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Evaluating Cardiovascular Devices Using Observational Analyses
It has long been accepted that observational analyses have an important role in evaluating use patterns and assessing the safety of different treatments, including cardiovascular devices, in clinical practice. With the proliferation of large electronic databases, there has been increasing interest in using observational analyses to also examine the comparative effectiveness of devices. However, these analyses are often met with skepticism because of concerns about whether they can generate credible evidence about causal effects. This is in part a result of the difficulty in meeting the assumptions necessary to interpret observational associations as causal effects and of the wide variability in analytic rigor. In this review, we outline frameworks and review methods for using observational analyses to answer questions about the effectiveness and safety of cardiovascular devices. We highlight the target trial framework as a practical tool for guiding observational comparative effectiveness analyses. We illustrate how the framework allows investigators planning and conducting observational analyses to organize their activities as responses to 3 prompting questions. First, what is the research question of the study (ie, “What do we want?”)? Second, what are the resources—including background knowledge, research concepts, principles and methods, and available data—that can be brought to bear on the research question (ie, “What do we have?”)? And third, what specific steps should be taken to use the available resources to answer the research question (ie, “What do we do?”)? We focus our exposition on the evaluation of cardiovascular devices, for which randomized trial data are often limited and there is a strong need for real-world evidence. In this setting, real-world evidence is usually derived from observational comparisons of the treatment of interest with relevant comparator groups using data captured during routine care. A principled approach to the planning and conduct of observational analyses can improve the quality of real-world evidence generation and ensure that the results of observational studies on medical devices can support meaningful conclusions about the risks and benefits of new devices.
Carbon-fixing strain-based biochar outperforms biochar alone in enhancing microbial symbiosis and soil organic carbon
NEXT-FRET maps nonequilibrium rerouting of <i>Escherichia coli</i> maltose-binding protein folding by its signal peptide and chaperones
Proteins fold through dynamic intermediates that dictate their routes to functional structures, with ensembles predominantly displaying heterogeneity across nanosecond-to-microsecond timescales. Directly observing these states in solution remains challenging as single-molecule methods often require technically demanding microfluidics, surface attachment that alters behavior, or denaturants that distort natural energy landscapes. Here we introduce NEXT-FRET, a solution-based single-molecule platform combining single-molecule FRET (smFRET) with time-varying Gaussian mixture modeling to resolve how diffusing proteins populate and interconvert between conformations under near-native conditions. By incorporating prior equilibrium information into time-dependent analysis, NEXT-FRET requires a few molecules per condition and accessible instrumentation, enabling application in the presence of chaperones and aggregation-prone precursors. We apply NEXT-FRET to the Escherichia coli Maltose-Binding Protein (MBP) and pre-MBP to reveal a long-sought closed on-pathway intermediate that exchanges with both native and unfolded states. The signal peptide raises the barrier selectively for the intermediate-to-native transition. Profiling interactions with chaperones shows that each stabilizes nonnative conformations distinctively, generating kinetic traps. These findings demonstrate that sequence features and proteostasis factors actively reshape the folding landscape. By following molecules out of equilibrium, NEXT-FRET reveals intermediates invisible at equilibrium. This reflects the inherent nonequilibrium character of cells, which maintain order through ongoing energy exchange and dissipation, with fluctuations governing the kinetics and connectivity of biomolecular states. By exposing transient intermediates and quantifying kinetic flows, NEXT-FRET offers a scalable strategy to interrogate nonequilibrium dynamics, providing mechanistic insights into protein (mis)folding, enzyme catalysis, ligand binding and broader biomolecular reactions with implications for biotechnology and therapeutics.
