Surface code quantum computing by lattice surgery

In recent years, surface codes have become a leading method for quantum error correction in theoretical large scale computational and communications architecture designs. Their comparatively high fault-tolerant thresholds and their natural 2-dimensional nearest neighbour (2DNN) structure make them an obvious choice for large scale designs in experimentally realistic systems. While fundamentally based on the toric code of Kitaev, there are many variants, two of which are the planar- and defect- based codes. Planar codes require fewer qubits to implement (for the same strength of error correction), but are restricted to encoding a single qubit of information. Interactions between encoded qubits are achieved via transversal operations, thus destroying the inherent 2DNN nature of the code. In this paper we introduce a new technique enabling the coupling of two planar codes without transversal operations, maintaining the 2DNN of the encoded computer. Our lattice surgery technique comprises splitting and merging planar code surfaces, and enables us to perform universal quantum computation (including magic state injection) while removing the need for braided logic in a strictly 2DNN design, and hence reduces the overall qubit resources for logic operations. Those resources are further reduced by the use of a rotated lattice for the planar encoding. We show how lattice surgery allows us to distribute encoded GHZ states in a more direct (and overhead friendly) manner, and how a demonstration of an encoded CNOT between two distance 3 logical states is possible with 53 physical qubits, half of that required in any other known construction in 2D.Comment: Published version. 29 pages, 18 figure

Variables Associated with Intravenous Rehydration and Hospitalization in Children with Acute Gastroenteritis: A Secondary Analysis of 2 Randomized Clinical Trials

Importance: Despite guidelines endorsing oral rehydration therapy, intravenous fluids are commonly administered to children with acute gastroenteritis in high-income countries. Objective: To identify factors associated with intravenous fluid administration and hospitalization in children with acute gastroenteritis. Design, Setting, and Participants: This study is a planned secondary analysis of the Pediatric Emergency Research Canada (PERC) and Pediatric Emergency Care Applied Research Network (PECARN) probiotic trials. Participants include children aged 3 to 48 months with 3 or more watery stools in 24 hours between November 5, 2013, and April 7, 2017, for the PERC study and July 8, 2014, and June 23, 2017, for the PECARN Study. Children were from 16 pediatric emergency departments throughout Canada (6) and the US (10). Data were analyzed from November 2, 2018, to March 16, 2021. Exposures: Sex, age, preceding health care visit, distance between home and hospital, country (US vs Canada), frequency and duration of vomiting and diarrhea, presence of fever, Clinical Dehydration Scale score, oral ondansetron followed by oral rehydration therapy, and infectious agent. Main Outcomes and Measures: Intravenous fluid administration and hospitalization. Results: This secondary analysis of 2 randomized clinical trials included 1846 children (mean [SD] age, 19.1 [11.4] months; 1007 boys [54.6%]), of whom 534 of 1846 (28.9%) received oral ondansetron, 240 of 1846 (13.0%) received intravenous rehydration, and 67 of 1846 (3.6%) were hospitalized. The following were independently associated with intravenous rehydration: higher Clinical Dehydration Scale score (mild to moderate vs none, odds ratio [OR], 8.73; 95% CI, 5.81-13.13; and severe vs none, OR, 34.15; 95% CI, 13.45-86.73); country (US vs Canada, OR, 6.76; 95% CI, 3.15-14.49); prior health care visit with intravenous fluids (OR, 4.55; 95% CI, 1.32-15.72); and frequency of vomiting (per 5 episodes, OR, 1.66; 95% CI, 1.39-1.99). The following were independently associated with hospitalization: higher Clinical Dehydration Scale score (mild to moderate vs none, OR, 11.10; 95% CI, 5.05-24.38; and severe vs none, OR, 23.55; 95% CI, 7.09-78.25) and country (US vs Canada, OR, 3.37; 95% CI, 1.36-8.40). Oral ondansetron was associated with reduced odds of intravenous rehydration (OR, 0.21; 95% CI, 0.13-0.32) and hospitalization (OR, 0.44; 95% CI, 0.21-0.89). Conclusions and Relevance: Intravenous rehydration and hospitalization were associated with clinical evidence of dehydration and lack of an oral ondansetron-supported oral rehydration period. Strategies focusing on oral ondansetron administration followed by oral rehydration therapy in children with dehydration may reduce the reliance on intravenous rehydration and hospitalization. Trial Registration: ClinicalTrials.gov Identifiers: NCT01853124 (PERC) and NCT01773967 (PECARN)

