Clinical Significance of Diffusion-Weighted Brain MRI Lesions After TAVR: Results of a Patient-Level Pooled Analysis.

BACKGROUND: Acute brain infarction detected by diffusion-weighted magnetic resonance imaging (DW-MRI) is common after transcatheter aortic valve replacement (TAVR), but its clinical relevance is uncertain. OBJECTIVES: The authors investigated the relationship between DW-MRI total lesion number (TLN), individual lesion volume (ILV), and total lesion volume (TLV) and clinical stroke outcomes after TAVR. METHODS: Patient-level data were pooled from 4 prospective TAVR embolic protection studies, with consistent predischarge DW-MRI acquisition and core laboratory analysis. C-statistic was used to determine the best DW-MRI measure associated with clinical stroke. RESULTS: A total of 495 of 603 patients undergoing TAVR completed the predischarge DW-MRI. At 30 days, the rate of clinical ischemic stroke was 6.9%. Acute ischemic brain injury was seen in 85% of patients with 5.5 ± 7.3 discrete lesions per patient, mean ILV of 78.2 ± 257.1 mm3, and mean TLV of 555 ± 1,039 mm3. The C-statistic was 0.84 for TLV, 0.81 for number of lesions, and 0.82 for maximum ILV in predicting ischemic stroke. On the basis of the TLV cutpoint as defined by receiver operating characteristic (ROC), patients with a TLV >500 mm3 (vs TLV ≤500 mm3) had more ischemic stroke (18.2% vs 2.3%; P < 0.0001), more disabling strokes (8.8% vs 0.9%; P < 0.0001), and less complete stroke recovery (44% vs 62.5%; P = 0.001) at 30 days. CONCLUSIONS: Our study confirms that the number, size, and total volume of acute brain infarction defined by DW-MRI are each associated with clinical ischemic strokes, disabling strokes, and worse stroke recovery in patients undergoing TAVR and may have value as surrogate outcomes in stroke prevention trials. (A Prospective, Randomized Evaluation of the TriGuard™ HDH Embolic Deflection Device During TAVI [DEFLECT III]; NCT02070731) (A Study to Evaluate the Neuro-embolic Consequences of TAVR [NeuroTAVR]; NCT02073864) (The REFLECT Trial: Cerebral Protection to Reduce Cerebral Embolic Lesions After Transcatheter Aortic Valve Implantation [REFLECT I]; NCT02536196) (The REFLECT Trial: Cerebral Protection to Reduce Cerebral Embolic Lesions After Transcatheter Aortic Valve Implantation [REFLECT II]; NCT02536196).

The burden of hyperkalaemia on hospital healthcare resources.

Hyperkalaemia is associated with prolonged hospital admission and worse mortality. Hyperkalaemia may also necessitate clinical consults, therapies for hyperkalaemia and high-dependency bed utilisation. We evaluated the 'hidden' human and organisational resource utilisation for hyperkalaemia in hospitalised patients. This was a single-centre, observational cohort study (Jan 2017-Dec 2020) at a tertiary-care hospital. The CogStack system (data processing and analytics platform) was used to search unstructured and structured data from individual patient records. Association between potassium and death was modelled using cubic spline regression, adjusted for age, sex, and comorbidities. Cox proportional hazards estimated the hazard of death compared with normokalaemia (3.5-5.0 mmol/l). 129,172 patients had potassium measurements in the emergency department. Incidence of hyperkalaemia was 85.7 per 1000. There were 49,011 emergency admissions. Potassium > 6.5 mmol/L had 3.9-fold worse in-hospital mortality than normokalaemia. Chronic kidney disease was present in 21% with potassium 5-5.5 mmol/L and 54% with potassium > 6.5 mmol/L. For diabetes, it was 20% and 32%, respectively. Of those with potassium > 6.5 mmol/L, 29% had nephrology review, and 13% critical care review; in this group 22% transferred to renal wards and 8% to the critical care unit. Dialysis was used in 39% of those with peak potassium > 6.5 mmol/L. Admission hyperkalaemia and hypokalaemia were independently associated with reduced likelihood of hospital discharge. Hyperkalaemia is associated with greater in-hospital mortality and reduced likelihood of hospital discharge. It necessitated significant utilisation of nephrology and critical care consultations and greater likelihood of patient transfer to renal and critical care.

