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Background: Patients with atrial fibrillation (AF) remain at increased risk of thromboembolism despite apparent maintenance of sinus rhythm with the cause often attributed to periods of asymptomatic AF. Atrial mechanical discordance, with the body of the left atrium (LA) in sinus rhythm and the left atrial appendage (LAA) in AF may also be a contributor., Objectives: The purpose of this study was to assess the frequency of electrocardiogram (ECG) rhythm and LAA and/right atrial appendage (RAA) Doppler ejection phenotype (transesophageal echocardiography [TEE]) discordance in patients undergoing cardiac surgery., Methods: A total of 124 patients undergoing coronary artery bypass graft (CABG), CABG and valve surgery, or isolated valve repair or replacement (valve ± CABG) were prospectively studied. Intraoperative surface ECG rhythm strip and TEE were performed before cardiopulmonary bypass. The ECG and TEE LAA/RAA Doppler spectrum were independently classified as sinus or AF., Results: Of 107 patients (age 65 ± 12 years; 31% female; 65% CABG, 31% valve ± CABG) without a history of AF, 39 (36%) had ECG and LAA and/or RAA discordance (ECG/LAA Doppler discordance, n = 12 [11%]; ECG/RAA Doppler discordance, n = 35 [33%]). There was no significant difference between concordant and discordant groups with regard to age, gender, history of hypertension, diabetes, heart failure, or stroke (all P  > 0.05)., Conclusions: A large minority of patients without a history of AF undergoing cardiac surgery have ECG/atrial appendage Doppler discordance, a setting that may promote thromboembolism in non-anticoagulated patients. Clinical parameters do not identify patients at increased risk for discordance., Competing Interests: Dr Cai is supported by Beijing Hospitals Authority Youth Programme, code: QML 20180302 and Young Scientists Fund of the 10.13039/501100001809National Natural Science Foundation of China, code NSFC 81601497. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.PERSPECTIVESCOMPETENCY IN MEDICAL KNOWLEDGE: In a large minority of patient undergoing cardiac surgery without a prior history of AF, transesophageal Doppler echocardiography demonstrates an AF atrial appendage phenotype, despite SR on the surface electrocardiogram. TRANSLATIONAL OUTLOOK: These findings identify a novel mechanism for stroke in the absence of electrocardiographic AF., (© 2024 The Authors.)

Research with enhanced potential pandemic pathogens (ePPP) makes pathogens substantially more lethal, communicable, immunosuppressive or otherwise capable of triggering a pandemic. We briefly relay an existing argument that the benefits of ePPP research do not outweigh its risks and then consider why proponents of these arguments continue to confidently endorse them. We argue that these endorsements may well be the product of common cognitive biases-in which case they would provide no challenge to the argument against ePPP research. If the case against ePPP research is strong, the views of professional experts do little to move the needle in favour of ePPP research., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