Impact of non-axillary sentinel node biopsy on staging and treatment of breast cancer patients

The purpose of this study was to evaluate the occurrence of lymphatic drainage to non-axillary sentinel nodes and to determine the implications of this phenomenon. A total of 549 breast cancer patients underwent lymphoscintigraphy after intratumoural injection of 99mTc-nanocolloid. The sentinel node was intraoperatively identified with the aid of intratumoural administered patent blue dye and a gamma-ray detection probe. Histopathological examination of sentinel nodes included step-sectioning at six levels and immunohistochemical staining. A sentinel node outside level I or II of the axilla was found in 149 patients (27%): internal mammary sentinel nodes in 86 patients, other non-axillary sentinel nodes in 44 and both internal mammary and other non-axillary sentinel nodes in nineteen patients. The intra-operative identification rate was 80%. Internal mammary metastases were found in seventeen patients and metastases in other non-axillary sentinel nodes in ten patients. Staging improved in 13% of patients with non-axillary sentinel lymph nodes and their treatment strategy was changed in 17%. A small proportion of clinically node negative breast cancer patients can be staged more precisely by biopsy of sentinel nodes outside level I and II of the axilla, resulting in additional decision criteria for postoperative regional or systemic therapy

The NANOGrav 15-year Data Set: Observations and Timing of 68 Millisecond Pulsars

We present observations and timing analyses of 68 millisecond pulsars (MSPs) comprising the 15-year data set of the North American Nanohertz Observatory for Gravitational Waves (NANOGrav). NANOGrav is a pulsar timing array (PTA) experiment that is sensitive to low-frequency gravitational waves. This is NANOGrav's fifth public data release, including both "narrowband" and "wideband" time-of-arrival (TOA) measurements and corresponding pulsar timing models. We have added 21 MSPs and extended our timing baselines by three years, now spanning nearly 16 years for some of our sources. The data were collected using the Arecibo Observatory, the Green Bank Telescope, and the Very Large Array between frequencies of 327 MHz and 3 GHz, with most sources observed approximately monthly. A number of notable methodological and procedural changes were made compared to our previous data sets. These improve the overall quality of the TOA data set and are part of the transition to new pulsar timing and PTA analysis software packages. For the first time, our data products are accompanied by a full suite of software to reproduce data reduction, analysis, and results. Our timing models include a variety of newly detected astrometric and binary pulsar parameters, including several significant improvements to pulsar mass constraints. We find that the time series of 23 pulsars contain detectable levels of red noise, 10 of which are new measurements. In this data set, we find evidence for a stochastic gravitational-wave background.Comment: 90 pages, 74 figures, 6 tables; published in Astrophysical Journal Letters as part of Focus on NANOGrav's 15-year Data Set and the Gravitational Wave Background. For questions or comments, please email [email protected]

12-HETrE inhibits platelet reactivity and thrombosis in part through the prostacyclin receptor

The dihomo-γ-linolenic acid (DGLA)-derived metabolite of 12-lipoxygenase, 12-hydroxy-eicosatrienoic acid (12-HETrE), was recently shown to potently inhibit thrombus formation without prolonging bleeding in murine models. Although 12-HETrE was found to inhibit platelet activation via the Gαs signaling pathway, the Gαs-coupled receptor by which 12-HETrE mediates its antiplatelet effects has yet to be identified. Defining the receptor by which 12-HETrE exerts its effects is key to determining its therapeutic potential as an antiplatelet drug. Therefore, the goal of this study was to determine the Gαs-coupled platelet receptor through which 12-HETrE exerts its antiplatelet effects. In this study, we showed that pharmacological inhibition of the prostacyclin (IP) receptor in human platelets or genetic ablation of IP in murine platelets prevented 12-HETrE from blocking aggregation in vitro. Furthermore, the antithrombotic effects of 12-HETrE were significantly diminished in IP knockout mice in vivo. Together these data demonstrate that the antiplatelet effects of 12-HETrE are at least partially dependent on IP signaling. Importantly, this work identified 12-HETrE as a novel regulator of IP signaling that may aid in the rationale for design of novel therapeutics to inhibit platelet function. Additionally, this study provides further insight into the mechanism by which DGLA supplementation inhibits platelets function

