A genetic basis for sex differences in Xp11 translocation renal cell carcinoma.

Xp11 translocation renal cell carcinoma (tRCC) is a rare, female-predominant cancer driven by a fusion between the transcription factor binding to IGHM enhancer 3 (TFE3) gene on chromosome Xp11.2 and a partner gene on either chromosome X (chrX) or an autosome. It remains unknown what types of rearrangements underlie TFE3 fusions, whether fusions can arise from both the active (chrXa) and inactive X (chrXi) chromosomes, and whether TFE3 fusions from chrXi translocations account for the female predominance of tRCC. To address these questions, we performed haplotype-specific analyses of chrX rearrangements in tRCC whole genomes. We show that TFE3 fusions universally arise as reciprocal translocations and that oncogenic TFE3 fusions can arise from chrXi:autosomal translocations. Female-specific chrXi:autosomal translocations result in a 2:1 female-to-male ratio of TFE3 fusions involving autosomal partner genes and account for the female predominance of tRCC. Our results highlight how X chromosome genetics constrains somatic chrX alterations and underlies cancer sex differences.

Structural Alterations Driving Castration-Resistant Prostate Cancer Revealed by Linked-Read Genome Sequencing.

Nearly all prostate cancer deaths are from metastatic castration-resistant prostate cancer (mCRPC), but there have been few whole-genome sequencing (WGS) studies of this disease state. We performed linked-read WGS on 23 mCRPC biopsy specimens and analyzed cell-free DNA sequencing data from 86 patients with mCRPC. In addition to frequent rearrangements affecting known prostate cancer genes, we observed complex rearrangements of the AR locus in most cases. Unexpectedly, these rearrangements include highly recurrent tandem duplications involving an upstream enhancer of AR in 70%-87% of cases compared with <2% of primary prostate cancers. A subset of cases displayed AR or MYC enhancer duplication in the context of a genome-wide tandem duplicator phenotype associated with CDK12 inactivation. Our findings highlight the complex genomic structure of mCRPC, nominate alterations that may inform prostate cancer treatment, and suggest that additional recurrent events in the non-coding mCRPC genome remain to be discovered.

An elementary quantum network of entangled optical atomic clocks.

Optical atomic clocks are our most precise tools to measure time and frequency1-3. Precision frequency comparisons between clocks in separate locations enable one to probe the space-time variation of fundamental constants4,5 and the properties of dark matter6,7, to perform geodesy8-10 and to evaluate systematic clock shifts. Measurements on independent systems are limited by the standard quantum limit; measurements on entangled systems can surpass the standard quantum limit to reach the ultimate precision allowed by quantum theory-the Heisenberg limit. Although local entangling operations have demonstrated this enhancement at microscopic distances11-16, comparisons between remote atomic clocks require the rapid generation of high-fidelity entanglement between systems that have no intrinsic interactions. Here we report the use of a photonic link17,18 to entangle two 88Sr+ ions separated by a macroscopic distance19 (approximately 2 m) to demonstrate an elementary quantum network of entangled optical clocks. For frequency comparisons between the ions, we find that entanglement reduces the measurement uncertainty by nearly [Formula: see text], the value predicted for the Heisenberg limit. Today's optical clocks are typically limited by dephasing of the probe laser20; in this regime, we find that entanglement yields a factor of 2 reduction in the measurement uncertainty compared with conventional correlation spectroscopy techniques20-22. We demonstrate this enhancement for the measurement of a frequency shift applied to one of the clocks. This two-node network could be extended to additional nodes23, to other species of trapped particles or-through local operations-to larger entangled systems.

Experimental quantum key distribution certified by Bell's theorem.

