Machine learning framework develops neutrophil extracellular traps model for clinical outcome and immunotherapy response in lung adenocarcinoma.

Neutrophil extracellular traps (NETs) are novel inflammatory cell death in neutrophils. Emerging studies demonstrated NETs contributed to cancer progression and metastases in multiple ways. This study intends to provide a prognostic NETs signature and therapeutic target for lung adenocarcinoma (LUAD) patients. Consensus cluster analysis performed by 38 reported NET-related genes in TCGA-LUAD cohorts. Then, WGCNA network was conducted to investigate characteristics genes in clusters. Seven machine learning algorithms were assessed for training of the model, the optimal model was picked by C-index and 1-, 3-, 5-year ROC value. Then, we constructed a NETs signature to predict the overall survival of LUAD patients. Moreover, multi-omics validation was performed based on NETs signature. Finally, we constructed stable knockdown critical gene LUAD cell lines to verify biological functions of Phospholipid Scramblase 1 (PLSCR1) in vitro and in vivo. Two NETs-related clusters were identified in LUAD patients. Among them, C2 cluster was provided as "hot" tumor phenotype and exhibited a better prognosis. Then, WGCNA network identified 643 characteristic genes in C2 cluster. Then, Coxboost algorithm proved its optimal performance and provided a prognostic NETs signature. Multi-omics revealed that NETs signature was involved in an immunosuppressive microenvironment and predicted immunotherapy efficacy. In vitro and in vivo experiments demonstrated that knockdown of PLSCR1 inhibited tumor growth and EMT ability. Besides, cocultural assay indicated that the knockdown of PLSCR1 impaired the ability of neutrophils to generate NETs. Finally, tissue microarray (TMA) for LUAD patients verified the prognostic value of PLSCR1 expression. In this study, we focus on emerging hot topic NETs in LUAD. We provide a prognostic NETs signature and identify PLSCR1 with multiple roles in LUAD. This work can contribute to risk stratification and screen novel therapeutic targets for LUAD patients.

Prevalence of metabolic syndrome among Vietnamese adult employees.

BACKGROUND AND AIMS: Metabolic syndrome (MtS) is associated with increased risk of many health disorders, especially cardiovascular diseases. In Vietnam, study examining MtS is meager and especially lacking for the workforce. We estimated the prevalence of MtS and its associated factors among Vietnamese employees. METHODS AND RESULTS: We analyzed secondary data of annual health check of employees of 300 Vietnamese companies from the Vinmec Healthcare System. We used three definitions for MtS: International Diabetes Federation (IDF), National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III), and NCEP ATP III-Asia. Of 57,997 participants evaluated, 48.5 % were males and 66.2 % were younger than 40 years old. The unadjusted MtS prevalence was 8.4 % (IDF), 10.2 % (NCEP ATP III), and 16.0 % (NCEP ATP III-Asia). The age-sex adjusted prevalence of MtS (NCEP ATP III-Asia) was 21.8 % (95 % confidence interval (CI): 21.4 %, 22.2 %). MtS prevalence increased with age, reached 49.6 % for age ≥60. The aging related increase was more remarkable in females than males (prevalence ratio (PR) (95 % CI) for age ≥60 comparing to age <30 years old in males vs. females was 4.0 (3.6, 4.3) vs. 20.1 (17.7, 22.9)). High blood triglyceride (83.4 %) and abdominal obesity (74.5 %) were the predominant contributors to MtS. CONCLUSION: In this relatively young Vietnamese working population, 16 % had MtS with high triglyceride and abdominal obesity being the predominant contributors. These findings emphasize the need for developing effective high triglyceride and abdominal obesity prevention and control programs to curb the emerging epidemic of metabolic disorders in the workforce.

Threshold level of Peptest in diagnosing gastroesophageal reflux disease with extraesophageal symptoms: Evidence from Vietnam.