New and Emerging Drug and Gene Therapies for Friedreich Ataxia.

The life shortening nature of Friedreich Ataxia (FRDA) demands the search for therapies that can delay, stop or reverse its relentless trajectory. This review provides a contemporary position of drug and gene therapies for FRDA currently in phase 1 clinical trials and beyond. Despite significant scientific advances in the specificity of both compounds and targets developed and investigated, challenges remain for the advancement of treatments in a limited recruitment population. Currently therapies focus on reducing oxidative stress and improving mitochondrial function, modulating frataxin controlled metabolic pathways and gene replacement and editing. Approval of omaveloxolone, the first treatment for individuals with FRDA aged 16 years and over, has created much excitement for both those living with FRDA and those that care for them. The process of approval of omaveloxolone by the US Food and Drug Administration highlighted the importance of sensitive outcome measures and the significant role of data from natural history studies.

Off-Label Use of Peripheral Paclitaxel Drug-Coated Balloons in Management of Recurrent Coronary In-Stent Restenosis.

Background: While not available for clinical use in the United States, dedicated drug-coated balloons (DCB) are currently under investigation for the management of coronary in-stent restenosis (ISR). Peripheral drug-coated balloons (P-DCB) have been used off-label for coronary ISR. Further data regarding this practice are needed. We aimed to describe outcomes in patients who underwent off-label P-DCB angioplasty for coronary ISR. Methods: We analyzed data on P-DCB angioplasty for coronary ISR at a single high-volume center between April 1, 2015, and December 30, 2017. Demographic and procedural details were collected, with systematic follow-up as clinically indicated. Results: Data from 31 patients treated with P-DCB angioplasty (mean age 68.0 ± 10.7 years) with coronary ISR (17 recurrent and 14 first time) were analyzed. Most patients presented with high-grade angina (81%) or myocardial infarction (13%). Treated ISR lesions were in native coronary arteries (68%), saphenous vein grafts (SVG, 23%), and the left internal mammary artery (10%). Diffuse intrastent ISR was common (69%) with a mean lesion length of 21.7 ± 12.4 mm. No postprocedural myocardial infarction occurred and 1 nonprocedural mortality occurred during index admission. At follow-up (median: 283, interquartile range [IQR]: 354 days), repeat angiography was performed in 19 patients (median: 212, IQR: 188 days), and 11 patients had target lesion recurrent ISR (Kaplan-Meier event-free survival estimate: 44.7%, 95% CI, 26.1%-76.5%). Conclusions: In the absence of availability of dedicated coronary DCB, treatment of coronary ISR using P-DCB angioplasty was feasible, although follow-up demonstrated continued risk for recurrent ISR in this high-risk population.

Percutaneous Coronary Revascularization Strategies After Myocardial Infarction: A Systematic Review and Network Meta-Analysis.