Human 15-LOX-1 active site mutations alter inhibitor binding and decrease potency.

Human 15-lipoxygenase-1 (h15-LOX-1 or h12/15-LOX) reacts with polyunsaturated fatty acids and produces bioactive lipid derivatives that are implicated in many important human diseases. One such disease is stroke, which is the fifth leading cause of death and the first leading cause of disability in America. The discovery of h15-LOX-1 inhibitors could potentially lead to novel therapeutics in the treatment of stroke, however, little is known about the inhibitor/active site interaction. This study utilizes site-directed mutagenesis, guided in part by molecular modeling, to gain a better structural understanding of inhibitor interactions within the active site. We have generated eight mutants (R402L, R404L, F414I, F414W, E356Q, Q547L, L407A, I417A) of h15-LOX-1 to determine whether these active site residues interact with two h15-LOX-1 inhibitors, ML351 and an ML094 derivative, compound 18. IC50 values and steady-state inhibition kinetics were determined for the eight mutants, with four of the mutants affecting inhibitor potency relative to wild type h15-LOX-1 (F414I, F414W, E356Q and L407A). The data indicate that ML351 and compound 18, bind in a similar manner in the active site to an aromatic pocket close to F414 but have subtle differences in their specific binding modes. This information establishes the binding mode for ML094 and ML351 and will be leveraged to develop next-generation inhibitors

Omega-6 DPA and its 12-lipoxygenase–oxidized lipids regulate platelet reactivity in a nongenomic PPARα-dependent manner

Arterial thrombosis is the underlying cause for a number of cardiovascular-related events. Although dietary supplementation that includes polyunsaturated fatty acids (PUFAs) has been proposed to elicit cardiovascular protection, a mechanism for antithrombotic protection has not been well established. The current study sought to investigate whether an omega-6 essential fatty acid, docosapentaenoic acid (DPAn-6), and its oxidized lipid metabolites (oxylipins) provide direct cardiovascular protection through inhibition of platelet reactivity. Human and mouse blood and isolated platelets were treated with DPAn-6 and its 12-lipoxygenase (12-LOX)-derived oxylipins, 11-hydroxy-docosapentaenoic acid and 14-hydroxy-docosapentaenoic acid, to assess their ability to inhibit platelet activation. Pharmacological and genetic approaches were used to elucidate a role for DPA and its oxylipins in preventing platelet activation. DPAn-6 was found to be significantly increased in platelets following fatty acid supplementation, and it potently inhibited platelet activation through its 12-LOX-derived oxylipins. The inhibitory effects were selectively reversed through inhibition of the nuclear receptor peroxisome proliferator activator receptor-α (PPARα). PPARα binding was confirmed using a PPARα transcription reporter assay, as well as PPARα-/- mice. These approaches confirmed that selectivity of platelet inhibition was due to effects of DPA oxylipins acting through PPARα. Mice administered DPAn-6 or its oxylipins exhibited reduced thrombus formation following vessel injury, which was prevented in PPARα-/- mice. Hence, the current study demonstrates that DPAn-6 and its oxylipins potently and effectively inhibit platelet activation and thrombosis following a vascular injury. Platelet function is regulated, in part, through an oxylipin-induced PPARα-dependent manner, suggesting that targeting PPARα may represent an alternative strategy to treat thrombotic-related diseases

DHA 12- LOX- derived oxylipins regulate platelet activation and thrombus formation through a PKA- dependent signaling pathway