Background and Aim: We aimed to evaluate the application of Peptest, a novel technique to detect pepsin in the saliva, and identify its threshold level for the diagnosis of gastroesophageal reflux disease (GERD) with extraesophageal symptoms. Methods: A cross-sectional study was conducted in two groups: patients with extraesophageal GERD symptoms (symptomatic group divided into GERD and non-GERD groups according to 24-h esophageal pH-impedance monitoring [pH-I] results) and healthy controls. For the symptomatic group, endoscopy, pH 24 h, high-resolution manometry (HRM), and salivary Peptest were performed. For the healthy control group, only Peptest was done. The accuracy of Peptest was compared with that of pH-I by the Lyon consensus criteria. Results: Chronic laryngitis was the most frequent extraesophageal symptom. On saliva testing, the GERD group had a higher prevalence of positive samples and pepsin concentration than the control group. Between GERD and non-GERD groups, the optimal threshold level was 31.2 ng/mL, with a sensitivity of 86.7% and specificity of 27.5%. The optimal threshold level was 31.4 ng/mL to differentiate GERD from healthy controls, with a sensitivity of 86.7% and specificity of 66.0%. Age, number of total refluxes, DeMeester score, post-reflux swallow-induced peristaltic wave (PSPW) index, and mean nocturnal baseline impedence (MNBI) were associated with pepsin concentration. Regarding HRM metrics, there was no significant difference of pepsin concentration between low/normal upper esophageal sphincter (UES) resting pressure, low/normal lower esophageal sphincter (LES) resting pressure, low/normal 4-s integrated relaxation pressure (IRP4s), and hypomotility/normal motility. Conclusion: Patients with extraesophageal symptoms had a higher prevalence of positive Peptest. The optimum threshold level of 31.4 ng/mL had high sensitivity and moderate specificity to differentiate between patients with GERD and healthy controls.

High-fidelity qutrit entangling gates for superconducting circuits.

Ternary quantum information processing in superconducting devices poses a promising alternative to its more popular binary counterpart through larger, more connected computational spaces and proposed advantages in quantum simulation and error correction. Although generally operated as qubits, transmons have readily addressable higher levels, making them natural candidates for operation as quantum three-level systems (qutrits). Recent works in transmon devices have realized high fidelity single qutrit operation. Nonetheless, effectively engineering a high-fidelity two-qutrit entanglement remains a central challenge for realizing qutrit processing in a transmon device. In this work, we apply the differential AC Stark shift to implement a flexible, microwave-activated, and dynamic cross-Kerr entanglement between two fixed-frequency transmon qutrits, expanding on work performed for the ZZ interaction with transmon qubits. We then use this interaction to engineer efficient, high-fidelity qutrit CZ† and CZ gates, with estimated process fidelities of 97.3(1)% and 95.2(3)% respectively, a significant step forward for operating qutrits on a multi-transmon device.

Synthesis, Biological Evaluation, and Molecular Modeling Studies of 1-Aryl-1H-pyrazole-Fused Curcumin Analogues as Anticancer Agents.

Addressing the growing burden of cancer and the shortcomings of chemotherapy in cancer treatment are the current research goals. Research to overcome the limitations of curcumin and to improve its anticancer activity via its heterocycle-fused monocarbonyl analogues (MACs) has immense potential. In this study, 32 asymmetric MACs fused with 1-aryl-1H-pyrazole (7a-10h) were synthesized and characterized to develop new curcumin analogues. Subsequently, via initial screening for cytotoxic activity, nine compounds exhibited potential growth inhibition against MDA-MB-231 (IC50 2.43-7.84 µM) and HepG2 (IC50 4.98-14.65 µM), in which seven compounds showing higher selectivities on two cancer cell lines than the noncancerous LLC-PK1 were selected for cell-free in vitro screening for effects on microtubule assembly activity. Among those, compounds 7d, 7h, and 10c showed effective inhibitions of microtubule assembly at 20.0 µM (40.76-52.03%), indicating that they could act as microtubule-destabilizing agents. From the screening results, three most potential compounds, 7d, 7h, and 10c, were selected for further evaluation of cellular effects on breast cancer MDA-MB-231 cells. The apoptosis-inducing study indicated that these three compounds could cause morphological changes at 1.0 µM and could enhance caspase-3 activity (1.33-1.57 times) at 10.0 µM in MDA-MB-231 cells, confirming their apoptosis-inducing activities. Additionally, in cell cycle analysis, compounds 7d and 7h at 2.5 µM and 10c at 5.0 µM also arrested MDA-MB-231 cells in the G2/M phase. Finally, the results from in silico studies revealed that the predicted absorption, distribution, metabolism, excretion, and the toxicity (ADMET) profile of the most potent MACs might have several advantages in addition to potential disadvantages, and compound 7h could bind into (ΔG -10.08 kcal·mol-1) and access wider space at the colchicine-binding site (CBS) than that of colchicine or nocodazole via molecular docking studies. In conclusion, our study serves as a basis for the design of promising synthetic compounds as anticancer agents in the future.