Cryptographic key exchange protocols traditionally rely on computational conjectures such as the hardness of prime factorization1 to provide security against eavesdropping attacks. Remarkably, quantum key distribution protocols such as the Bennett-Brassard scheme2 provide information-theoretic security against such attacks, a much stronger form of security unreachable by classical means. However, quantum protocols realized so far are subject to a new class of attacks exploiting a mismatch between the quantum states or measurements implemented and their theoretical modelling, as demonstrated in numerous experiments3-6. Here we present the experimental realization of a complete quantum key distribution protocol immune to these vulnerabilities, following Ekert's pioneering proposal7 to use entanglement to bound an adversary's information from Bell's theorem8. By combining theoretical developments with an improved optical fibre link generating entanglement between two trapped-ion qubits, we obtain 95,628 key bits with device-independent security9-12 from 1.5 million Bell pairs created during eight hours of run time. We take steps to ensure that information on the measurement results is inaccessible to an eavesdropper. These measurements are performed without space-like separation. Our result shows that provably secure cryptography under general assumptions is possible with real-world devices, and paves the way for further quantum information applications based on the device-independence principle.

High-fidelity laser-free universal control of trapped ion qubits.

Universal control of multiple qubits-the ability to entangle qubits and to perform arbitrary individual qubit operations1-is a fundamental resource for quantum computing2, simulation3 and networking4. Qubits realized in trapped atomic ions have shown the highest-fidelity two-qubit entangling operations5-7 and single-qubit rotations8 so far. Universal control of trapped ion qubits has been separately demonstrated using tightly focused laser beams9-12 or by moving ions with respect to laser beams13-15, but at lower fidelities. Laser-free entangling methods16-20 may offer improved scalability by harnessing microwave technology developed for wireless communications, but so far their performance has lagged the best reported laser-based approaches. Here we demonstrate high-fidelity laser-free universal control of two trapped-ion qubits by creating both symmetric and antisymmetric maximally entangled states with fidelities of [Formula: see text] and [Formula: see text], respectively (68 per cent confidence level), corrected for initialization error. We use a scheme based on radiofrequency magnetic field gradients combined with microwave magnetic fields that is robust against multiple sources of decoherence and usable with essentially any trapped ion species. The scheme has the potential to perform simultaneous entangling operations on multiple pairs of ions in a large-scale trapped-ion quantum processor without increasing control signal power or complexity. Combining this technology with low-power laser light delivered via trap-integrated photonics21,22 and trap-integrated photon detectors for qubit readout23,24 provides an opportunity for scalable, high-fidelity, fully chip-integrated trapped-ion quantum computing.

Lin28: A microRNA regulator with a macro role.

Lin28, a highly conserved RNA-binding protein, has emerged as a modulator of the processing of the let-7 microRNA. This role for Lin28 has important implications for our mechanistic understanding of pluripotency, the timing of development, and oncogenesis.

Endoscopic Ultrasound-Guided vs Endoscopic Retrograde Cholangiopancreatography-Guided Biliary Drainage as Primary Approach to Malignant Distal Biliary Obstruction: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

INTRODUCTION: Endoscopic ultrasound-guided biliary drainage (EUS-BD) is an alternative to endoscopic retrograde cholangiopancreatography (ERCP)-guided transpapillary drainage in malignant distal biliary obstruction (MDBO). This meta-analysis of randomized controlled trials (RCTs) aims to compare the outcomes of these 2 approaches. METHODS: Electronic databases from January 2005 through December 2023 were searched for RCTs comparing outcomes of EUS-BD and ERCP for treating MDBO. Pooled proportions, risk ratio (RR), and odds ratio were calculated using random-effects models. RESULTS: Five RCTs comprising 519 patients were included in the final analysis. The pooled RR for overall technical success with EUS-BD compared with ERCP was 1.05 (95% confidence interval [CI] = 0.96-1.16, P = 0.246, I2 = 61%) and for clinical success was 0.99 (95% CI = 0.95-1.04, P = 0.850, I2 = 0%). The pooled rate of procedure-related pancreatitis was 7.20% (95% CI = 3.60-13.80, I2 = 34%) in the ERCP group compared with zero in the EUS-BD group. The pooled RR for stent dysfunction with EUS-BD compared with ERCP was 0.48 (95% CI = 0.28-0.83, P = 0.008, I2 = 7%). The weighted mean procedure time was 13.43 (SD = 10.12) minutes for EUS-BD compared with 21.06 (SD = 6.64) minutes for ERCP. The mean stent patency was 194.11 (SD = 52.12) days in the EUS-BD group and 187 (SD = 60.70) days in the ERCP group. DISCUSSION: EUS-BD is an efficient and safe alternative to ERCP in MDBO. An almost nonexistent risk of procedure-related pancreatitis, lower procedure time, and ease of use make this an attractive primary approach to biliary decompression in centers with expertise.

