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Background Recent data suggest that colchicine may reduce cardiovascular events among patients presenting with acute coronary syndromes. This sub-study of the Australian COPS trial aimed to assess whether colchicine affects health status outcomes. Methods Health status was assessed at baseline and 12-months using the EuroQol-5 Dimension 5-level (EQ-5D-5L) score and the full 19-question Seattle Angina Questionnaire (SAQ). Data were available for 786 patients (388 randomized to colchicine, 398 to placebo). Results Baseline characteristics were well matched between groups; mean age was 60.1 (SD 14.8) years, and 20% were female. Baseline health status scores were impaired, and most parameters demonstrated significant improvement from baseline to 12-months (EQ-5D-5L Visual Analogue Score [VAS] 69.3 to 77.7; SAQ angina frequency score 83.0 to 95.3, both p Conclusions Treatment with colchicine did not appear to affect change in measures of health status following acute coronary syndromes, but it did lead to a greater likelihood of improvement in physical limitation scores. Funding Acknowledgement Type of funding sources: Public hospital(s). Main funding source(s): Peninsula Health, Monash University

The p63 transcription factor, a member of the p53 family, plays an oncogenic role in squamous cancers, while in breast cancers its expression is often repressed. In the canonical conserved Hippo pathway, known to play a complex role in regulating growth of cancer cells, the protein kinases MST1/2 and LATS1/2 act sequentially to phosphorylate and inhibit the YAP/TAZ transcription factors. We found that in the MCF10A mammary epithelial cell line as well as in squamous and breast cancer cell lines, expression of ΔNp63 RNA and protein is strongly repressed by inhibition of the Hippo pathway protein kinases in a manner that is independent of p53. While MST1/2 and LATS1 are required for p63 expression, the next step of the pathway, namely phosphorylation and degradation of the YAP/TAZ transcriptional activators is not required for repression of p63. This suggests that regulation of p63 expression occurs by a non-canonical version of the Hippo pathway. We additionally identified additional genes that were similarly regulated suggesting the broader importance of this pathway. Interestingly, we observed that experimentally lowering p63 expression leads to increased YAP protein levels, thereby constituting a feedback loop. These results, which reveal the intersection of the Hippo and p63 pathways, may prove useful for the control of their activities in cancer cells.One Sentence SummaryRegulation of p63 expression occurs by a non-canonical version of the Hippo pathway in mammary epithelial, breast carcinoma and head and neck squamous carcinoma cells

A retrospective cohort study in a predominantly Black population undergoing standard treatment for lupus nephritis (LN) was used to estimate the incidence of and risk factors for Complete Response (CR) according to modified ALMS and BLISS criteria by 12 months.Patients with biopsy-proven LN class III or IV ± V, urine protein to creatinine ratio (uPCR) ≥1 gm/gm and eGFR 50 ml/min/1.73 mOut of 173 patients, 86.1% were female, 77.5% were Black, and over half (59.5%) had non-commercial insurance. By 12 months, 20.6% (95% CI: 14.6-28.6%) achieved mALMS CR and 33.7% (95% CI: 26.4-42.4%) achieved mBLISS CR. Factors associated with mBLISS CR were commercial insurance (adjusted CR-Ratio=3.5; 95% CI: 1.9 to 6.7; P 0.001), albumin (adjusted CR-Ratio = 1.8 per 1 g/dL ↑ in albumin; P = 0.02), and low C4 (adjusted CR-Ratio = 2.6; P = 0.03). Cumulative incidence of ESRD at 3 years was 23.1% (95% CI: 15.7-31.3%) and 6.1% (95% CI: 2.8-11.1%) for mortality. Patients with non-commercial insurance were more likely to develop ESRD with cumulative incidence of 30.4% (95% CI: 19.6-41.9%) vs 12.7% (95% CI: 5.0-24.2%) for patients with commercial insurance (P = 0.024).In a primarily Black, uninsured LN population, despite achieving similar CR rates at 12 months, the incidence of ESRD and mortality exceeded those observed in controlled clinical trials with placebo arms.