N,2,6-Trisubstituted 1H-benzimidazole derivatives as a new scaffold of antimicrobial and anticancer agents: design, synthesis, in vitro evaluation, and in silico studies.

Compounds containing benzimidazole moiety occupy privileged chemical space for discovering new bioactive substances. In continuation of our recent work, 69 benzimidazole derivatives were designed and synthesized with good to excellent yields of 46-99% using efficient synthesis protocol i.e. sodium metabisulfite catalyzed condensation of aromatic aldehydes with o-phenylenediamines to form 2-arylbenzimidazole derivatives followed by N-alkylation by conventional heating or microwave irradiation for diversification. Potent antibacterial compounds against MSSA and MRSA were discovered such as benzimidazole compounds 3k (2-(4-nitrophenyl), N-benzyl), 3l (2-(4-chlorophenyl), N-(4-chlorobenzyl)), 4c (2-(4-chlorophenyl), 6-methyl, N-benzyl), 4g (2-(4-nitrophenyl), 6-methyl, N-benzyl), and 4j (2-(4-nitrophenyl), 6-methyl, N-(4-chlorobenzyl)) with MIC of 4-16 µg mL-1. In addition, compound 4c showed good antimicrobial activities (MIC = 16 µg mL-1) against the bacteria strains Escherichia coli and Streptococcus faecalis. Moreover, compounds 3k, 3l, 4c, 4g, and 4j have been found to kill HepG2, MDA-MB-231, MCF7, RMS, and C26 cancer cells with low µM IC50 (2.39-10.95). These compounds showed comparable drug-like properties as ciprofloxacin, fluconazole, and paclitaxel in computational ADMET profiling. Finally, docking studies were used to assess potential protein targets responsible for their biological activities. Especially, we found that DHFR is a promising target both in silico and in vitro with compound 4c having IC50 of 2.35 µM.

An ambivalent prostate nodule after Bacillus Calmette-Guérin therapy.

A 65-year-old patient without specific associated pathology was treated for a high-grade non-invasive papillary urothelial carcinoma by surgery associated with repeated intravesical Bacillus Calmette-Guérin (BCG) instillations. During follow-up, magnetic resonance imaging (MRI) found a clinically indurated prostate nodule with suspected extensive capsular invasion. Prostatic biopsies showed epithelioid and giant-cell granuloma associated with a single focus of adenocarcinoma. Urinary culture test and specific PCR confirmed the involvement of Mycobacterium bovis. The patient was treated first by rifampin, isoniazid and ethambutol and then by rifampin and isoniazid for a total duration of 9 months, with MRI reassessment at various intervals. After BCG therapy, systemic infectious complications but also local complications such as granulomatous disease have been reported, but prostatic abscesses with M. bovis mimicking cancer on MRI are rare. Consequently, we advise specific local urinary and prostate samples to test for mycobacteria (staining, culture, PCR) in order to avoid aggressive high-risk prostatic surgery.

Electron shelving of a superconducting artificial atom.

Interfacing long-lived qubits with propagating photons is a fundamental challenge in quantum technology. Cavity and circuit quantum electrodynamics (cQED) architectures rely on an off-resonant cavity, which blocks the qubit emission and enables a quantum non-demolition (QND) dispersive readout. However, no such buffer mode is necessary for controlling a large class of three-level systems that combine a metastable qubit transition with a bright cycling transition, using the electron shelving effect. Here we demonstrate shelving of a circuit atom, fluxonium, placed inside a microwave waveguide. With no cavity modes in the setup, the qubit coherence time exceeds 50 µs, and the cycling transition's radiative lifetime is under 100 ns. By detecting a homodyne fluorescence signal from the cycling transition, we implement a QND readout of the qubit and account for readout errors using a minimal optical pumping model. Our result establishes a resource-efficient (cavityless) alternative to cQED for controlling superconducting qubits.

Fear-Related Reasons for Avoiding Sexual Intercourse in Early Pregnancy: A Cross-Sectional Study.