What changes people's judgments on moral issues, such as the ethics of abortion or eating meat? On some views, moral judgments result from deliberation, such that reasons and reasoning should be primary drivers of moral change. On other views, moral judgments reflect intuition, with reasons offered as post-hoc rationalizations. We test predictions of these accounts by investigating whether exposure to a moral philosophy course (vs. control courses) changes moral judgments, and if so, via what mechanism(s). In line with deliberative accounts of morality, we find that exposure to moral philosophy changes moral views. In line with intuitionist accounts, we find that the mechanism of change is reduced reliance on intuition, not increased reliance on deliberation; in fact, deliberation is related to increased confidence in judgments, not change. These findings suggest a new way to reconcile deliberative and intuitionist accounts: Exposure to reasons and evidence can change moral views, but primarily by discounting intuitions., Competing Interests: Declaration of Competing Interest We have no known conflicts of interest to disclose. All pre-registrations, materials, analysis scripts, and data available at https://osf.io/y5tdu/. We are grateful to Eric Schwitzgebel and members of the Concepts and Cognition Lab for valuable feedback on this research., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Primary extraosseous intracranial Ewing's sarcoma, also known as a peripheral primitive neuroectodermal tumor or "small round blue cell tumor," is an extremely rare entity with limited representation in the literature beyond the pediatric population., Observations: A 67-year-old male suffering occipital headache, nausea, and gait disturbance was found to have a large, avidly contrast-enhancing cerebellopontine angle mass extending into the cervical spinal canal with associated mass effect on medulla, cerebellum, fourth ventricle, and cervical spinal cord. This mass was not present on the imaging from 8 years prior. He underwent surgical debulking and pathology results demonstrated a malignant small round cell tumor showing diffuse immunopositivity for cytokeratins, CD99 and NKX2.2 with EWRS1-FLI1 rearrangement in 84% of the nuclei confirmatory of Ewing's sarcoma. After 14 cycles of chemotherapy and 6 weeks of radiotherapy, 22 months after discovery, the patient remains in clinical and radiographic remission with complete return to his baseline functioning., Lessons: Primary skull base extraosseous Ewing's sarcoma should be considered in the differential diagnosis even in the elderly population when imaging studies demonstrate aggressive tumor growth patterns. Tumor debulking to establish a diagnosis followed by adjuvant chemoradiation therapy can result in clinical improvement with remission.

Patients frequently visit the emergency department with conditions that place them at risk of worse outcomes when accompanied by coagulopathy. Routine tests of coagulation-prothrombin time, partial thromboplastin time, platelets, and fibrinogen-have shortcomings that limit their use in providing emergency care. One alternative is to investigate coagulation disturbance with viscoelastic monitoring (VEM), a coagulation test that measures the timing and strength of blood clot development in real time. VEM is widely used and studied in cardiac surgery, liver transplant surgery, anesthesia, and trauma. In this article, we review the technique of VEM and the biologic rationale of using it in addition to routine tests of coagulation in emergency clinical situations. Then, we review the evidence (or lack thereof) for using VEM in the diagnosis and treatment of specific conditions. Finally, we describe the limitations of the test and future directions for clinical use and research in emergency medicine., (Copyright © 2020 American College of Emergency Physicians. Published by Elsevier Inc. All rights reserved.)

Objective: Transcranial magnetic stimulation (TMS) can cause seizures in healthy individuals and patients. However, the rate at which this occurs is unknown. We estimated the risk of seizure and other adverse events with TMS., Methods: We surveyed laboratories and clinics about seizures and other events observed between 2012 and 2016 (inclusive). Respondents (N = 174) reported an estimated 318,560 TMS sessions., Results: Twenty-four seizures were reported (.08/1000 sessions). TMS delivered within published guidelines to subjects without recognized risk factors caused 4 seizures (<.02/1000 sessions). High-frequency (>1 Hz) rTMS delivered within published guidelines to individuals without known risk factors was no more likely to cause seizures than low-frequency and single/paired-pulse TMS. Subject risk factors (e.g., brain lesions and epilepsy) increased seizure risk substantially. Seizures appeared more common when safety guidelines were exceeded. Seizures were most likely to occur within the first few exposures to TMS., Conclusions: TMS delivered within published guidelines to individuals without risk factors appears to cause fewer than 1 seizure per 60,000 sessions. The assumption that repetitive TMS is riskier than single and paired pulses under these conditions should be reevaluated., Significance: This information should help laboratories, clinics, and regulatory authorities form updated safety policies for TMS., (Copyright © 2019 International Federation of Clinical Neurophysiology. All rights reserved.)