International Classification System for Ocular Complications of Anti-VEGF Agents in Clinical Trials.

PURPOSE: Complications associated with intravitreal anti-VEGF therapies are reported inconsistently in the literature, thus limiting an accurate evaluation and comparison of safety between studies. This study aimed to develop a standardized classification system for anti-VEGF ocular complications using the Delphi consensus process. DESIGN: Systematic review and Delphi consensus process. PARTICIPANTS: Twenty-five international retinal specialists participated in the Delphi consensus survey. METHODS: A systematic literature search was conducted to identify complications of intravitreal anti-VEGF agent administration based on randomized controlled trials (RCTs) of anti-VEGF therapy. A comprehensive list of complications was derived from these studies, and this list was subjected to iterative Delphi consensus surveys involving international retinal specialists who voted on inclusion, exclusion, rephrasing, and addition of complications. Furthermore, surveys determined specifiers for the selected complications. This iterative process helped to refine the final classification system. MAIN OUTCOME MEASURES: The proportion of retinal specialists who choose to include or exclude complications associated with anti-VEGF administration. RESULTS: After screening 18 229 articles, 130 complications were categorized from 145 included RCTs. Participant consensus via the Delphi method resulted in the inclusion of 91 complications (70%) after 3 rounds. After incorporating further modifications made based on participant suggestions, such as rewording certain phrases and combining similar terms, 24 redundant complications were removed, leaving a total of 67 complications (52%) in the final list. A total of 14 complications (11%) met exclusion thresholds and were eliminated by participants across both rounds. All other remaining complications not meeting inclusion or exclusion thresholds also were excluded from the final classification system after the Delphi process terminated. In addition, 47 of 75 proposed complication specifiers (63%) were included based on participant agreement. CONCLUSIONS: Using the Delphi consensus process, a comprehensive, standardized classification system consisting of 67 ocular complications and 47 unique specifiers was established for intravitreal anti-VEGF agents in clinical trials. The adoption of this system in future trials could improve consistency and quality of adverse event reporting, potentially facilitating more accurate risk-benefit analyses. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Verifiable Blind Quantum Computing with Trapped Ions and Single Photons.

We report the first hybrid matter-photon implementation of verifiable blind quantum computing. We use a trapped-ion quantum server and a client-side photonic detection system networked via a fiber-optic quantum link. The availability of memory qubits and deterministic entangling gates enables interactive protocols without postselection-key requirements for any scalable blind server, which previous realizations could not provide. We quantify the privacy at ≲0.03 leaked classical bits per qubit. This experiment demonstrates a path to fully verified quantum computing in the cloud.

Evaluating fingerprint-like patterns in the healthy Henle fiber layer using enface OCT imaging.

