Citations

Cholangiocarcinoma (CCA), the second most common primary liver tumor, is associated with a dismal outcome, and useful prognostic markers are not currently available in clinical practice. SerpinB3, a serine protease inhibitor, was recently found to play a relevant role in malignant transformation in different cancers. The aim of the present study was to determine the expression of SerpinB3/4 in tissue and serum samples of patients with CCA in relation to clinical outcomes. SerpinB3/4 was assessed in the tissue microarrays (TMAs) of 123 surgically resected CCAs. ELISA assays were carried out in 188 patients with CCA to detect the free and IgM-linked forms of SerpinB3/4. Overall survival was analyzed in relation to SerpinB3/4 expression, and Cox models were used to identify the variables associated with survival. High levels of SerpinB3/4 (TMA score 2+/3+) were detected in 15 tumors (12.2%), characterized by a more advanced TNM stage (III/IV: 64.3% vs. 31.3%; p = 0.031) and lower overall patient survival, independently of CCA subclass (intrahepatic CCA: median 1.1 (0.8—Not Estimable, NE) vs. 2.4 (1.8–3.4) years; p = 0.0007; extrahepatic CCA: median 0.8 (0.2—NE) vs. 2.2 (1.5–5.4) years; p = 0.011). Vascular invasion (p = 0.027) and SerpinB3/4 scores (p = 0.0016) were independently associated with mortality in multivariate analysis. Patients who had detectable free or IgM-linked SerpinB3/4 in their serum showed poorer survival (1 vs. 2.4 years, p = 0.015, for free SerpinB3/4, and 1 vs. 2.6 years, p = 0.0026, for SerpinB3/4–IgM). In conclusion, high levels of SerpinB3/4 in tissue and serum in CCA are associated with poor outcomes after surgery, regardless of tumor subclass.

Abstract Background: Venous thromboembolism (VTE) in pregnancy is a major cause of maternal morbidity and mortality, and the use of preventive low-molecular-weight heparin (LMWH) can be challenging. Clinical guidelines recommend eliciting pregnant individuals’ preferences towards the use of daily injections of LMWH and discussing the best option through a shared decision-making (SDM) approach. Our aim was to identify individuals’ preferences concerning each of the main clinical outcomes, and categorize attributes influencing the use of LMWH during pregnancy. Methods: Design: Convergent mixed-methods. Participants: Pregnant women or those planning a pregnancy with VTE recurrence risk. Intervention: A SDM intervention about thromboprophylaxis with LMWH in pregnancy. Analysis: Quantitatively, we report preference scores assigned to each of the health states. Qualitatively, we categorized preference attributes using Burke’s pentad of motives framework: scene, agent, agency, act, and purpose. We use mixed-method convergent analysis to report findings using side-by-side comparison of concordance/discordance. Results: The least valued health state was to experience a pulmonary embolism (PE), followed by major obstetrical bleeding (MOB), deep vein thrombosis (DVT), and using daily injections of LMWH (valued as closest to a ‘healthy pregnancy’). Women's previous experiences, access to care (scene) and shared decision-making (agent) affected preferences. LMWH's benefits were noted, but substantial drawbacks described (agency). The main goal was avoiding the risk of VTE (purpose). Side-by-side comparisons revealed concordance between motives and DVT and PE health states. Discordance appeared between using daily injections of LMWH and agent- and agency motives and between MOB and the agency motive. Conclusions: Mixed-methods provide a nuanced understanding of women's LMWH preferences, by quantifying health states preferences and exploring attributes qualitatively. Incorporating both methods may improve patient-centered care around preference-sensitive decisions in thromboprophylaxis during pregnancy.