Despite advances in the overall management of acute myocardial infarction (AMI), cardiogenic shock in the setting of AMI (CS-AMI) continues to be associated with poor patient outcomes. There are multiple devices that can be used in CS-AMI to support the failing circulation, although their utility in improving outcomes as compared with conventional pharmacotherapy of vasopressors and inotropes remains to be established. This contemporary review provides an update on the evidence base for each of these techniques. In CS-AMI, acute thrombotic occlusion of a major epicardial artery leads to hypoxia and myocardial ischaemia in the territory subtended by that vessel. The resultant regional dysfunction in myocardial contractility can severely compromise stroke volume and result in acute circulatory failure, systemic hypoperfusion, lactic acidosis, multi-organ failure and ultimately death.

Colchicine, thought to exert its effect via reduction of inflammation, has recently been studied in patients following acute coronary syndromes (ACS). We performed a meta-analysis of all available randomized controlled trials (RCTs) in this high-risk cohort, evaluating efficacy and safety.MEDLINE, PubMed, EMBASE, clinical trial registries, and select conference proceedings were searched for RCTs comparing colchicine to placebo in patients following ACS. The primary outcome was trial-defined major adverse cardiovascular events (MACE). Secondary endpoints included stroke, myocardial infarction (MI), all-cause and cardiovascular death, and urgent revascularization. Analysis was performed at the longest available clinical follow-up.Two RCTs with a pooled sample size of 5540 patients with 2778 (50.1%) receiving colchicine and 2762 (49.9%) placebo were included. In order to maximize consistency, composite efficacy endpoints between trials were modified. Compared to placebo, patients receiving colchicine had reduction in study-defined composite endpoint (5.5% vs. 7.6%) OR 0.67 (95% CI 0.46-0.98, p = 0.04, IThese data suggest colchicine, in addition to guideline-directed medical therapy following acute coronary syndrome reduces MACE, cerebrovascular accidents, and rates of urgent revascularization at 2 years of follow-up.

The GaCl3-catalyzed [4 + 2] cycloaddition between alkoxy- and aryl-activated donor-acceptor cyclobutane diesters and cis-diazene 1a (4-phenyl-1,2,4-triazoline-3,5-dione, PTAD) is disclosed. The reaction provides hexahydropyridazine derivatives as single diastereomers in good to excellent yields in most cases. The structural assignment of the cycloadduct 3b was unambiguously established by single-crystal X-ray diffraction.

The p53 tumor suppressor protein, known to be critically important in several processes including cell-cycle arrest and apoptosis, is highly regulated by multiple mechanisms, most certifiably the Murine Double Minute 2–Murine Double Minute X (MDM2–MDMX) heterodimer. The role of MDM2–MDMX in cell-cycle regulation through inhibition of p53 has been well established. Here we report that in cells either lacking p53 or expressing certain tumor-derived mutant forms of p53, loss of endogenous MDM2 or MDMX, or inhibition of E3 ligase activity of the heterocomplex, causes cell-cycle arrest. This arrest is correlated with a reduction in E2F1, E2F3, and p73 levels. Remarkably, direct ablation of endogenous p73 produces a similar effect on the cell cycle and the expression of certain E2F family members at both protein and messenger RNA levels. These data suggest that MDM2 and MDMX, working at least in part as a heterocomplex, may play a p53-independent role in maintaining cell-cycle progression by promoting the activity of E2F family members as well as p73, making them a potential target of interest in cancers lacking wild-type p53.

Current methods to differentiate human embryonic stem cells (hESCs) towards neural lineages are predominantly based on costly biochemical reagents and complex physical cues. These existing methods are seriously hindered by extensive time requirements and low yield. However, stem cells use in clinical applications requires the quantity and quality of the cells while remaining cost efficient. Innovative approaches that overcome these current constraints and enhance the successful rate of motor neuron transplantation are in critical demand. Iron, a trace element, is essential for development and function of the central nervous system. The effects of ferric ions on the neuronal differentiation have yet to be shown. We utilize elevated ferric concentrations to drastically curtail the differentiation rate of hESCs, effectively enumerating motor neuron phenotype. This innovative protocol can expedite the generation of motor neurons for regenerative medicine in an economical and time efficient manner. The neuron like derived stem cells with iron expressed increased levels of motor neuron markers HOXB4 and HB9. Furthermore, the iron treatment was able to generate more matured and functional motor-neuron-like cells that are ~1.5 times more sensitive to depolarization when compared to the control. Our method provides an expedited approach to harvest motor-neuron-like cells for disease, traumatic injury regeneration, and drug screening