PURPOSE: Enface OCT may disclose a distinct "fingerprint-like' pattern within the HFL in various macular disorders. This study aims to investigate the frequency and characteristics of this pattern in healthy eyes and identify potential factors influencing its visibility. METHODS: Two, independent masked reading center graders evaluated for the presence and prominence of a fingerprint pattern in the Henle fiber layer (HFL) on enface OCT images from 33 healthy subjects (66 eyes). The prominence of the pattern was rated qualitatively using a 0-3 scale, with 3 indicating the strongest prominence. Tilt angles (relative to the normal/perpendicular at the center) of the retina were measured on horizontal and vertical B-scans, and the retinal curvature was assessed using ImageJ, in order to determine the impact of the incident light angle on the visibility and prominence of the fingerprint pattern. Inter-grader agreement using Cohen's kappa and the frequency and percentage of patterns in the entire enface image and in each quadrant were calculated and compared using the Friedman test with Dunn's post-test. A generalized estimating equation (GEE) was used to analyze the association between these metrics and fingerprint prominence. RESULTS: Substantial inter-grader agreement was observed (Cohen's kappa = 0.71) for assessing the prominence of the fingerprint pattern. Over 70% of eyes exhibited some evidence of the pattern (score ≥1). Significant difference in pattern prominence across quadrants was detected (p < 0.05), with lowest prominence in the temporal quadrant (p < 0.001 for pairwise comparisons against all other quadrants). The GEE analysis to account for the extent of the effect of scan tilt angle and RPE curvature was not able to predict the prominence of the fingerprint pattern, highlighting that angle of incidence (of the scanning laser light) alone could not explain the pattern. CONCLUSIONS: This study confirms that a fingerprint-like pattern within the HFL can also be observed in healthy eyes, challenging the notion that this finding is only manifest in the setting of disease. In addition, the lack of correlation with angle of incident light suggests that the pattern may be related to other intrinsic characteristics of the HFL.

Topographic analysis of local OCT biomarkers which predict progression to atrophy in age-related macular degeneration.

PURPOSE: To define optical coherence tomography (OCT) biomarkers that precede the development of complete retinal pigment epithelium and outer retinal atrophy (cRORA) at that location in eyes with age-related macular degeneration (AMD). METHODS: In this retrospective case-control study, patients with dry AMD who had evidence of cRORA and OCT data available for 4 years (48 ± 4 months) prior to the first visit with evidence of cRORA were included. The visit 4 years prior to the development of cRORA was defined as the baseline visit, and the region on the OCT B-scans of future cRORA development was termed the case region. A region in the same eye at the same distance from the foveal center as the case region that did not progress to cRORA was selected as the control region. OCT B-scans at the baseline visit through both the case and control regions were evaluated for the presence of soft and cuticular drusen, drusen with hyporeflective cores (hcD), drusenoid pigment epithelial detachments (PED), subretinal drusenoid deposits (SDD), thick and thin double-layer signs (DLS), intraretinal hyperreflective foci (IHRF), and acquired vitelliform lesions (AVL). RESULTS: A total of 57 eyes of 41 patients with dry AMD and evidence of cRORA were included. Mean time from the baseline visit to the first visit with cRORA was 44.7 ± 6.5 months. The presence of soft drusen, drusenoid PED, AVL, thin DLS, and IHRF at the baseline visit was all associated with a significantly increased risk of cRORA at that location. Multivariable logistic regression revealed that IHRF (OR, 8.559; p < 0.001), drusenoid PED (OR, 7.148; p = 0.001), and a thin DLS (OR, 3.483; p = 0.021) were independent predictors of development of cRORA at that location. CONCLUSIONS: IHRF, drusenoid PED, and thin DLS are all local risk factors for the development of cRORA at that same location. These findings would support the inclusion of these features within a more granular staging system defining specific steps in the progression from early AMD to atrophy.

PREVALENCE AND PERSISTENCE OF HYPERTRANSMISSION DEFECTS OF VARIOUS SIZES IN EYES WITH INTERMEDIATE AGE-RELATED MACULAR DEGENERATION.