Abstract Background Progressive apraxia of speech (PAOS) is characterized by difficulties with motor speech programming and planning. PAOS targets gray matter (GM) and white matter (WM) microstructure that can be assessed using diffusion tensor imaging (DTI) and multishell applications, such as neurite orientation dispersion and density imaging (NODDI). In this study, we aimed to apply DTI and NODDI to add further insight into PAOS tissue microstructure. Methods Twenty‐two PAOS patients and 26 age‐ and sex‐matched controls, recruited by the Neurodegenerative Research Group (NRG) at Mayo Clinic, underwent diffusion MRI on 3T MRI. Brain maps of fractional anisotropy (FA) and mean diffusivity (MD) from DTI and intracellular volume fraction (ICVF) and isotropic volume fraction (IsoVF) from NODDI were generated. Global WM and GM, and specific WM tracts were identified using tractography and lobar GM regions. Results Global WM differences between PAOS and controls were greatest for ICVF, and global GM differences were greatest for MD and IsoVF. Abnormalities in key WM tracts involved in PAOS, including the body of the corpus callosum and frontal aslant tract, were identified with FA, MD, and ICVF, with excellent differentiation of PAOS from controls (area under the receiver operating characteristic curves >.90). MD and ICVF identified abnormalities in arcuate fasciculus, thalamic radiations, and corticostriatal tracts. Significant correlations were identified between an index of articulatory errors and DTI and NODDI metrics from the arcuate fasciculus, frontal aslant tract, and inferior longitudinal fasciculus. Conclusions DTI and NODDI represent different aspects of brain tissue microstructure, increasing the number of potential biomarkers for PAOS.

Abstract Context Circulating lactate concentration is an important determinant of exercise tolerance. Objective This work aimed to determine the role of hyperglycemia on lactate metabolism during exercise in individuals with type 1 diabetes (T1D). Methods The protocol at the University of Virginia compared 7 T1D participants and 7 participants without diabetes (ND) at euglycemia (5.5 mM) or hyperglycemia (9.2 mM) in random order in T1D and at euglycemia in ND. Intervention included [1-13C] lactate infusion, exercise at 65% maximal oxygen uptake (VO2max), euglycemia, and hyperglycemia visits. The main outcome measure was lactate turnover before, during, and after 60 minutes of exercise at 65% VO2max. Results A 2-compartment model with loss only from the peripheral compartment described lactate kinetics. Volume of distribution of the accessible compartment was similar between T1D and ND individuals (P = .76) and concordant with plasma volume (∼40 mL/kg). Circulating lactate concentrations were higher (P < .001) in T1D participants during exercise at hyperglycemia than euglycemia. Exercise-induced lactate appearance did not differ (P = .13) between hyperglycemia and euglycemia. However, lactate clearance (CL) was lower (P = .03) during hyperglycemia than euglycemia in T1D participants. There were no differences in any of the aforementioned parameters between T1D and ND participants during euglycemia. Conclusion Hyperglycemia modulates lactate metabolism during exercise by lowering CL, leading to higher circulating lactate concentrations in T1D individuals. This novel observation implies that exercise during hyperglycemia can lead to higher circulating lactate concentrations thus increasing the likelihood of reaching the lactate threshold sooner in T1D, and has high translational relevance both for providers and recreationally active people with T1D.

To evaluate deep learning-based calcium segmentation and quantification on ECG-gated cardiac CT scans compared with manual evaluation. Automated calcium quantification was performed using a neural network based on mask regions with convolutional neural networks (R-CNNs) for multi-organ segmentation. Manual evaluation of calcium was carried out using proprietary software. This is a retrospective study of archived data. This study used 40 patients to train the segmentation model and 110 patients were used for the validation of the algorithm. The Pearson correlation coefficient between the reference actual and the computed predictive scores shows high level of correlation (0.84; P < .001) and high limits of agreement (±1.96 SD; −2000, 2000) in Bland–Altman plot analysis. The proposed method correctly classifies the risk group in 75.2% and classifies the subjects in the same group. In total, 81% of the predictive scores lie in the same categories and only seven patients out of 110 were more than one category off. For the presence/absence of coronary artery calcifications, the deep learning model achieved a sensitivity of 90% and a specificity of 94%. Fully automated model shows good correlation compared with reference standards. Automating process reduces evaluation time and optimizes clinical calcium scoring without additional resources.