Despite advances in the overall management of acute myocardial infarction (AMI), cardiogenic shock in the setting of AMI (CS-AMI) continues to be associated with poor patient outcomes. There are multiple devices that can be used in CS-AMI to support the failing circulation, although their utility in improving outcomes as compared with conventional pharmacotherapy of vasopressors and inotropes remains to be established. This contemporary review provides an update on the evidence base for each of these techniques. In CS-AMI, acute thrombotic occlusion of a major epicardial artery leads to hypoxia and myocardial ischaemia in the territory subtended by that vessel. The resultant regional dysfunction in myocardial contractility can severely compromise stroke volume and result in acute circulatory failure, systemic hypoperfusion, lactic acidosis, multi-organ failure and ultimately death.

Boundary conditions for Majorana fermions in d=1+1 dimensions fall into one of two SPT phases, associated to a mod 2 anomaly. Here we consider boundary conditions for 2N Majorana fermions that preserve a $U(1)^N$ symmetry. In general, the left-moving and right-moving fermions carry different charges under this symmetry, and implementation of the boundary condition requires new degrees of freedom, which manifest themselves in a boundary central charge, $g$. We follow the boundary RG flow induced by turning on relevant boundary operators. We identify the infra-red boundary state. In many cases, the boundary state flips SPT class, resulting in an emergent Majorana mode needed to cancel the anomaly. We show that the ratio of UV and IR boundary central charges is given by $g^2_{IR} / g^2_{UV} = {\rm dim}\,({\cal O})$, the dimension of the perturbing boundary operator. Any relevant operator necessarily has ${\rm dim}({\cal O}) < 1$, ensuring that the central charge decreases in accord with the g-theorem., 47 pages. v2: references added

Resolution measurements were made using 14.1 MeV neutrons from a high-yield, portable DT neutron generator and a neutron camera based on a scintillation screen viewed by a digital camera. Resolution measurements were made using a custom-built, plastic, USAF-1951 resolution chart, of dimensions 125 &times, 98 &times, 25.4 mm3, and by calculating the modulation transfer function from the edge-spread function from edges of plastic and steel objects. A portable neutron generator with a yield of 3 &times, 109 n/s (DT) and a spot size of 1.5 mm was used to irradiate the object with neutrons for 10 min. The neutron camera, based on a 6LiF/ZnS:Cu-doped polypropylene scintillation screen and digital camera was placed at a distance of 140 cm, and produced an image with a spatial resolution of 0.35 cycles per millimeter.

In principle, there is no obstacle to gapping fermions preserving any global symmetry that does not suffer a 't Hooft anomaly. In practice, preserving a symmetry that is realised on fermions in a chiral manner necessitates some dynamics beyond simple quadratic mass terms. We show how this can be achieved using familiar results about supersymmetric gauge theories and, in particular, the phenomenon of confinement without chiral symmetry breaking. We present simple models that gap fermions while preserving a symmetry group under which they transform in chiral representations. For example, we show how to gap a collection of 4d fermions that carry the quantum numbers of one generation of the Standard Model, but without breaking electroweak symmetry. We further show how to gap fermions in groups of 16 while preserving certain discrete symmetries that exhibit a mod 16 anomaly., 21 pages. v2: references added

Percutaneous coronary intervention (PCI) of severely calcified lesions is known to result in lower procedural success rates, higher complication rates, and worse long-term clinical outcomes compared to noncalcified lesions. Adequate lesion preparation through calcium modification is crucial in ensuring procedural success and reducing adverse cardiovascular outcomes. There are numerous calcium modification devices currently available whose usefulness depends on the nature of the calcific disease and its anatomical distribution. It can be challenging for the interventionists to decide which device is best suited for their patient. There is also emerging evidence for intravascular imaging in guiding selection of calcium modification devices using parameters such as calcium distribution and depth that directly impact on procedural success and clinical outcomes. In this review we aim to discuss the pathophysiology of coronary calcification, evaluate strategies and technologies of calcium modification and propose an A-M-A-S-A algorithm in managing calcified coronary lesions.