INTRODUCTION: Several studies have reported women's worry that sexual intercourse may harm the course of pregnancy. This worry might lead to avoidance of sexual intercourse during pregnancy. AIM: To assess if fears about harming the pregnancy are associated with avoidance of sexual intercourse during pregnancy. METHODS: A cross-sectional study was conducted on 250 Vietnamese pregnant women in the first or second trimester who visited our hospital for antenatal care. We explored 5 types of fears including miscarriage/preterm labor, premature rupture of membranes, bleeding, infection, and injury to the fetus. Fears were measured by modified questions from the Reasons For Not Engaging in Sexual Activity During Pregnancy questionnaire. Using the total fear score, pregnant women were categorized into having low, moderate, and high fear. MAIN OUTCOME MEASURE: Not having sexual intercourse during the past 4 weeks. RESULTS: 72 (28.8%) pregnant women had no sexual intercourse for the past 4 weeks. All types of fear were considered important among pregnant women; the more important fears were infection and injury to the fetus. In multivariable regression analysis, the prevalence of not having sexual intercourse was higher in both women who had moderate (adjusted prevalence ratio = 2.84, 95% CI 1.42-5.67) and high fear (adjusted prevalence ratio = 4.39, 95% CI 2.28-8.44). CONCLUSION: Avoidance of sexual intercourse was common among Vietnamese pregnant women and was associated with the fears about harming the pregnancy. This can be a target in the health education programs for pregnancy couples. Thanh C. Phan, Long B. Hoang, Thanh K. Tran, et al. Fear-Related Reasons for Avoiding Sexual Intercourse in Early Pregnancy: A Cross-Sectional Study. Sex Med 2021;9:100430.

Rates of inflammatory bowel disease in Hispanics comparable to non-Hispanic Whites: results of a cohort study.

PURPOSE: Previous studies have suggested that inflammatory bowel disease (IBD) occurs at higher rates among non-Hispanic Whites (NHWs) compared to other ethnicities; however, Hispanics as the largest minority in the United States remain underrepresented in IBD research and we hypothesize that they have similar rates of IBD. We examined the epidemiology, demographics, clinical presentation, and treatment of IBD in a predominantly Hispanic cohort in Los Angeles (LA) County. METHODS: This was a retrospective cohort study based at Olive View-UCLA Medical Center, one of the three major safety-net hospitals in LA County. Electronic medical records from 2015 to 2018 were queried, and biopsy-proven cases of IBD (n = 170) were identified. Outcomes included the incidence and prevalence of IBD, disease distribution, treatment, and IBD-related surgery. RESULTS: The incidence of IBD among Hispanics was 175 (95% confidence interval [CI] 127-240) and 113 (95% CI 62-200) for NHWs per 100,000 person-years. Prevalence of IBD per 100,000 people was 418 (95% CI 341-512) for Hispanics and 557 (95% CI 431-739) for NHWs. Notably, the proportion of Hispanic IBD patients with a history of smoking was 21.5% vs 50.8% in NHWs (p = 0.011). There were no significant differences between the two groups with regard to Montreal classification, pharmacotherapy, or IBD-related surgery. CONCLUSIONS: In one of the largest US studies of Hispanics with IBD, and the only one to have both clinical and histopathologic confirmation as inclusion criteria, we found the incidence and prevalence of IBD among Hispanics to be higher than previously recognized and comparable to NHWs. Additionally, Hispanic IBD patients had lower rates of smoking compared to NHWs.

The superconducting quasicharge qubit.

The non-dissipative nonlinearity of Josephson junctions1 converts macroscopic superconducting circuits into artificial atoms2, enabling some of the best-controlled qubits today3,4. Three fundamental types of superconducting qubit are known5, each reflecting a distinct behaviour of quantum fluctuations in a Cooper pair condensate: single-charge tunnelling (charge qubit6,7), single-flux tunnelling (flux qubit8) and phase oscillations (phase qubit9 or transmon10). Yet, the dual nature of charge and flux suggests that circuit atoms must come in pairs. Here we introduce the missing superconducting qubit, 'blochnium', which exploits a coherent insulating response of a single Josephson junction that emerges from the extension of phase fluctuations beyond 2π (refs. 11-14). Evidence for such an effect has been found in out-of-equilibrium direct-current transport through junctions connected to high-impedance leads15-19, although a full consensus on the existence of extended phase fluctuations is so far absent20-22. We shunt a weak junction with an extremely high inductance-the key technological innovation in our experiment-and measure the radiofrequency excitation spectrum as a function of external magnetic flux through the resulting loop. The insulating character of the junction is manifested by the vanishing flux sensitivity of the qubit transition between the ground state and the first excited state, which recovers rapidly for transitions to higher-energy states. The spectrum agrees with a duality mapping of blochnium onto a transmon, which replaces the external flux by the offset charge and introduces a new collective quasicharge variable instead of the superconducting phase23,24. Our findings may motivate the exploration of macroscopic quantum dynamics in ultrahigh-impedance circuits, with potential applications in quantum computing and metrology.

