Efficient Certified RAT Verification

Clausal proofs have become a popular approach to validate the results of SAT solvers. However, validating clausal proofs in the most widely supported format (DRAT) is expensive even in highly optimized implementations. We present a new format, called LRAT, which extends the DRAT format with hints that facilitate a simple and fast validation algorithm. Checking validity of LRAT proofs can be implemented using trusted systems such as the languages supported by theorem provers. We demonstrate this by implementing two certified LRAT checkers, one in Coq and one in ACL2

Effects of movement velocity and training frequency of resistance exercise on functional performance in older adults: a randomised controlled trial

Objectives: To investigate the effects that high-velocity, low-load (HVLL) and low-velocity, high-load (LVHL) resistance exercise, performed once or twice-weekly, have on indices of functional performance (primary outcome), maximal strength, and body composition (secondary outcomes) in older adults. Methods: In a randomised, controlled, multi-armed, parallel design, 54 moderately-highly active, but resistance exercise naïve older adults (aged 60–79 years), attended baseline and post-10-week intervention assessment sessions. Physical and functional assessments were completed, and predicted one-repetition maximums (1-RM) were obtained for eight exercises. Participants were then randomised into one of five conditions: HVLL once-weekly (HVLL1: n = 11) or twice-weekly (HVLL2: n = 11), LVHL once-weekly (LVHL1: n = 10) or twice-weekly (LVHL2: n = 11), no-exercise control condition (CON: n = 11). The HVLL conditions completed 3 sets of 14 repetitions at 40% 1-RM and the LVHL conditions, 3 sets of 7 repetitions at 80% 1-RM. In total, 50 participants completed all testing and were included in analyses. Results: Only LVHL2 improved 30-sec chair stand performance (p =.035; g = 0.89), arm curls (p =.011; g = 1.65) and grip-strength (p =.015; g = 0.34) compared to CON. LVHL2 improved maximal strength compared to CON for 7/8 exercises (p <.05). Whereas, LVHL1 and HVLL2 only improved seated row and chest press compared to CON (p <.05). Conclusion: Possibly due to the lower intensity nature of the HVLL conditions, LVHL, twice-weekly was most beneficial for improving functional performance and strength in moderately-highly active older adults. Therefore, we recommend that exercise professionals ensure resistance exercise sessions have sufficient intensity of effort and volume, in order to maximise functional performance and strength gains in older adults. 

Response to ‘High Risk of Neutropenia for Hormone-naive Prostate Cancer Patients Receiving STAMPEDE-style Upfront Docetaxel Chemotherapy in Usual Clinical Practice’, by Tanguay et al

Madam — Tanguay and colleagues presented data on patients treated with docetaxel [1]. We agree that the reported rates of neutropenia-based toxicities vary across the trials, as do the categories against which toxicities are reported

Rapid RHD Zygosity Determination Using Digital PCR.

BACKGROUND: Paternal zygosity testing is used for determining homo- or hemizygosity of RHD in pregnancies that are at a risk of hemolytic disease of the fetus and newborn. At present, this is achieved by using real-time PCR or the Rhesus box PCR, which can be difficult to interpret and unreliable, particularly for black African populations. METHODS: DNA samples extracted from 58 blood donors were analyzed using 2 multiplex reactions for RHD-specific targets against a reference (AGO1)(2) to determine gene dosage by digital PCR. Results were compared with serological data, and the correct genotype for 2 discordant results was determined by long-range PCR, next-generation sequencing, and conventional Sanger sequencing. RESULTS: The results showed clear and reliable determination of RHD zygosity using digital PCR and revealed that 4 samples did not match the serologically predicted genotype. Sanger sequencing and long-range PCR (LR-PCR) followed by next-generation sequencing revealed that the correct genotypes for samples 729M and 351D, which were serologically typed as R1R2 (DCe/DcE), were R2r' (DcE/dCe) for 729M and R1r" (DCe/dcE), R0r(y) (Dce/dCE), or RZr (DCE/dce) for 351D, in concordance with the digital PCR data. CONCLUSIONS: Digital PCR provides a highly accurate method to rapidly define blood group zygosity and has clinical application in the analysis of Rh phenotyped or genotyped samples. The vast majority of current blood group genotyping platforms are not designed to define zygosity, and thus, this technique may be used to define paternal RH zygosity in pregnancies that are at a risk of hemolytic disease of the fetus and newborn and can distinguish between homo- and hemizygous RHD-positive individuals