The GaCl

Eight Majorana fermions in $d=1+1$ dimensions enjoy a triality that permutes the representation of the $SO(8)$ global symmetry in which the fermions transform. This triality plays an important role in the quantization of the superstring, and in the analysis of interacting topological insulators and the associated phenomenon of symmetric mass generation. The purpose of these notes is to provide an introduction to the triality and its applications, with careful attention paid to various ${\bf Z}_2$ global and gauge symmetries and their coupling to background spin structures., 19 pages plus 2 appendices. v2: Typos fixed

Introduction: IV rt-PA guidelines exclude therapeutically anticoagulated or thrombocytopenic patients. These exclusion criteria may limit thrombolytic therapy to patients who might benefit, especially with the increased use of novel oral anticoagulants (NOACs). The objective of this study is to determine if IV rt-PA is safe, especially in this patient population. Methods: Retrospective analysis of IV rt-PA treated patients receiving oral anticoagulation (warfarin (INR > 1.7)), novel oral anticoagulant (NOAC), therapeutic heparin, low-molecular weight heparin (LMWH), or with thrombocytopenia (platelets < 100K). Patients were treated using SMART criteria (consent obtained for off label rt-PA use). Safety was evaluated by symptomatic intracerebral hemorrhage (sICH) rate ≤36hr after treatment. Results: 81 patients were identified. 35 patients received therapeutic warfarin and 1 had coagulopathy (unclear etiology); mean INR=2.2 (range 1.7-3). 5 received therapeutic IV heparin, 6 full dose (1 mg/kg BID) LMWH, and 22 therapeutic NOACs. 12 had thrombocytopenia (mean platelet count 77K). There was a consistent increase in NOAC use in this cohort; 25% of the patients were taking NOACs from 2012-14, increasing to 71% from 2015-17. Out of all patients, 7 received intra-arterial (IA) rt-PA, and 8 thrombectomy. There were 3 sICH (3.75%), none in patients taking NOACs; for all sICHs there were mitigating factors that contributed (undiagnosed malignancy, adjunctive IA rt-PA, incorrect time of onset). Two developed hematoma at the catheter site with no clinical effect. Conclusions: These data suggest that IV rt-PA can be safely administered in therapeutically anticoagulated and thrombocytopenic patients, and sICH rates were similar to the NINDS cohort. The use of IV rt-PA in these patients may increase eligibility for acute stroke therapy, particularly where IA therapy is unavailable. Furthermore, preliminary results for patients taking NOACs indicate a good safety profile in this growing subpopulation.

We study boundary states for Dirac fermions in d=1+1 dimensions that preserve Abelian chiral symmetries, meaning that the left- and right-moving fermions carry different charges. We derive simple expressions, in terms of the fermion charge assignments, for the boundary central charge and for the ground state degeneracy of the system when two different boundary conditions are imposed at either end of an interval. We show that all such boundary states fall into one of two classes, related to SPT phases supported by (-1)^F, which are characterised by the existence of an unpaired Majorana zero mode., 41 pages. v2: reference added, minor corrections. v3: more references added; version accepted for publication in JHEP

We explore the phase structure of the Standard Model as the relative strengths of the SU(2) weak force and SU(3) strong force are varied. With a single generation of fermions, the structure of chiral symmetry breaking suggests that there is no phase transition as we interpolate between the SU(3)-confining phase and the SU(2)-confining phase. Remarkably, the massless left-handed neutrino, familiar in our world, morphs smoothly into a massless right-handed down-quark. With multiple generations, a similar metamorphosis occurs, but now proceeding via a phase transition. In the second half of the paper we introduce a two-parameter extension of the Standard Model, a chiral gauge theory with gauge group U(1) x Sp(r) x SU(N). We again explore the phase structure of the theory as the relative strengths of the Sp(r) and SU(N) gauge couplings vary., Comment: 21+18 pages. v2 typos corrected and reference added, version to accepted for publication in SciPost

Cycloadditions of strained carbocycles promoted by Lewis acids are powerful methods to construct heterocyclic frameworks. In fact, the formal [3+2] cycloadditions of donor-acceptor (DA) cyclopropanes with nitriles has seen particular success in synthesis. In this work, we report on the first [4+2] cycloaddition of nitriles with DA cyclobutanes by Lewis acid activation. Tetrahydropyridine derivatives were obtained in up to 91 % yield from various aryl-activated cyclobutane diesters and aliphatic or aromatic nitriles.