BACKGROUND: Complete revascularization with percutaneous coronary intervention improves outcomes compared with culprit revascularization following myocardial infarction (MI) with multivessel coronary artery disease. An all-cause mortality reduction has never been demonstrated. Debate also remains regarding the optimal timing of complete revascularization (immediate or staged), and method of evaluation of nonculprit lesions (physiology or angiography). OBJECTIVES: This study aims to perform an updated systematic review with frequentist and Bayesian network meta-analyses including the totality of randomized data investigating revascularization strategies in patients presenting with MI and multivessel coronary artery disease. METHODS: The primary comparison tested complete vs culprit revascularization. Timing and methods of achieving complete revascularization were assessed. The prespecified primary outcome was all-cause mortality. Outcomes were expressed as relative risk (RR) (95% CI). RESULTS: Twenty-four eligible trials randomized 16,371 patients (weighted mean follow-up: 26.4 months). Compared with culprit revascularization, complete revascularization reduced all-cause mortality in patients with any MI (RR: 0.85; 95% CI: 0.74-0.99; P = 0.04). Cardiovascular mortality, MI, major adverse cardiac events and repeat revascularization were also significantly reduced. In patients presenting with ST-segment elevation myocardial infarction, the point estimate for all-cause mortality with complete revascularization was RR: 0.91 (95% CI: 0.78-1.05; P = 0.18). Rates of stent thrombosis, major bleeding, and acute kidney injury were similar. Immediate complete revascularization ranked higher than staged complete revascularization for all endpoints. CONCLUSIONS: Complete revascularization following MI reduces all-cause mortality, cardiovascular mortality, MI, major adverse cardiac events, and repeat revascularization. There may be benefits to immediate complete revascularization, but additional head-to-head trials are needed.

Wide-Band Unambiguous Quantum Sensing via Geodesic Evolution.

We present a quantum sensing technique that utilizes a sequence of π pulses to cyclically drive the qubit dynamics along a geodesic path of adiabatic evolution. This approach effectively suppresses the effects of both decoherence noise and control errors while simultaneously removing unwanted resonance terms, such as higher harmonics and spurious responses commonly encountered in dynamical decoupling control. As a result, our technique offers robust, wide-band, unambiguous, and high-resolution quantum sensing capabilities for signal detection and individual addressing of quantum systems, including spins. To demonstrate its versatility, we showcase successful applications of our method in both low-frequency and high-frequency sensing scenarios. The significance of this quantum sensing technique extends to the detection of complex signals and the control of intricate quantum environments. By enhancing detection accuracy and enabling precise manipulation of quantum systems, our method holds considerable promise for a variety of practical applications.

One-Year Outcomes of Transseptal Mitral Valve-in-Valve in Intermediate Surgical Risk Patients.

BACKGROUND: Transcatheter mitral valve-in-valve replacement offers a less-invasive alternative for high-risk patients with bioprosthetic valve failure. Limited experience exists in intermediate-risk patients. We aim to evaluate 1-year outcomes of the PARTNER 3 mitral valve-in-valve study. METHODS: This prospective, single-arm, multicenter study enrolled symptomatic patients with a failing mitral bioprosthesis demonstrating greater than or equal to moderate stenosis and regurgitation and Society of Thoracic Surgeons score ≥3% and <8%. A balloon-expandable transcatheter heart valve (SAPIEN 3, Edwards Lifesciences) was used via a transeptal approach. The primary end point was the composite of all-cause mortality and stroke at 1 year. RESULTS: A total of 50 patients from 12 sites underwent mitral valve-in-valve from 2018 to 2021. The mean age was 70.1±9.7 years, mean Society of Thoracic Surgeons score was 4.1%±1.6%, and 54% were female. There were no primary end point events (mortality or stroke) through 1 year, and no left-ventricular outflow tract obstruction, endocarditis, or mitral valve reintervention was reported. Six patients (12%) required rehospitalization, including heart failure (n=2), minor procedural side effects (n=2), and valve thrombosis (n=2; both resolved with anticoagulation). An additional valve thrombosis was associated with no significant clinical sequelae. From baseline to 1 year, all subjects with available data had none/trace or mild (grade 1+) mitral regurgitation and the New York Heart Association class improved in 87.2% (41/47) of patients. CONCLUSIONS: Mitral valve-in-valve with a balloon-expandable valve via transseptal approach in intermediate-risk patients was associated with improved symptoms and quality of life, adequate transcatheter valve performance, and no mortality or stroke at 1-year follow-up. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03193801.

A CCG expansion in ABCD3 causes oculopharyngodistal myopathy in individuals of European ancestry.

