified specific trigger foods by reintroduction. Maintenance stage patients were categorized into those actively following the elimination diet (ACTIVE) and those no longer on their prescribed diet (FORMER). Participants completed a study-specific questionnaire assessing patient experiences related to SFED use. RESULTS: Forty-two participants were identified as having reached the SFED's maintenance stage. 57% (24/42) of the maintenance stage patients were ACTIVE users. FORMER users rated the SFED's effectiveness at treating symptoms (5.45 ± 3.96, 10 max.) lower than ACTIVE users (8.29 ± 2.76, p = .02). A greater percentage of FORMER users (100%) agreed social situations create challenges in following the diet compared to ACTIVE users (67%, p < .05). Anxiety related to SFED was also higher among FORMER users (64%) compared to ACTIVE users (21%, p < .01). Both ACTIVE (95.8%) and FORMER (81.8%, NSS) users would recommend the elimination diet to other EoE patients. CONCLUSIONS: Understanding SFED adherence is multifactorial and complex. Factors influencing SFED adherence during long-term maintenance with diet therapy include diet effectiveness, social situations, and diet-related anxiety. Despite a lower than expected long-term adherence to maintenance of an elimination diet, the majority would recommend diet therapy as a treatment to other EoE patients.

The Effect of Adding Subarachnoid Epinephrine to Hyperbaric Bupivacaine and Morphine for Repeat Cesarean Delivery: A Double-Blind Prospective Randomized Control Trial.

BACKGROUND: Spinal anesthesia has become the most common type of anesthetic for cesarean delivery. The major limitation to spinal anesthesia is that the duration of the anesthetic may not be adequate in the event of a prolonged surgery. Some practitioners add epinephrine to hyperbaric bupivacaine to increase the duration, although its effect has not been fully studied. We therefore aimed to evaluate whether adding epinephrine to the spinal medication prolongs the duration of action of the resultant block in women presenting for repeat cesarean delivery. METHODS: Sixty-eight patients were randomized to receive no epinephrine (NE group), epinephrine 100 µg (low-dose [LD] group), or epinephrine 200 µg (high-dose [HD] group) with a standardized spinal mixture (1.5 mL 0.75% hyperbaric bupivacaine with 0.25 mg morphine). Sixty-five patients were included for primary analysis. Our primary outcome was time to intraoperative activation of the epidural catheter or postoperative regression of sensory blockade to T-10 dermatome level as measured by pinprick sensation; motor recovery was a secondary outcome, and graded via a Modified Bromage scale. RESULTS: Block onset time, vital sign changes, and the incidence of hypotension; nausea, and vomiting were similar among groups. Median difference in time to T-10 regression was greatest in the HD group compared to the NE group (median difference [min] [95% confidence interval]: 40 [15-60]; P = .007), followed by the HD group to the LD group (30 [15-45]; P = .007). Comparisons of LD to NE were not significant, but trended to an increase in T-10 regression time (10 [-15 to 30]; P = .76). Median difference in time to knee extension (Bromage 3) was also greatest in the HD group when compared to both the LD and NE group (median difference [min] [95% confidence interval]: 30 [0-60]; P = .034, 60 [0-93]; P = .007). Median difference time to knee extension (min) between the LD and NE group was also significant (37.5 [15-60]; P = .001]. Pain scores during the procedure were higher in the NE group (median [interquartile range] HD: 0 [0-0], LD: 0 [0-0], NE: 0 [0-3]; P = .02) during uterine closure and were otherwise not significantly different from the other groups. CONCLUSIONS: In this single center, prospective, double-blind, randomized control trial, the addition of epinephrine 200 µg to hyperbaric bupivacaine and preservative-free morphine for repeat cesarean delivery prolonged the duration of the sensory blockade. Motor blockade was similarly prolonged and block quality may have been enhanced.

Serious gaming for orthotopic liver transplant anesthesiology: A randomized control trial.

Anesthetic management of orthotopic liver transplantation (OLT) is complex. Given the unequal distributions of liver transplant surgeries performed at different centers, anesthesiology providers receive relatively uneven OLT training and exposure. One well-suited modality for OLT training is the "serious game," an interactive application created for the purpose of imparting knowledge or skills, while leveraging the self-motivating elements of video games. We therefore developed a serious game designed to teach best practices for the anesthetic management of a standard OLT and determined if the game would improve resident performance in a simulated OLT. Forty-four residents on the liver transplant rotation were randomized to either the gaming group (GG) or the control group (CG) prior to their introductory simulation. Both groups were given access to the same educational materials and literature during their rotation, but the GG also had access to the OLT Trainer. Performance on the simulations were recorded on a standardized grading rubric. Both groups experienced an increase in score relative to baseline that was statistically significant at every stage. The improvements in scores were greater for the GG participants than the CG participants. Overall score improvement between the GG and CG (mean [standard deviation]) was statistically significant (GG, 7.95 [3.65]; CG, 4.8 [4.48]; P = 0.02), as were scores for preoperative assessment (GG, 2.67 [2.09]; CG, 1.17 [1.43]; P = 0.01) and anhepatic phase (GG, 1.62 [1.01]; CG, 0.75 [1.28]; P = 0.02). Of the residents with game access, 81% were "very satisfied" or "satisfied" with the game overall. In conclusion, adding a serious game to an existing educational curriculum for liver transplant anesthesia resulted in significant learning gains for rotating anesthesia residents. The intervention was straightforward to implement and cost-effective. Liver Transplantation 23 430-439 2017 AASLD.

Regulation of scleraxis transcriptional activity by serine phosphorylation.