Cycloadditions of strained carbocycles promoted by Lewis acids are powerful methods to construct heterocyclic frameworks. In fact, the formal [3+2] cycloadditions of donor-acceptor (DA) cyclopropanes with nitriles has seen particular success in synthesis. In this work, we report on the first [4+2] cycloaddition of nitriles with DA cyclobutanes by Lewis acid activation. Tetrahydropyridine derivatives were obtained in up to 91 % yield from various aryl-activated cyclobutane diesters and aliphatic or aromatic nitriles.

Quantum Hall matrix models are simple, solvable quantum mechanical systems which capture the physics of certain fractional quantum Hall states. Recently, it was shown that the Hall viscosity can be extracted from the matrix model for Laughlin states. Here we extend this calculation to the matrix models for a class of non-Abelian quantum Hall states. These states, which were previously introduced by Blok and Wen, arise from the conformal blocks of Wess-Zumino-Witten conformal field theory models. We show that the Hall viscosity computed from the matrix model coincides with a result of Read, in which the Hall viscosity is determined in terms of the weights of primary operators of an associated conformal field theory., Comment: v2: 9 pages, references added, to appear in PRB

Background: The time dependent benefit of rt-PA in acute stroke patients is established. However, only limited data exist on LVO outcomes post remote telemedicine administered rt-PA. We report the outcomes of such patients. Methods: A retrospective study of the CPMC stroke database was performed. Primary outcome measures were neurologic outcome at discharge, mortality, and TICI reperfusion scores of mechanical thrombectomy (MT) treated patients. The safety outcome measure was symptomatic hemorrhage rate (SICH; NIHSS > 1 at ≤ 36hr). Results: From 1/2014-2/2018, 233 transferred rt-PA patients were identified. Median age was 73, and median NIHSS 6. Risk factors included hypertension (69%), dyslipidemia (43%), AF (27%), prior stroke/TIA (26%), CAD (26%), DM (24%), smoking (16%), and CHF (13%). The post rt-PA SICH rate was 4% and discharge mRS≤2 rate was 43%. Mortality rate was 11%, 43% required help at discharge, and 40% were discharged home. For the 61 patients who received rt-PA + MT, the SICH rate was 2% and mortality rate 12%. Median discharge NIHSS was 2 and mRS ≤2 rate was 19%. Of the 233 transferred patients, 40 had a pre rt-PA CTA with LVO available for review. For these patients, median time to scan was 76 min. Median time to repeat CTA at CPMC was 180 min. LVO was 80% anterior circulation, clot migration was seen in 5%, and >90% of MT patients had AF. Post rt-PA recanalization rate was 12% (0% posterior circulation). MT after rt-PA was performed in 62% (TICI ≥ 2b 88%). Longer time to treatment trended towards poorer result and longer MT time. Average NIHSS dropped from 12 to 5 and average discharge mRS was 3. Conclusions: These data confirm that remote IV rt-PA followed by MT is safe and effective. Of LVO rt-PA patients 17% experienced full or partial recanalization suggesting repeat imaging is appropriate before initiating MT, possibly with the exception of posterior circulation strokes because of poor response to rt-PA. AF is common and may predict need for MT after rt-PA. A trend was observed towards improved TICI score and shorter recanalization time with a shorter latency between rt-PA and MT. These data support the use of stroke systems of care to ensure rapid triage and treatment of LVO patients.

What values of the Standard Model hypercharges result in a mathematically consistent quantum field theory? We show that the constraints imposed by the lack of gauge anomalies can be recast as the equation x^3 + y^3 = z^3. If hypercharge is quantised, then x, y and z must be integers. The trivial (and only) solutions, with x=0 or y=0, reproduce the hypercharge assignments seen in Nature. This argument does not rely on the mixed gauge-gravitational anomaly, which is automatically vanishing if hypercharge is quantised and the gauge anomalies vanish., Comment: 2.25 pages. v2: References added. v3: More references, and comment on the right handed neutrino