Oculopharyngodistal myopathy (OPDM) is an inherited myopathy manifesting with ptosis, dysphagia and distal weakness. Pathologically it is characterised by rimmed vacuoles and intranuclear inclusions on muscle biopsy. In recent years CGG • CCG repeat expansion in four different genes were identified in OPDM individuals in Asian populations. None of these have been found in affected individuals of non-Asian ancestry. In this study we describe the identification of CCG expansions in ABCD3, ranging from 118 to 694 repeats, in 35 affected individuals across eight unrelated OPDM families of European ancestry. ABCD3 transcript appears upregulated in fibroblasts and skeletal muscle from OPDM individuals, suggesting a potential role of over-expression of CCG repeat containing ABCD3 transcript in progressive skeletal muscle degeneration. The study provides further evidence of the role of non-coding repeat expansions in unsolved neuromuscular diseases and strengthens the association between the CGG • CCG repeat motif and a specific pattern of muscle weakness.

Structural Variants at the LMNB1 Locus: Deciphering Pathomechanisms in Autosomal Dominant Adult-Onset Demyelinating Leukodystrophy.

OBJECTIVES: We aimed to elucidate the pathogenic mechanisms underlying autosomal dominant adult-onset demyelinating leukodystrophy (ADLD), and to understand the genotype/phenotype correlation of structural variants (SVs) in the LMNB1 locus. BACKGROUND: Since the discovery of 3D genome architectures and topologically associating domains (TADs), new pathomechanisms have been postulated for SVs, regardless of gene dosage changes. ADLD is a rare genetic disease associated with duplications (classical ADLD) or noncoding deletions (atypical ADLD) in the LMNB1 locus. METHODS: High-throughput chromosome conformation capture, RNA sequencing, histopathological analyses of postmortem brain tissues, and clinical and neuroradiological investigations were performed. RESULTS: We collected data from >20 families worldwide carrying SVs in the LMNB1 locus and reported strong clinical variability, even among patients carrying duplications of the entire LMNB1 gene, ranging from classical and atypical ADLD to asymptomatic carriers. We showed that patients with classic ADLD always carried intra-TAD duplications, resulting in a simple gene dose gain. Atypical ADLD was caused by LMNB1 forebrain-specific misexpression due to inter-TAD deletions or duplications. The inter-TAD duplication, which extends centromerically and crosses the 2 TAD boundaries, did not cause ADLD. Our results provide evidence that astrocytes are key players in ADLD pathology. INTERPRETATION: Our study sheds light on the 3D genome and TAD structural changes associated with SVs in the LMNB1 locus, and shows that a duplication encompassing LMNB1 is not sufficient per se to diagnose ADLD, thereby strongly affecting genetic counseling. Our study supports breaking TADs as an emerging pathogenic mechanism that should be considered when studying brain diseases. ANN NEUROL 2024.

Ethnic differences in postprandial fatty acid trafficking and utilisation between overweight and obese White European and Black African-Caribbean men.

Black African-Caribbean (BAC) populations are at greater risk of cardiometabolic disease than White Europeans (WE), despite lower fasting triacylglycerol (TAG) concentrations. However, limited data exist regarding postprandial fatty acid metabolism in BAC populations. This study determined the ethnic differences in postprandial fatty acid metabolism between overweight and obese WE and BAC men. WE (n=10) and BAC (n=9) men consumed two consecutive moderate-to-high fat meals; the first labelled with U-13C palmitate. The plasma concentration and appearance of meal-derived fatty acids in very-low density lipoprotein (VLDL)-TAG, chylomicron-TAG, and NEFA were determined over 8-hours. Indirect calorimetry with 13CO2 enrichment determined total and meal-derived fatty acid oxidation rates, and plasma b-hydroxybutyrate (3-OHB) concentration was measured to assess ketogenesis. BAC exhibited lower postprandial TAG (P=0.006) and VLDL-TAG (P=0.002) concentrations than WE. The appearance of meal-derived fatty acids in VLDL-TAG was lower in BAC than WE (P=0.004). Following the second meal, BAC showed a trend for lower chylomicron-TAG concentration (P=0.057). There were no ethnic differences in the appearance of meal-derived fatty acids in chylomicron-TAG. Cumulative fatty acid oxidation and the NEFA:3-OHB ratio were similar in WE and BAC. In conclusion, BAC exhibit lower postprandial TAG concentrations compared with WE men, driven by lower VLDL-TAG concentrations and possibly lower chylomicron-TAG in the late postprandial period. In BAC, the lower VLDL-TAG concentration was partially driven by a lower appearance of meal-derived fatty acids in VLDL-TAG. These findings suggest that postprandial fatty acid trafficking may be a less important determinant of cardiometabolic risk in BAC than WE men.