PURPOSE: To determine the prevalence and rate of persistence over 2 years of various-sized hypertransmission defects (hyperTDs) in eyes with intermediate age-related macular degeneration. METHODS: Retrospective analysis of optical coherence tomography data from consecutive intermediate age-related macular degeneration patients. Choroidal en face optical coherence tomography images were evaluated for the presence and number of hyperTDs of three different sizes based on greatest linear dimension (small, 63-124 µ m; medium, 125-249 µ m; large, ≥250 µ m) at baseline and at the 2-year follow-up. Interreader agreement was determined by Gwet's agreement coefficient. Disagreements between graders were resolved by the senior investigator to yield a single consensus for all cases. RESULTS: From 273 intermediate age-related macular degeneration eyes (247 patients), 72 and 76 hyperTD lesions were independently identified by two graders at baseline and overall agreement coefficient was 0.89 (95% CI, 0.86-0.93). After adjudication by the senior grader, the final consensus yielded 78 hyperTD lesions from 46 eyes (16.8%) of 42 patients (17.0%) in this study cohort. Among eyes with follow-up optical coherence tomography, 32 of 45 hyperTD lesions (71.1%) persisted. The rates of persistence were 100.0%, 72.7%, and 53.3% in large, medium, and small hyperTD sizes, respectively. CONCLUSION: HyperTDs were present in a significant proportion of intermediate age-related macular degeneration eyes. Acceptable interreader agreement was demonstrated in identifying hyperTD. Larger hyperTD lesions were more likely to persist over 2 years.

PIGMENT EPITHELIAL DETACHMENT THICKNESS AND VARIABILITY AFFECTS VISUAL OUTCOMES IN PATIENTS WITH NEOVASCULAR AGE-RELATED MACULAR DEGENERATION.

PURPOSE: To evaluate the impact of pigment epithelial detachment (PED) thickness (i.e., height) and thickness variability on best-corrected visual acuity outcomes in patients with neovascular age-related macular degeneration in the Phase 3 HAWK and HARRIER trials. METHODS: Optical coherence tomography images from the pooled brolucizumab 6 mg and aflibercept 2 mg arms were analyzed for the maximum PED thickness across the macula at baseline through to week 96. Best-corrected visual acuity outcomes were compared in patients with different PED thickness and variability cut-off thresholds. RESULTS: Greater PED thickness at baseline or at week 12 was associated with lower mean best-corrected visual acuity gain from baseline to week 96 (baseline PED ≥200 µ m: +4.6 letters; <200 µ m: +7.0 letters; week 12 PED ≥100 µ m: +5.6 letters; <100 µ m: +6.6 letters). Eyes with the largest PED thickness variability from week 12 through week 96 gained fewer letters from baseline at week 96 (≥33 µ m: +3.3 letters; <9 µ m: +6.2 letters). Furthermore, increased PED thickness at week 48 was associated with higher prevalence of intraretinal and subretinal fluid. CONCLUSION: In this treatment-agnostic analysis, greater PED thickness and PED thickness variability were associated with poorer visual outcomes in patients with neovascular age-related macular degeneration and greater neovascular activity.

The Progression of Stargardt Disease as Determined by Spectral-Domain Optical Coherence Tomography over a 24-Month Period (ProgStar Report No. 18).

INTRODUCTION: The aim of this study was to evaluate the progression of atrophy as determined by spectral-domain optical coherence tomography (SD-OCT) in patients with molecularly confirmed ABCA4-associated Stargardt disease type 1 (STGD1) over a 24-month period in a multicenter prospective cohort study. METHODS: SD-OCT images from 428 eyes of 236 patients were analyzed. Change of mean thickness (MT) and intact area were estimated after semiautomated segmentation for the following individual layers in the central subfield (CS), inner ring (IR), and outer ring (OR) of the ETDRS grid: retinal pigment epithelium (RPE), outer segments (OSs), inner segments (IS), outer nuclear layer (ONL) inner retina (IR), and total retina. RESULTS: Statistically significant decreases of all outer retinal layers (RPE, OS, IS, and ONL) could be observed over a 24-month period both in decline of mean retinal thickness and intact area (p < 0.0001, respectively), whereas the IR showed an increase of retinal thickness in the CS and IR and remained unchanged in the OR. CONCLUSIONS: Significant loss could be detected in outer retinal layers by SD-OCT over a 24-month period in patients with STGD1. Loss of thickness and/or intact area of such layers may serve as potential endpoints for clinical trials that aim to slow down the disease progression of STGD1.

Identification of fluoxetine as a direct NLRP3 inhibitor to treat atrophic macular degeneration.