The influence of methylphenidate on the power spectrum of ADHD children – an MEG study

BACKGROUND: The present study was dedicated to investigate the influence of Methylphenidate (MPH) on cortical processing of children who were diagnosed with different subtypes of Attention Deficit Hyperactivity Disorder (ADHD). As all of the previous studies investigating power differences in different frequency bands have been using EEG, mostly with a relatively small number of electrodes our aim was to obtain new aspects using high density magnetoencephalography (MEG). METHODS: 35 children (6 female, 29 male) participated in this study. Mean age was 11.7 years (± 1.92 years). 17 children were diagnosed of having an Attention-Deficit/Hyperactivity Disorder of the combined type (ADHDcom, DSM IV code 314.01); the other 18 were diagnosed for ADHD of the predominantly inattentive type (ADHDin, DSM IV code 314.0). We measured the MEG during a 5 minute resting period with a 148-channel magnetometer system (MAGNES™ 2500 WH, 4D Neuroimaging, San Diego, USA). Power values were averaged for 5 bands: Delta (D, 1.5–3.5 Hz), Theta (T, 3.5–7.5 Hz), Alpha (A, 7.5–12.5 Hz), Beta (B, 12.5–25 Hz) and Global (GL, 1.5–25 Hz).). Additionally, attention was measured behaviourally using the D2 test of attention with and without medication. RESULTS: The global power of the frequency band from 1.5 to 25 Hz increased with MPH. Relative Theta was found to be higher in the left hemisphere after administration of MPH than before. A positive correlation was found between D2 test improvement and MPH-induced power changes in the Theta band over the left frontal region. A linear regression was computed and confirmed that the larger the improvement in D2 test performance, the larger the increase in Theta after MPH application. CONCLUSION: Main effects induced by medication were found in frontal regions. Theta band activity increased over the left hemisphere after MPH application. This finding contradicts EEG results of several groups who found lower levels of Theta power after MPH application. As relative Theta correlates with D2 test improvement we conclude that MEG provide complementary and therefore important new insights to ADHD

Generation of Three-Qubit Entangled States using Superconducting Phase Qubits

Entanglement is one of the key resources required for quantum computation, so experimentally creating and measuring entangled states is of crucial importance in the various physical implementations of a quantum computer. In superconducting qubits, two-qubit entangled states have been demonstrated and used to show violations of Bell's Inequality and to implement simple quantum algorithms. Unlike the two-qubit case, however, where all maximally-entangled two-qubit states are equivalent up to local changes of basis, three qubits can be entangled in two fundamentally different ways, typified by the states $|\mathrm{GHZ}> = (|000> + |111>)/\sqrt{2}$ and $|\mathrm{W}> = (|001> + |010> + |100>)/\sqrt{3}$. Here we demonstrate the operation of three coupled superconducting phase qubits and use them to create and measure $|\mathrm{GHZ}>$ and $|\mathrm{W}>$ states. The states are fully characterized using quantum state tomography and are shown to satisfy entanglement witnesses, confirming that they are indeed examples of three-qubit entanglement and are not separable into mixtures of two-qubit entanglement.Comment: 9 pages, 5 figures. Version 2: added supplementary information and fixed image distortion in Figure 2

Adding abiraterone to androgen deprivation therapy in men with metastatic hormone-sensitive prostate cancer: a systematic review and meta-analysis