Completeness of revascularization by FFRCT in stable angina: Association to adverse cardiovascular outcomes.

BACKGROUND: The prognostic impact of complete coronary revascularization relative to non-invasive testing methods is unknown. OBJECTIVES: To assess the association between completeness of revascularization defined by CTA-derived fractional flow reserve (FFRCT) and cardiovascular outcomes in patients with stable angina. METHODS: Multicenter 3-year follow-up study of patients with new onset stable angina and ≥ 30% stenosis by CTA. The lesion-specific FFRCT value (two cm-distal-to-stenosis) was registered in all vessels with stenosis and considered abnormal when ≤ 0.80. Patients with FFRCT ≤ 0.80 were categorized as: Completely revascularized (CR-FFRCT), all vessels with FFRCT ≤ 0.80 revascularized; incompletely revascularized (IR-FFRCT), ≥ 1 vessels with FFRCT ≤ 0.80 non-revascularized. Early revascularization (< 90 days from index CTA) categorized vessels as revascularized. The primary endpoint comprised cardiovascular death and non-fatal myocardial infarction; the secondary endpoint vessel-specific late revascularization and non-fatal myocardial infarction. RESULTS: Amongst 900 patients and 1759 vessels, FFRCT was ≤ 0.80 in 377 (42%) patients, 536 (30%) vessels; revascularization was performed in 244 (27%) patients, 340 (19%) vessels. Risk of the primary endpoint was higher for IR-FFRCT (15/210 [7.1%]) compared to CR-FFRCT (4/167 [2.4%]), RR: 2.98; 95% CI: 1.01-8.8, p â€‹= â€‹0.036, and to normal FFRCT (3/523 [0.6%]), RR: 12.45; 95% CI: 3.6-42.6, p â€‹< â€‹0.001. Incidence of the secondary endpoint was higher in non-revascularized vessels with FFRCT ≤ 0.80 (29/250 [12%]) compared to revascularized vessels with FFRCT ≤ 0.80 (5/286 [1.7%]), p â€‹= â€‹0.001, and to vessels with FFRCT > 0.80 (10/1223 [0.8%]), p â€‹< â€‹0.001. CONCLUSION: Incomplete revascularization of patients with lesion-specific FFRCT ≤ 0.80 is associated to unfavorable cardiovascular outcomes compared to those with complete revascularization or FFRCT > 0.80.

Robust parahydrogen-induced polarization at high concentrations.

Parahydrogen-induced polarization (PHIP) is a potent technique for generating target molecules with high nuclear spin polarization. The PHIP process involves a chemical reaction between parahydrogen and a target molecule, followed by the transformation of nuclear singlet spin order into magnetization of a designated target nucleus through magnetic field manipulations. Although the singlet-to-magnetization polarization transfer process works effectively at moderate concentrations, it is observed to become much less efficient at high molar polarization, defined as the product of polarization and concentration. This strong dependence on the molar polarization is attributed to interference due to the field produced by the sample magnetization during polarization transfer, which leads to complex dynamics and can severely affect the scalability of the technique. We address this challenge with a pulse sequence that suppresses the influence of the distant dipolar field, while simultaneously achieving singlet-to-magnetization polarization transfer to the desired target spins, free from restrictions on the molar polarization.