Nicotinamide adenine dinucleotide (NAD + ) extends longevity in experimental organisms, raising interest in its impact on human health. De novo NAD + biosynthesis from tryptophan is evolutionarily conserved yet considered supplanted among higher species by biosynthesis from nicotinamide (NAM). Here we show that a bottleneck enzyme in de novo biosynthesis, quinolinate phosphoribosyltransferase (QPRT), defends renal NAD + and mediates resistance to acute kidney injury (AKI). Following murine AKI, renal NAD + fell, quinolinate rose, and QPRT declined. QPRT +/- mice exhibited higher quinolinate, lower NAD + , and higher AKI susceptibility. Metabolomics suggested an elevated urinary quinolinate/tryptophan ratio (uQ/T) as an indicator of reduced QPRT. Elevated uQ/T predicted AKI and other adverse outcomes in critically ill patients. A phase 1 placebo-controlled study of oral NAM demonstrated a dose-related increase in circulating NAD + metabolites. NAM was well tolerated and was associated with less AKI. Therefore, impaired NAD + biosynthesis may be a feature of high-risk hospitalizations for which NAD + augmentation could be beneficial.

Anaplastic large cell lymphoma (ALCL) is a rare type of non-Hodgkin lymphoma that can involve the skin primarily or secondarily. Our case describes an unusual presentation of eruptive tumors localized to the leftbreast region several years following breast cancer surgery and radiation for carcinoma of the breast. This report highlights the challenges in reachingthe diagnosis of an aggressive systemic lymphoma presenting on the skin.

Background: Tumor stage and folliculotropic mycosis fungoides are uncommon subtypes of cutaneous T-cell lymphoma (CTCL) with an aggressive disease course. Romidepsin is a histone deacetylase inhibitor approved by the US Food and Drug Administration for patients with CTCL who have received ≥ 1 previous systemic therapy. In the present study, we examined the efficacy and safety of romidepsin in patients from the pivotal, single-arm, open-label, phase II study of relapsed or refractory CTCL with cutaneous tumors and/or folliculotropic disease involvement., Materials and Methods: Patients with CTCL who had received ≥ 1 previous systemic therapy received romidepsin at 14 mg/m 2 on days 1, 8, and 15 of 28-day cycles. Responses were determined by a composite endpoint (assessments of the skin, blood, and lymph nodes). Patients with cutaneous tumors and/or folliculotropic disease involvement were identified by review of diagnosis and histology reports., Results: The objective response rate to romidepsin was 45% in patients with cutaneous tumors (n = 20) and 60% in patients with folliculotropic disease involvement (n = 10)., Conclusion: Romidepsin is active in subtypes of CTCL with less favorable outcomes, such as tumor stage and folliculotropic mycosis fungoides., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Objectives: The objective of this study was to characterize the association between lactate levels and hospital length of stay (LOS) after cardiac surgery., Design: A retrospective study using prospectively collected data from the Society of Thoracic Surgeons adult cardiac surgery database., Setting: A tertiary-care hospital., Participants: Patients in the database who presented for major cardiac surgery between 2002 and 2014 and whose lactate level was measured within 3 hours after skin closure., Interventions: None., Measurements and Main Results: The authors performed multivariable linear regression with adjustment for more than 30 variables to assess the association between postoperative lactate levels and hospital LOS. The study included 1,208 patients whose median LOS was 6 days (quartiles: 5, 9). Median LOS in the low-, moderate-, and high-lactate groups was 5 days (quartiles: 4, 7), 6 days (quartiles: 5, 9) and 9 days (quartiles: 6, 17), respectively; p<0.001. In multivariable analysis, patients with a moderate lactate level had a 1.08 times (95% CI: 1.00-1.17; p = 0.04) longer LOS compared with those with a low lactate level. Patients with a high lactate level had a 1.12 times (95% CI: 1.00-1.26; p = 0.04) longer LOS compared with those with a low lactate level. Lactate levels also were associated with intensive care unit LOS and nonsurgical postoperative complications., Conclusions: Postoperative lactate levels are associated with increased hospital LOS for patients undergoing major cardiac surgery., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Purpose: AND-34/BCAR3 (Breast Cancer Anti-Estrogen Resistance 3) associates with the focal adhesion adaptor protein, p130CAS/BCAR1. Expression of AND-34 regulates epithelial cell growth pattern, motility, and growth factor dependence. We sought to establish the effects of the loss of AND-34 expression in a mammalian organism., Methods: AND-34(-/-) mice were generated by homologous recombination. Histopathology, in situ hybridization, and western blotting were performed on murine tissues., Results: Western analyses confirmed total loss of expression in AND-34(-/-) splenic lymphocytes. Mice lacking AND-34 are fertile and have normal longevity. While AND-34 is widely expressed in wild type mice, histologic analysis of multiple organs in AND-34(-/-) mice is unremarkable and analyses of lymphocyte development show no overt changes. A small percentage of AND-34(-/-) mice show distinctive small white eye lesions resulting from the migration of ruptured cortical lens tissue into the anterior chamber. Following initial vacuolization and liquefaction of the lens cortex first observed at postnatal day three, posterior lens rupture occurs in all AND-34(-/-) mice, beginning as early as three weeks and seen in all mice at three months. Western blot analysis and in situ hybridization confirmed the presence of AND-34 RNA and protein in lens epithelial cells, particularly at the lens equator. Prior data link AND-34 expression to the activation of Akt signaling. While Akt Ser 473 phosphorylation was readily detectable in AND-34(+/+) lens epithelial cells, it was markedly reduced in the AND-34(-/-) lens epithelium. Basal levels of p130Cas phosphorylation were higher in AND-34(+/+) than in AND-34(-/-) lens epithelium., Conclusions: These results demonstrate the loss of AND-34 dysregulates focal adhesion complex signaling in lens epithelial cells and suggest that AND-34-mediated signaling is required for maintenance of the structural integrity of the adult ocular lens.