BACKGROUND: There is a need to synthesise the results of numerous randomised controlled trials evaluating the addition of therapies to androgen deprivation therapy (ADT) for men with metastatic hormone-sensitive prostate cancer (mHSPC). This systematic review aims to assess the effects of adding abiraterone acetate plus prednisone/prednisolone (AAP) to ADT. METHODS: Using our framework for adaptive meta-analysis (FAME), we started the review process before trials had been reported and worked collaboratively with trial investigators to anticipate when eligible trial results would emerge. Thus, we could determine the earliest opportunity for reliable meta-analysis and take account of unavailable trials in interpreting results. We searched multiple sources for trials comparing AAP plus ADT versus ADT in men with mHSPC. We obtained results for the primary outcome of overall survival (OS), secondary outcomes of clinical/radiological progression-free survival (PFS) and grade III-IV and grade V toxicity direct from trial teams. Hazard ratios (HRs) for the effects of AAP plus ADT on OS and PFS, Peto Odds Ratios (Peto ORs) for the effects on acute toxicity and interaction HRs for the effects on OS by patient subgroups were combined across trials using fixed-effect meta-analysis. FINDINGS: We identified three eligible trials, one of which was still recruiting (PEACE-1 (NCT01957436)). Results from the two remaining trials (LATITUDE (NCT01715285) and STAMPEDE (NCT00268476)), representing 82% of all men randomised to AAP plus ADT versus ADT (without docetaxel in either arm), showed a highly significant 38% reduction in the risk of death with AAP plus ADT (HR = 0.62, 95% confidence interval [CI] = 0.53-0.71, p = 0.55 × 10(-10)), that translates into a 14% absolute improvement in 3-year OS. Despite differences in PFS definitions across trials, we also observed a consistent and highly significant 55% reduction in the risk of clinical/radiological PFS (HR = 0.45, 95% CI = 0.40-0.51, p = 0.66 × 10(-36)) with the addition of AAP, that translates to a 28% absolute improvement at 3 years. There was no evidence of a difference in the OS benefit by Gleason sum score, performance status or nodal status, but the size of the benefit may vary by age. There were more grade III-IV acute cardiac, vascular and hepatic toxicities with AAP plus ADT but no excess of other toxicities or death. INTERPRETATION: Adding AAP to ADT is a clinically effective treatment option for men with mHSPC, offering an alternative to docetaxel for men who are starting treatment for the first time. Future research will need to address which of these two agents or whether their combination is most effective, and for whom

Preparation and Measurement of Three-Qubit Entanglement in a Superconducting Circuit

Traditionally, quantum entanglement has played a central role in foundational discussions of quantum mechanics. The measurement of correlations between entangled particles can exhibit results at odds with classical behavior. These discrepancies increase exponentially with the number of entangled particles. When entanglement is extended from just two quantum bits (qubits) to three, the incompatibilities between classical and quantum correlation properties can change from a violation of inequalities involving statistical averages to sign differences in deterministic observations. With the ample confirmation of quantum mechanical predictions by experiments, entanglement has evolved from a philosophical conundrum to a key resource for quantum-based technologies, like quantum cryptography and computation. In particular, maximal entanglement of more than two qubits is crucial to the implementation of quantum error correction protocols. While entanglement of up to 3, 5, and 8 qubits has been demonstrated among spins, photons, and ions, respectively, entanglement in engineered solid-state systems has been limited to two qubits. Here, we demonstrate three-qubit entanglement in a superconducting circuit, creating Greenberger-Horne-Zeilinger (GHZ) states with fidelity of 88%, measured with quantum state tomography. Several entanglement witnesses show violation of bi-separable bounds by 830\pm80%. Our entangling sequence realizes the first step of basic quantum error correction, namely the encoding of a logical qubit into a manifold of GHZ-like states using a repetition code. The integration of encoding, decoding and error-correcting steps in a feedback loop will be the next milestone for quantum computing with integrated circuits.Comment: 7 pages, 4 figures, and Supplementary Information (4 figures)

Reversible Keap1 inhibitors are preferential pharmacological tools to modulate cellular mitophagy

Mitophagy orchestrates the autophagic degradation of dysfunctional mitochondria preventing their pathological accumulation and contributing to cellular homeostasis. We previously identified a novel chemical tool (hereafter referred to as PMI), which drives mitochondria into autophagy without collapsing their membrane potential (ΔΨm). PMI is an inhibitor of the protein-protein interaction (PPI) between the transcription factor Nrf2 and its negative regulator, Keap1 and is able to up-regulate the expression of autophagy-associated proteins, including p62/SQSTM1. Here we show that PMI promotes mitochondrial respiration, leading to a superoxide-dependent activation of mitophagy. Structurally distinct Keap1-Nrf2 PPI inhibitors promote mitochondrial turnover, while covalent Keap1 modifiers, including sulforaphane (SFN) and dimethyl fumarate (DMF), are unable to induce a similar response. Additionally, we demonstrate that SFN reverses the effects of PMI in co-treated cells by reducing the accumulation of p62 in mitochondria and subsequently limiting their autophagic degradation. This study highlights the unique features of Keap1-Nrf2 PPI inhibitors as inducers of mitophagy and their potential as pharmacological agents for the treatment of pathological conditions characterized by impaired mitochondrial quality control