Poly(ornithine)-based self-assembling drug for recovery of hyperammonemia and damage in acute liver injury.

Oligo-peptides, including monomeric amino acids, have received much attention as bioactive molecules and drugs. One of the biggest problems of these compounds, however, is their very short bioavailability due to instant metabolism and rapid excretion. To solve this problem, we newly designed a poly(ethylene glycol) (PEG)-block-polypeptide self-assembling based drug for the treatment of acute liver injury. Here, PEG-block-poly(L-Ornithine) (PEG-b-POrn) was synthesized via a ring opening polymerization, and a nano-sized polyion self-assembling complex (NanoOrn) was prepared by simply mixing polycationic PEG-b-POrn with polyanionic chondroitin sulfate. The obtained NanoOrn was quite stable under high ionic strength and different pH conditions and NanoOrn exhibited extremely low toxicity in vitro and in vivo as compared to the original PEG-b-POrn. As compared to monomeric L-ornithine, administration of NanoOrn to mice significantly improved bioavailability of liberated ornithine, especially in the liver. Interestingly, NanoOrn treatment in acetaminophen (APAP)-induced acute liver injury mice remarkably suppressed blood ammonia levels and liver injury markers, resulting in more effective improvement of liver damage compared to monomeric ornithine via activation of ornithine transcarbomylase. These results show that the self-assembling polypeptide NanoOrn may provide a new concept and promising therapeutics as nanomedicines.

Baryon-Number Violation by Two Units and the Deuteron Lifetime.

We calculate the lifetime of the deuteron with dimension-nine quark operators that violate baryon number by two units. We construct an effective field theory for |ΔB|=2 interactions that give rise to neutron-antineutron (n-n[over ¯]) oscillations and dinucleon decay within a consistent power counting. We calculate the ratio of the deuteron lifetime to the square of the n-n[over ¯] oscillation time up to next-to-leading order. Our result, which is analytical and has a quantified uncertainty, is smaller by a factor ≃2.5 than earlier estimates based on nuclear models, which impacts the indirect bound on the n-n[over ¯] oscillation time and future experiments. We discuss how combined measurements of n-n[over ¯] oscillations and deuteron decay can help to identify the sources of baryon-number violation.

Rubisco condensate formation by CcmM in ß-carboxysome biogenesis.

Cells use compartmentalization of enzymes as a strategy to regulate metabolic pathways and increase their efficiency1. The α- and ß-carboxysomes of cyanobacteria contain ribulose-1,5-bisphosphate carboxylase/oxygenase (Rubisco)-a complex of eight large (RbcL) and eight small (RbcS) subunits-and carbonic anhydrase2-4. As HCO3- can diffuse through the proteinaceous carboxysome shell but CO2 cannot5, carbonic anhydrase generates high concentrations of CO2 for carbon fixation by Rubisco6. The shell also prevents access to reducing agents, generating an oxidizing environment7-9. The formation of ß-carboxysomes involves the aggregation of Rubisco by the protein CcmM10, which exists in two forms: full-length CcmM (M58 in Synechococcus elongatus PCC7942), which contains a carbonic anhydrase-like domain8 followed by three Rubisco small subunit-like (SSUL) modules connected by flexible linkers; and M35, which lacks the carbonic anhydrase-like domain11. It has long been speculated that the SSUL modules interact with Rubisco by replacing RbcS2-4. Here we have reconstituted the Rubisco-CcmM complex and solved its structure. Contrary to expectation, the SSUL modules do not replace RbcS, but bind close to the equatorial region of Rubisco between RbcL dimers, linking Rubisco molecules and inducing phase separation into a liquid-like matrix. Disulfide bond formation in SSUL increases the network flexibility and is required for carboxysome function in vivo. Notably, the formation of the liquid-like condensate of Rubisco is mediated by dynamic interactions with the SSUL domains, rather than by low-complexity sequences, which typically mediate liquid-liquid phase separation in eukaryotes12,13. Indeed, within the pyrenoids of eukaryotic algae, the functional homologues of carboxysomes, Rubisco adopts a liquid-like state by interacting with the intrinsically disordered protein EPYC114. Understanding carboxysome biogenesis will be important for efforts to engineer CO2-concentrating mechanisms in plants15-19.