Microsatellite primers are often developed in one species and used to assess neutral variability in related species. Such analyses may be confounded by ascertainment bias (i.e. a decline in amplification success and allelic variability with increasing genetic distance from the source of the microsatellites). In addition, other factors, such as the size of the microsatellite, whether it consists of perfect or interrupted tandem repeats, and whether it is autosomal or X-linked, can affect variation. To test the relative importance of these factors on microsatellite variation, we examine patterns of amplification and allelic diversity in 52 microsatellite loci amplified from five individuals in each of six populations of Cyrtodiopsis stalk-eyed flies that range from 2.2 % to 11.2% mitochondrial DNA sequence divergence from the population used for microsatellite development. We find that amplification success and most measures of allelic diversity declined with genetic distance from the source population, in some cases an order of magnitude faster than in birds or mammals. The median and range of the repeat array length did not decline with genetic distance. In addition, for loci on the X chromosome, we find evidence of lower observed heterozygosity compared with loci on autosomes. The differences in variability between X-linked and autosomal loci are not adequately explained by differences in effective population sizes of the chromosomes. We suggest, instead, that periodic selection events associated with X-chromosome meiotic drive, which is present in many of these populations, reduces X-linked variation.

AND-34 is a murine protein that binds by a cdc25-like GDP exchange factor domain to the focal adhesion docking protein p130Cas. Overexpression of either of the human homologues of AND-34 and p130Cas, BCAR3 and BCAR1, respectively, has been reported to induce resistance to antiestrogens in breast cancer cell lines. Here we show that overexpression of AND-34 leads to activation of the Rho family GTPases Cdc42 and Rac. Consistent with these findings, BCAR3 overexpression induced alterations in F-actin distribution and augmented both autophosphorylation and kinase activity of the Cdc42/Rac-responsive serine/threonine kinase PAK1. p130Cas-associated BCAR3 protein was detected in the estrogen-independent breast cancer cell line 578-T, but not in estrogen-dependent MCF7 or ZR-75-1 cells. Stable ZR-75-1 transfectants overexpressing BCAR3, but not vector-only transfectants, grew in the presence of the pure antiestrogen ICI 182,780. Stable transfection with RacV12, a constitutively active form of Rac1, also induced antiestrogen resistance in ZR-75-1 cells. Transient transfection of BCAR3 in estrogen-dependent MCF7 cells induced activation of luciferase constructs containing the proximal 1745 or 163 bp but not 66 bp of the cyclin D1 promoter. Such cyclin D1 promoter activation was inhibited by dominant negative forms of Rac1 and PAK1. Overexpression of the PAK1 autoinhibitory domain (residues 83-149) but not an inactive PAK1 autoinhibitory domain point mutant (L107F) also blocked BCAR3-mediated cyclin D1 activation. These studies suggest that AND-34/BCAR3 induces antiestrogen resistance in breast cancer cell lines by a Rac1- and PAK1-dependent pathway.