BackgroundThe effects of docosahexaenoic acid (DHA) on cardiovascular disease are controversial and a mechanistic understanding of how this omega- 3 polyunsaturated fatty acid (Ï - 3 PUFA) regulates platelet reactivity and the subsequent risk of a thrombotic event is warranted. In platelets, DHA is oxidized by 12- lipoxygenase (12- LOX) producing the oxidized lipids (oxylipins) 11- HDHA and 14- HDHA. We hypothesized that 12- LOX DHA- oxylipins may be involved in the beneficial effects observed in dietary supplemental treatment with Ï - 3 PUFAs or DHA itself.ObjectivesTo determine the effects of DHA, 11- HDHA, and 14- HDHA on platelet function and thrombus formation, and to elucidate the mechanism by which these Ï - 3 PUFAs regulate platelet activation.Methods and resultsDHA, 11- HDHA, and 14- HDHA attenuated collagen- induced human platelet aggregation, but only the oxylipins inhibited - ºIIbβ3 activation and decreased - º- granule secretion. Furthermore, treatment of whole blood with DHA and its oxylipins impaired platelet adhesion and accumulation to a collagen- coated surface. Interestingly, thrombus formation was only diminished in mice treated with 11- HDHA or 14- HDHA, and mouse platelet activation was inhibited following acute treatment with these oxylipins or chronic treatment with DHA, suggesting that under physiologic conditions, the effects of DHA are mediated through its oxylipins. Finally, the protective mechanism of DHA oxylipins was shown to be mediated via activation of protein kinase A.ConclusionsThis study provides the first mechanistic evidence of how DHA and its 12- LOX oxylipins inhibit platelet activity and thrombus formation. These findings support the beneficial effects of DHA as therapeutic intervention in atherothrombotic diseases.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/167023/1/jth15184-sup-0001-Supinfo.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/167023/2/jth15184.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/167023/3/jth15184_am.pd

12(S)-HETrE, a 12-Lipoxygenase Oxylipin of Dihomo-&ggr;-Linolenic Acid, Inhibits Thrombosis via G&agr;s Signaling in Platelets

ObjectiveDietary supplementation with polyunsaturated fatty acids has been widely used for primary and secondary prevention of cardiovascular disease in individuals at risk; however, the cardioprotective benefits of polyunsaturated fatty acids remain controversial because of lack of mechanistic and in vivo evidence. We present direct evidence that an omega-6 polyunsaturated fatty acid, dihomo-γ-linolenic acid (DGLA), exhibits in vivo cardioprotection through 12-lipoxygenase (12-LOX) oxidation of DGLA to its reduced oxidized lipid form, 12(S)-hydroxy-8Z,10E,14Z-eicosatrienoic acid (12(S)-HETrE), inhibiting platelet activation and thrombosis.Approach and resultsDGLA inhibited ex vivo platelet aggregation and Rap1 activation in wild-type mice, but not in mice lacking 12-LOX expression (12-LOX(-/-)). Similarly, wild-type mice treated with DGLA were able to reduce thrombus growth (platelet and fibrin accumulation) after laser-induced injury of the arteriole of the cremaster muscle, but not 12-LOX(-/-) mice, supporting a 12-LOX requirement for mediating the inhibitory effects of DGLA on platelet-mediated thrombus formation. Platelet activation and thrombus formation were also suppressed when directly treated with 12(S)-HETrE. Importantly, 2 hemostatic models, tail bleeding and arteriole rupture of the cremaster muscle, showed no alteration in hemostasis after 12(S)-HETrE treatment. Finally, the mechanism for 12(S)-HETrE protection was shown to be mediated via a Gαs-linked G-protein-coupled receptor pathway in human platelets.ConclusionsThis study provides the direct evidence that an omega-6 polyunsaturated fatty acid, DGLA, inhibits injury-induced thrombosis through its 12-LOX oxylipin, 12(S)-HETrE, which strongly supports the potential cardioprotective benefits of DGLA supplementation through its regulation of platelet function. Furthermore, this is the first evidence of a 12-LOX oxylipin regulating platelet function in a Gs α subunit-linked G-protein-coupled receptor-dependent manner