Cardiac fibroblasts are the major extracellular matrix producing cells in the heart. Our laboratory was the first to demonstrate that the transcription factor scleraxis induces collagen 1α2 expression in both cardiac fibroblasts and myofibroblasts. Here we identify a novel post-translational mechanism by which scleraxis activity is regulated and determine its effect on transcription of genes targeted by scleraxis. Putative serine phosphorylation sites on scleraxis were revealed by in silico analysis using motif prediction software. Mutation of key serine residues to alanine, which cannot be phosphorylated, significantly attenuated the expression of fibrillar type I collagen and myofibroblast marker genes that are normally induced by scleraxis. Down-regulation of collagen 1α2 expression was due to reduced binding of the non-phosphorylated scleraxis mutant to specific E-box DNA-binding sites within the promoter as determined by chromatin immunoprecipitation in human cardiac myofibroblast cells and by electrophoretic mobility shift assay. This is the first evidence suggesting that scleraxis is phosphorylated under basal conditions. The phosphorylation sequence matched that targeted by Casein Kinase 2, and inhibition of this kinase activity disrupted the ability of scleraxis to modulate the expression of its target genes while also attenuating TGFß-induced expression of type I collagen and myofibroblast phenotype conversion marker genes. These results demonstrate a novel mechanism for regulation of scleraxis activity, which may prove to be tractable for pharmacologic manipulation.

Regulation of fibronectin gene expression in cardiac fibroblasts by scleraxis.

The glycoprotein fibronectin is a key component of the extracellular matrix. By interacting with numerous matrix and cell surface proteins, fibronectin plays important roles in cell adhesion, migration and intracellular signaling. Up-regulation of fibronectin occurs in tissue fibrosis, and previous studies have identified the pro-fibrotic factor TGFß as an inducer of fibronectin expression, although the mechanism responsible remains unknown. We have previously shown that a key downstream effector of TGFß signaling in cardiac fibroblasts is the transcription factor scleraxis, which in turn regulates the expression of a wide variety of extracellular matrix genes. We noted that fibronectin expression tracked closely with scleraxis expression, but it was unclear whether scleraxis directly regulated the fibronectin gene. Here, we report that scleraxis acts via two E-box binding sites in the proximal human fibronectin promoter to govern fibronectin expression, with the second E-box being both sufficient and necessary for scleraxis-mediated fibronectin expression to occur. A combination of electrophoretic mobility shift and chromatin immunoprecipitation assays indicated that scleraxis interacted to a greater degree with the second E-box. Over-expression or knockdown of scleraxis resulted in increased or decreased fibronectin expression, respectively, and scleraxis null mice presented with dramatically decreased immunolabeling for fibronectin in cardiac tissue sections compared to wild-type controls. Furthermore, scleraxis was required for TGFß-induced fibronectin expression: TGFß lost its ability to induce fibronectin expression following scleraxis knockdown. Together, these results demonstrate a novel and required role for scleraxis in the regulation of cardiac fibroblast fibronectin gene expression basally or in response to TGFß.

Abdominal Organ Transplantation: Noteworthy Literature in 2023.

This review highlights noteworthy literature published in 2023 and pertinent to anesthesiologists and critical care physicians caring for patients undergoing abdominal organ transplantation. We feature 9 studies from 593 peer-reviewed papers on pancreatic transplantation, 3 from 194 on intestinal transplantation, and 28 from over 4513 on kidney transplantation. The liver transplantation section includes a special focus on 20 studies from 5666 clinical trial publications. We explore a broad range of topics, including donor management, perioperative recipient management, and innovative pharmacologic and mechanical interventions tested for the improvement of patient and graft outcomes and survival.

Safety and efficacy of intrathecal baclofen trials for the treatment of hypertonia: a retrospective cohort study.

OBJECTIVE: Intrathecal baclofen (ITB) is an effective treatment for refractory hypertonia in children. ITB has long been effective for the treatment of spasticity, and indications have naturally evolved to include dystonia and mixed pediatric movement disorders (PMDs). The established uses for ITB trials are insurance prerequisite, mixed tone, and family request. Despite agreement for ITB therapy by a multidisciplinary group of subspecialists in a complex PMD program, insurance companies often require an ITB trial be performed. A longitudinal cohort was identified to determine the safety and efficacy of ITB trials and to determine the utility of test dosing in this population. METHODS: Retrospective data analysis was performed for patients with hypertonia who underwent ITB bolus trials at the authors' institution between 2021 and 2023. Nonmodifiable risk factors and clinical variables were collected. RESULTS: Thirty-one patients (11 female) underwent 32 ITB trials. Of these patients, 67.7% had a diagnosis of mixed hypertonia, 32.3% pure spasticity, and 9.1% secondary dystonia. The mean age at test dose was 12.8 years, and 58.1% of patients were born premature. The mode Gross Motor Function Classification System score was 5. The mean difference in Barry-Albright Dystonia Scale (BADS) scores was -7.33 points (p = 0.01) at 2.5 hours postoperatively. The mean difference in upper-extremity modified Ashworth Scale (mAS) scores was -5.36 points (p = 0.003), and that for lower-extremity mAS scores was -6.61 (p < 0.001). In total, 21.9% of patients developed a post-dural puncture headache. Conversion to a permanent baclofen pump was performed in 22/32 (68.8%) patients. Of those who did not pursue pump placement, 1 patient had high surgical risk, 1 had an ineffective response, 1 had a bad reaction to the test dose and cited both regression and increased discomfort, and 2 declined despite an effective trial owing to family preferences. CONCLUSIONS: ITB trials require hospitalization in some form and carry risks of procedural complications. The decision to pursue a trial should be made on a case-by-case basis by clinicians and should not be determined by insurance companies. The complication rate of ITB trials is high, and a test dose is unnecessary in this fragile population.