Given our interest in cyclic nucleotide phosphodiesterase inhibitors in chronic lymphocytic leukemia (CLL), we studied the effects of sulindac sulfone (exisulind), a non- cyclooxygenase-inhibitory end metabolite of the NSAID sulindac that has been reported to inhibit cGMP phosphodiesterases. We focused on a novel benzylamide analogue of sulindac sulfone, CP461, which is in clinical trials as a chemotherapeutic agent. As previously reported for colon carcinoma cell lines, we found that CP461 induced a rise in cGMP levels and blocked cell proliferation in the CLL cell line WSU-CLL. Surprisingly, however, cell cycle analysis revealed that CP461 caused G(2)-M arrest with an EC(50) of 1.1 micro M. G(2)-M arrest was associated with phosphorylation of Bcl2 (but not BAD, Bax, or Bcl-XL): both of these end points were abrogated by treatment with a calcium chelator. Although CP461 induces p53 up-regulation, G(2)-M arrest and Bcl2 phosphorylation were independent of p53. Because microtubule-active drugs such as vincristine also induced G(2)-M arrest and Bcl2 phosphorylation in WSU-CLL, whereas the genotoxic drugs etoposide and doxorubicin did not, we examined the effect of CP461 on microtubules by indirect immunofluoresence microscopy. CP461 eliminated microtubules rapidly, with reduction detected within 30 min of drug treatment. CP461 also induced marked changes in cell shape. Neither sulindac sulfide (a cyclooxygenase inhibitor) nor sulindac sulfone induced G(2)-M arrest, Bcl2 phosphorylation, microtubule disassembly, or cell shape changes. Treatment with 30 micro M CP461 induced greater than 50% apoptosis in 10 of 10 primary CLL leukemic cell samples, whereas the same drug concentration had only marginal effects (14% apoptosis) on whole mononuclear cells. Our work demonstrates that addition of a benzylamide moiety to sulindac compounds results in markedly altered pharmacological properties that may be of use in the therapy of lymphoid malignancies.

Purpose: cAMP phosphodiesterase (PDE) 4 is a family of enzymes the inhibition of which induces chronic lymphocytic leukemia (CLL) apoptosis. However, leukemic cells from a subset of CLL patients are relatively resistant to treatment with the PDE4 inhibitor rolipram, particularly when this drug is used in the absence of an adenylate cyclase stimulus such as forskolin. Elevated cAMP levels induce compensatory up-regulation of several cyclic nucleotide PDE families in other model systems. We here examine the hypothesis that CLL cells that survive treatment with rolipram do so as a result of residual PDE activity that is not inhibited by this drug., Experimental Design: We examined by Western analysis the effect of rolipram treatment on CLL expression of PDE3B, PDE4A, PDE4B, PDE4D, and PDE7A. We also examined the ability of rolipram (PDE4 inhibitor) or cilostamide (PDE3 inhibitor), alone or together, to induce apoptosis or elevate cyclic AMP in leukemic cells from patients with CLL., Results: Rolipram increased levels of PDE4B and, to a variable extent, PDE4D. When combined with forskolin, rolipram also increased levels of a second family of PDEs, PDE3B. Addition of the specific PDE3 inhibitor, cilostamide, modestly augmented rolipram-induced apoptosis in five of seven "rolipram-resistant" CLL samples., Conclusions: Although this work confirms that PDE4 appears to be the most important PDE target for induction of apoptosis in CLL, combination therapy with PDE3 and PDE4 inhibitors or use of dual-selective drugs may be of benefit in a subset of relatively PDE4-inhibitor resistant CLL patients.