The atrophic form of age-related macular degeneration (dry AMD) affects nearly 200 million people worldwide. There is no Food and Drug Administration (FDA)-approved therapy for this disease, which is the leading cause of irreversible blindness among people over 50 y of age. Vision loss in dry AMD results from degeneration of the retinal pigmented epithelium (RPE). RPE cell death is driven in part by accumulation of Alu RNAs, which are noncoding transcripts of a human retrotransposon. Alu RNA induces RPE degeneration by activating the NLRP3-ASC inflammasome. We report that fluoxetine, an FDA-approved drug for treating clinical depression, binds NLRP3 in silico, in vitro, and in vivo and inhibits activation of the NLRP3-ASC inflammasome and inflammatory cytokine release in RPE cells and macrophages, two critical cell types in dry AMD. We also demonstrate that fluoxetine, unlike several other antidepressant drugs, reduces Alu RNA-induced RPE degeneration in mice. Finally, by analyzing two health insurance databases comprising more than 100 million Americans, we report a reduced hazard of developing dry AMD among patients with depression who were treated with fluoxetine. Collectively, these studies identify fluoxetine as a potential drug-repurposing candidate for dry AMD.

Immune Checkpoint Therapy Combinations in Adult Advanced MiT Family Translocation Renal Cell Carcinomas.

BACKGROUND: There remains a paucity of data regarding the efficacy of immune checkpoint therapy (ICT) combinations ± vascular endothelial growth factor (VEGF) targeted therapy (TT) in translocation renal cell carcinoma (tRCC). METHODS: This is a retrospective study of patients with advanced tRCC treated with ICT combinations at 11 centers in the US, France, and Belgium. Only cases with confirmed fluorescence in situ hybridization (FISH) were included. Objective response rates (ORR) and progression-free survival (PFS) were assessed by RECIST, and overall survival (OS) was estimated by Kaplan-Meier methods. RESULTS: There were 29 patients identified with median age of 38 (21-70) years, and F:M ratio 0.9:1. FISH revealed TFE3 and TFEB translocations in 22 and 7 patients, respectively. Dual ICT and ICT + VEGF TT were used in 18 and 11 patients, respectively. Seventeen (59%) patients received ICT combinations as first-line therapy. ORR was 1/18 (5.5%) for dual ICT and 4/11 (36%) for ICT + VEGF TT. At a median follow-up of 12.9 months, median PFS was 2.8 and 5.4 months in the dual ICT and ICT + VEGF TT groups, respectively. Median OS from metastatic disease was 17.8 and 30.7 months in the dual ICT and ICT + VEGF TT groups, respectively. CONCLUSION: In this retrospective study of advanced tRCC, limited response and survival were seen after frontline dual ICT combination therapy, while ICT + VEGF TT therapy offered some efficacy. Due to the heterogeneity of tRCC, insights into the biological underpinnings are necessary to develop more effective therapies.

Preclinical evaluation of semi-automated laser ablation for pulmonary vein isolation: A comparative study.

INTRODUCTION: Visually-guided laser balloon ablation (VGLA) currently requires careful manual rotation of the laser to create overlapping lesions. A novel semi-automated VGLA may reduce ablation times and lesion gaps. We aimed to compare semi-automated (SA) VGLA to that of manual (MN) VGLA. METHODS: Acute: Nine swine underwent right superior pulmonary vein isolation (PVI) using either SA (n = 3, 13-18 W), MN (n = 3, 8.5-12 W), or radiofrequency (RF, n = 3, 25-40 W) and were killed acutely. Chronic: 16 swine, underwent PVI using either SA (n = 8, 15 W) or MN (n = 8, 10 W), and were survived for 1 month before being killed. All hearts were then submitted for pathological evaluation. RESULTS: Acute: PVI was successful in all 9/9 swine with lesion counts significantly lower in the SA arm (5.3 ± 5.9, 33.7 ± 10.0, and 28.0 ± 4.4 in SA, MN, and RF arms; p = .007 for SA and MN). At necropsy, circumferentiality and transmurality were 98% and 94% in SA, 98% and 80% in MN, and 100% and 100% in RF arms. A single steam pop was noted on sectioning in the SA arm swine and occurred in the high dose (18 W) strategy. Chronic: PVI was acutely successful in 16/16 swine with no difference in PVI durability rates (62.5% vs. 75.0%), lesion transmurality (95.8 ± 17.4% vs.91.9 ± 25.9%), and circumferentiality (95.8 ± 6.6% vs. 94.8 ± 6.3%) between SA and MN arms. Catheter use time and lesion counts were lower in the SA arm compared to the MN arm (11.5 ± 12.7 vs. 21.8 ± 3.8 min, p = .046 and 4.8 ± 3.83 vs. 35.4 ± 4.4, p < .001). CONCLUSION: Motor-assisted semi-automated laser balloon ablation can improve upon procedural efficiency by reducing ablation time.