Unraveling the Molecular Dance: Insights into TREM2/DAP12 Complex Formation in Alzheimer's Disease through Molecular Dynamics Simulations.

Alzheimer's disease (AD) is a widespread neurodegenerative condition affecting millions globally. Recent research has implicated variants of the triggering receptor expressed in myeloid cells 2 (TREM2) as risk factors for AD. TREM2, an immunomodulatory receptor on microglial surfaces, plays a pivotal role in regulating microglial activation by association with DNAX-activation protein 12 (DAP12). Despite its significance, the mechanism underlying the formation of the complex between the transmembrane domains (TMDs) of TREM2 and DAP12 remains unclear. This study employs multiscale molecular dynamics (MD) simulations to investigate three TMD complex models, including two derived from experiments and one generated by AlphaFold2. Conducted within a lipid membrane consisting of an 80:20 mixture of phosphatidylcholine (POPC) and cholesterol, our analysis reveals hydrogen-bonding interactions between K26 of TREM2 and D16 of DAP12 in all three models, consistent with previous experimental findings. Our results elucidate the different spatial conformations observed in the models and offer insights into the structure of the TREM2/DAP12 TMD complex. Furthermore, we elucidate the role of charged residues in the assembly structure of the complex within the lipid membrane. These findings enhance our understanding of the molecular mechanism governing TREM2/DAP12 complex formation, providing a foundation for designing novel therapeutic strategies to address AD and other neurodegenerative diseases.

Clinical findings and outcome in feline tetanus: a multicentric retrospective study of 27 cases and review of the literature.

Tetanus is a toxigenic illness caused by the action of Clostridium tetani neurotoxin (TeNT), which results in partial or generalized muscle stiffness in infected mammals and birds. The disease is rarely reported in cats due to their innate resistance to the toxin. This multicentric retrospective study aimed to describe a significant population of cats with a diagnosis of tetanus and report their signalment, clinical and neurological signs, diagnostic findings, treatment, and outcome. A retrospective search through medical records from 11 referral centers in Europe resulted in the identification of 27 cases of feline tetanus from July 2005 to April 2023. These cases were further compared with previously reported cases in the veterinary literature. Young cats were more commonly represented than older cats, with a median age of 4 years. Clinical signs were initially characterized by a lame and/or stiff limb, near the primary injury site, in 17/26 (65%) cats. Signs were focal or multifocal in 21/27 (78%) cats of this study and one typical sign was the inability to flex the most severely affected limbs. Electrodiagnostic studies revealed characteristic changes, such as continuous spontaneous motor unit discharges in both agonist and antagonist muscles. Such studies are particularly useful in focal and multifocal cases and should be performed to further support the diagnosis. The toxin was successfully identified in one case using the mouse bioassay. Treatment included antibiotherapy (metronidazole) in most cases, muscle relaxants, appropriate nursing cares and handling of potential complications. Overall, the outcome appeared to be positive, with only 1/27 (3.7%) cats being euthanized due to financial restrains. 23/25 (92%) cats returned to an independent ambulatory capacity on all limbs within a median delay of 25 days. Mild to moderate long-term sequelae were reported in eight (30%) cats. This multicentric study is the first to bring together such a large number of cats affected with tetanus. Presentation of the disease in cats differs from that observed in humans and dogs, with most cats being locally affected. Compared to previous reports of tetanus, this series of cats had a better outcome overall, especially for cats affected with generalized tetanus.

A Guide to Transcatheter Aortic Valve Design and Systematic Planning for a Redo-TAV (TAV-in-TAV) Procedure.

Transcatheter aortic valve replacement (TAVR) has become more common than surgical aortic valve replacement since 2016, with over 200,000 procedures globally each year. As patients increasingly outlive their TAVR devices, managing these cases is a growing concern. Treatment options include surgical removal of the old TAVR device (transcatheter aortic valve [TAV] explant) or implantation of a new transcatheter aortic valve (redo TAV). Redo TAV is complex because of the unique designs of TAV devices; compatibility issues; and the need for individualized planning based on factors such as implant depth, shape, and coronary artery relationships. This review serves as a comprehensive guide for redo TAV, detailing the design characteristics of TAV devices, device compatibility, standardized terminology, and a structured approach for computed tomography analysis. It aims to facilitate decision making, risk identification, and achieving optimal outcomes in redo TAV procedures.