Patient Satisfaction and Healthcare Utilization Using Telemedicine in Liver Transplant Recipients.

BACKGROUND: Post-liver transplantation care is limited to tertiary care centers. Concentration at expert centers leads to high-volume clinics with long wait times and decreased accessibility. AIM: To assess whether telemedicine can be utilized to overcome barriers to care while sustaining strong patient-physician relationships. METHODS: The Patient Satisfaction Questionnaire-18, Telemedicine Satisfaction Questionnaire, and Health Utilization Questionnaire were used to assess patient satisfaction and healthcare utilization among patients who received care via video connection (telemedicine group) and in clinic (control group). Propensity matching was performed. Scores for questionnaires were reported as mean and standard deviations (SD) and were compared by one-way multivariate analysis of variance and one-way analysis of variance. RESULTS: There were 21 matched telemedicine patients in our study. Overall mean age (± SD) was 51 (± 5.62) years and 52 (± 6.12) years for telemedicine group and control group, respectively. General patient satisfaction was similar between the two groups (p = 0.89). While telemedicine patients were just as satisfied with communication and interpersonal approach compared to clinic patients, they experienced significantly less commute (p < 0.0001) and waiting (p < 0.0001) times. Given ease of using telemedicine without compromising patient-physician interaction, 90% (19/21) of the telemedicine patients opted to use the service again. CONCLUSION: Telemedicine appeared to be both a time and cost-saving alternative to clinic follow-up without compromise of the valuable patient-physician relationship. Telemedicine has the potential to improve clinic flow, reduce wait times, and decrease costs for liver transplant recipients.

C-reactive protein point of care testing in the management of acute respiratory infections in the Vietnamese primary healthcare setting - a cost benefit analysis.

Aim: We assess the cost-benefit implications of C-reactive protein (CRP) testing in reducing antibiotic prescription for acute respiratory infection in Viet Nam by comparing the incremental costs of CRP testing with the economic costs of antimicrobial resistance averted due to lower antibiotic prescribing. Findings: Patients in the CRP group and the controls incurred similar costs in managing their illness, excluding the costs of the quantitative CRP tests, provided free of charge in the trial context. Assuming a unit cost of $1 per test, the incremental cost of CRP testing was $0.93 per patient. Based on a previous modelling analysis, the 20 percentage point reduction in prescribing observed in the trial implies a societal benefit of $0.82 per patient. With the low levels of adherence to the test results observed in the trial, CRP testing would not be cost-beneficial. The sensitivity analyses showed, however, that with higher adherence to test results their use would be cost-beneficial.

Demonstration of Protection of a Superconducting Qubit from Energy Decay.

Long-lived transitions occur naturally in atomic systems due to the abundance of selection rules inhibiting spontaneous emission. By contrast, transitions of superconducting artificial atoms typically have large dipoles, and hence their lifetimes are determined by the dissipative environment of a macroscopic electrical circuit. We designed a multilevel fluxonium artificial atom such that the qubit's transition dipole can be exponentially suppressed by flux tuning, while it continues to dispersively interact with a cavity mode by virtual transitions to the noncomputational states. Remarkably, energy decay time T_{1} grew by 2 orders of magnitude, proportionally to the inverse square of the transition dipole, and exceeded the benchmark value of T_{1}>2 ms (quality factor Q_{1}>4×10^{7}) without showing signs of saturation. The dephasing time was limited by the first-order coupling to flux noise to about 4 µs. Our circuit validated the general principle of hardware-level protection against bit-flip errors and can be upgraded to the 0-π circuit [P. Brooks, A. Kitaev, and J. Preskill, Phys. Rev. A 87, 052306 (2013)PLRAAN1050-294710.1103/PhysRevA.87.052306], adding protection against dephasing and certain gate errors.