SGLT2 inhibitors reduce sudden cardiac death risk in heart failure: Meta-analysis of randomized clinical trials.

INTRODUCTION: Multiple randomized controlled trials have demonstrated sodium-glucose cotransporter-2 inhibitors (SGLT2i) decrease the composite endpoint of cardiovascular death or heart failure hospitalizations in all heart failure patients. It is uncertain whether SGLT2i impacts the risk of sudden cardiac death in patients with heart failure. METHODS: A comprehensive search was performed to identify relevant data published before August 28, 2022. Trials were included if: (1) all patients had clinical heart failure (2) SGLT2i and placebo were compared (3) all patients received conventional medical therapy and (4) reported outcomes of interest (sudden cardiac death [SCD], ventricular arrhythmias, atrial arrhythmias). RESULTS: SCD was reported in seven of the eleven trials meeting selection criteria: 10 796 patients received SGLT2i and 10 796 received placebo. SGLT2i therapy was associated with a significant reduction in the risk of SCD (risk ratios [RR]: 0.68; 95% confidence intervals [CI]: 0.48-0.95; p = .03; I2 = 0%). Absent dedicated rhythm monitoring, there were no significant differences in the incidence of sustained ventricular arrhythmias not associated with SCD (RR: 1.03; 95% CI: 0.83-1.29; p = .77; I2 = 0%) or atrial arrhythmias (RR: 0.91; 95% CI: 0.77-1.09; p = .31; I2 = 29%) between patients receiving an SGLT2i versus placebo. CONCLUSION: SGLT2i therapy is associated with a reduced risk of SCD in patients with heart failure receiving contemporary medical therapy. Prospective trials are needed to determine the long-term impact of SGLT2i therapy on atrial and ventricular arrhythmias.

Breaking the Entangling Gate Speed Limit for Trapped-Ion Qubits Using a Phase-Stable Standing Wave.

All laser-driven entangling operations for trapped-ion qubits have hitherto been performed without control of the optical phase of the light field, which precludes independent tuning of the carrier and motional coupling. By placing ^{88}Sr^{+} ions in a λ=674 nm standing wave, whose relative position is controlled to ≈λ/100, we suppress the carrier coupling by a factor of 18, while coherently enhancing the spin-motion coupling. We experimentally demonstrate that the off-resonant carrier coupling imposes a speed limit for conventional traveling-wave Mølmer-Sørensen gates; we use the standing wave to surpass this limit and achieve a gate duration of 15 µs, restricted by the available laser power.

Robust Quantum Memory in a Trapped-Ion Quantum Network Node.

We integrate a long-lived memory qubit into a mixed-species trapped-ion quantum network node. Ion-photon entanglement first generated with a network qubit in ^{88}Sr^{+} is transferred to ^{43}Ca^{+} with 0.977(7) fidelity, and mapped to a robust memory qubit. We then entangle the network qubit with a second photon, without affecting the memory qubit. We perform quantum state tomography to show that the fidelity of ion-photon entanglement decays ∼70 times slower on the memory qubit. Dynamical decoupling further extends the storage duration; we measure an ion-photon entanglement fidelity of 0.81(4) after 10 s.