Co-shared genomic alterations within tumors from patients with both myeloproliferative neoplasms and lymphoma.

Not available.

Resumen: Consenso internacional para la nomenclatura y clasificación de la válvula aórtica bicúspide congénita y su aortopatía, con fines clínicos, quirúrgicos, intervencionistas y de investigación / Summary: International consensus statement on nomenclature and classification of the congenital bicuspid aortic valve and its aortopathy, for clinical, surgical, interventional and research purposes

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Abstract This consensus of nomenclature and classification for congenital bicuspid aortic valve and its aortopathy is evidence-based and intended for universal use by physicians (both pediatricians and adults), echocardiographers, advanced cardiovascular imaging specialists, interventional cardiologists, cardiovascular surgeons, pathologists, geneticists, and researchers spanning these areas of clinical and basic research. In addition, as long as new key and reference research is available, this international consensus may be subject to change based on evidence-based data1.

Effect of Sex and Flow Status on Outcomes After Surgical or Transcatheter Aortic Valve Replacement.

Background: Low stroke volume index <35 ml/m2 despite preserved ejection fraction (paradoxical low flow [PLF]) is associated with adverse outcomes in patients with aortic stenosis undergoing transcatheter aortic valve replacement (TAVR) or surgical aortic valve replacement (SAVR). However, whether the risk associated with PLF is similar in both sexes is unknown. Objectives: The purpose of this study was to analyze the risk associated with PLF in severe aortic stenosis for men and women randomized to TAVR or SAVR. Methods: Patients with ejection fraction ≥50% from the PARTNER (Placement of Aortic Transcatheter Valves) 2 and 3 trials were stratified by sex and treatment arm. The impact of PLF on the 2-year occurrence of the composite of death or heart failure hospitalization (primary endpoint) and of all-cause mortality alone (secondary endpoint) was analyzed. Analysis of variance was used to assess baseline differences between groups. Multivariate Cox regression analysis was used to identify predictors of the endpoint. Results: Out of 2,242 patients, PLF was present in 390 men and 239 women (30% vs 26%, P = 0.06). PLF was associated with a higher rate of NYHA functional class III to IV dyspnea (60% vs 54%, P < 0.001) and a higher prevalence of atrial fibrillation (39% vs 24%, P < 0.001). PLF was a significant predictor of the primary endpoint among women undergoing SAVR in multivariate analysis (adjusted HR: 2.25 [95% CI: 1.14-4.43], P = 0.02) but was not associated with a worse outcome in any of the other groups (all P > 0.05). Conclusions: In women with PLF, TAVR may improve outcomes compared to SAVR. PLF appears to have less impact on outcomes in men.

Stress-dependent condensate formation regulated by the ubiquitin-related modifier Urm1.

The ability of proteins and RNA to coalesce into phase-separated assemblies, such as the nucleolus and stress granules, is a basic principle in organizing membraneless cellular compartments. While the constituents of biomolecular condensates are generally well documented, the mechanisms underlying their formation under stress are only partially understood. Here, we show in yeast that covalent modification with the ubiquitin-like modifier Urm1 promotes the phase separation of a wide range of proteins. We find that the drop in cellular pH induced by stress triggers Urm1 self-association and its interaction with both target proteins and the Urm1-conjugating enzyme Uba4. Urmylation of stress-sensitive proteins promotes their deposition into stress granules and nuclear condensates. Yeast cells lacking Urm1 exhibit condensate defects that manifest in reduced stress resilience. We propose that Urm1 acts as a reversible molecular "adhesive" to drive protective phase separation of functionally critical proteins under cellular stress.