OBJECTIVES: Systemic thrombolysis improves outcomes in patients with pulmonary embolism (PE) but is associated with the risk of hemorrhage. The data on efficacy and safety of reduced-dose alteplase are limited. The study objective was to compare the characteristics, outcomes, and complications of patients with PE treated with full- or reduced-dose alteplase regimens. DESIGN: Multicenter retrospective observational study. SETTING: Tertiary care hospital and 15 community and academic centers of a large healthcare system. PATIENTS: Hospitalized patients with PE treated with systemic alteplase. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Pre- and post-alteplase hemodynamic and respiratory variables, patient outcomes, and complications were compared. Propensity score (PS) weighting was used to adjust for imbalances of baseline characteristics between reduced- and full-dose patients. Separate analyses were performed using the unweighted and weighted cohorts. Ninety-eight patients were treated with full-dose (100 mg) and 186 with reduced-dose (50 mg) regimens. Following alteplase, significant improvements in shock index, blood pressure, heart rate, respiratory rate, and supplemental oxygen requirements were observed in both groups. Hemorrhagic complications were lower with the reduced-dose compared with the full-dose regimen (13% vs. 24.5%, p = 0.014), and most were minor. Major extracranial hemorrhage occurred in 1.1% versus 6.1%, respectively (p = 0.022). Complications were associated with supratherapeutic levels of heparin anticoagulation in 37.5% of cases and invasive procedures in 31.3% of cases. The differences in complications persisted after PS weighting (15.4% vs. 24.7%, p = 0.12 and 1.3% vs. 7.1%, p = 0.067), but did not reach statistical significance. There were no significant differences in mortality, discharge destination, ICU or hospital length of stay, or readmission after PS weighting. CONCLUSIONS: In a retrospective, PS-weighted observational study, when compared with the full-dose, reduced-dose alteplase results in similar outcomes but fewer hemorrhagic complications. Avoidance of excessive levels of anticoagulation or invasive procedures should be considered to further reduce complications.

Abstract Multisource feedback has long been a recommended tool to assess clinical competencies within graduate medical education. Additionally, incorporating feedback supplied by patients and other members of the healthcare team can provide the framework to bridge perspectives and viewpoints that may be different from their own. This, in effect, can aid in fortifying values in diversity, equity, and inclusivity by developing more knowledgeable, empathetic, and respectful future healthcare providers.

Abstract Background Carbapenem-resistant Enterobacterales (CRE) are an urgent public health threat in the United States. Objective Describe the clinical and molecular epidemiology of CRE in a multicenter pediatric cohort. Methods CRACKLE-1 and CRACKLE-2 are prospective cohort studies with consecutive enrollment of hospitalized patients with CRE infection or colonization between 24 December 2011 and 31 August 2017. Patients younger than age 18 years and enrolled in the CRACKLE studies were included in this analysis. Clinical data were obtained from the electronic health record. Carbapenemase genes were detected using polymerase chain reaction and whole-genome sequencing. Results Fifty-one children were identified at 18 healthcare system study sites representing all U.S. census regions. The median age was 8 months, with 67% younger than age 2 years. Median number of days from admission to culture collection was 11. Seventy-three percent of patients had required intensive care and 41% had a history of mechanical ventilation. More than half of children had no documented comorbidities (Q1, Q3 0, 2). Sixty-seven percent previously received antibiotics during their hospitalization. The most common species isolated were Enterobacter species (41%), Klebsiella pneumoniae (27%), and Escherichia coli (20%). Carbapenemase genes were detected in 29% of isolates tested, which was lower than previously described in adults from this cohort (61%). Thirty-four patients were empirically treated on the date of culture collection, but only 6 received an antibiotic to which the CRE isolate was confirmed susceptible in vitro. Thirty-day mortality was 13.7%. Conclusions CRE infection or colonization in U.S. children was geographically widespread, predominantly affected children younger than age 2 years, associated with significant mortality, and less commonly caused by carbapenemase-producing strains than in adults.