Targeting Lymph Node Entry to Improve Cardiac Graft Tolerance
Biomechanical evaluation of structural integrity after tibial plateau leveling osteotomy in dogs using finite element analysis
Beyond antibodies in GAD65 autoimmunity: Reframing pathogenesis through intrathecal B–T cell cross-talk
A New Dawn for Pre-Hospital Heparin in STEMI? Insights From the HEPARIN STEMI Trial
Efficient removal of tetracycline from aqueous media using a novel Zr-MOF/CuCo2O4 nanocomposite: synthesis, characterization, and mechanistic insights
Letter by Pan and Ding Regarding Article, “Oral Pathobionts Aggravate Myocardial Infarction Through Mobilization of B2 Cells”
Design optimization of wearable antennas using an adaptive network-based fuzzy inference system
Politics embodied: How politics shapes and is shaped by the bodily experience of emotions
Political emotions are widely acknowledged as key drivers of political participation and polarization. Yet while it is well established that political emotions matter, far less is known about how they are felt and represented in the body. Across a preregistered, nationally representative study ( N = 992), we introduce an embodied approach to political emotion using the validated emBODY-tool, which allows participants to map where in the body they experience sensations when feeling canonical emotions (e.g., anger) and their political counterparts (e.g., “political anger”). Specifically, we address three questions: 1) how political emotions are embodied and differ from their nonpolitical counterparts, 2) whether political dispositions influence how these political emotions are embodied, and 3) how their embodied experience interacts with political dispositions in explaining political attitudes and behavior. Pixelwise bodily sensation maps and aggregated “embodied impact” metrics show that political anger, anxiety, depression, disgust, and hope do not merely mirror their canonical forms, but take on distinct bodily patterns. Political ideology, but not political sophistication, modulates these bodily experiences, with Democrat-leaning participants reporting more intense sensations for negative political emotions, suggesting the presence of “ideological bodies.” Crucially, political participation is not explained by how intensely people report feeling emotions, but is instead closely linked to how strongly these emotions are embodied in the body. Together, our findings underscore the body’s central role in democratic engagement by showing how political contexts shape embodied emotional experience and how these embodied experiences shape politics and democracy.
HEV-Targeted Antibody-Drug Conjugate Promotes Long-Term Cardiac Allograft Acceptance
BACKGROUND: The entrance of naive T cells into lymph nodes (LNs) is a crucial step for induction of heart transplant acceptance under costimulatory blockade. Specialized blood vessels within the LN known as high endothelial venules (HEVs) mediate this process. HEVs express a key glycoprotein containing 6-sulfo sialyl Lewis X, the binding site for L-selectin on the membrane of naive T cells. The proper formation of this carbohydrate requires sulfation by N-acetylglucosamine 6-O-sulfotransferases, particularly CHST4. Given the critical role of CHST4 in HEVs and transplant immunity, we aimed to develop a first-in-class antibody-drug conjugate (ADC) targeting the CHST4/HEV axis to deliver immunoregulatory therapeutics to LNs and promote long-term cardiac transplant survival. METHODS: We used CHST4 knockout mice and inducible diphtheria toxin receptor mouse models to investigate the role of CHST4 in HEV function during heart allograft transplantation. To assess the impact of CHST4 deficiency on heart transplant outcomes, we used fully major histocompatibility complex–mismatched and single major histocompatibility complex class II–mismatched models to study acute and chronic heart transplant rejection, respectively. We developed a first-in-class, dual-payload antibody-drug conjugate aimed at promoting regulatory T cells by conjugating rapamycin and tubastatin A to the HEV-targeting MHA112 antibody. The efficacy of this ADC was tested in murine heart allograft models. RESULTS: Loss of CHST4 expression by HEVs impaired the entry of naive T cells into LNs and consequently reduced regulatory T cell formation, thereby disrupting cardiac transplant acceptance under costimulatory blockade. Treatment with the HEV-targeted ADC carrying rapamycin and tubastatin A prolonged murine heart allograft survival and suppressed chronic rejection, a major barrier to long-term graft success. Mechanistically, this ADC enhanced regulatory T cell induction, reduced proinflammatory T cells within lymph nodes, and decreased immune cell infiltration in cardiac allografts, achieving these effects with substantially lower doses of rapamycin and tubastatin A compared with administration of the free drugs. CONCLUSIONS: Our findings uncover a key mechanistic role for CHST4 in HEVs in facilitating the regulatory T cell generation within the LN and promoting heart transplant acceptance. Moreover, we introduce a promising CHST4-based, HEV-targeted ADC therapy as a potential strategy to suppress heart transplant rejection.
Prediction of hydraulic support pressure in a coal longwall face by integrating multi-head attention and temporal feature learning
Swartkrans <i>Paranthropus</i> and Sterkfontein <i>Australopithecus</i> from southern Africa had different locomotor repertoires
Southern African hominin fossils traditionally attributed to Paranthropus robustus and Australopithecus africanus are differentiated from each other by their dentition and cranial architecture, but their postcranial anatomy has typically been regarded functionally as broadly similar (i.e., terrestrial bipedalism with some degree of arboreal locomotion). Testing the hypothesis of a similar locomotor repertoire between these two taxa has been complicated by a lack of postcranial fossils attributable to P. robustus . Here, we detail our comparative examination of the internal bone anatomy of a recently described c. 1.8 Ma P. robustus articulating femur and tibia, which suggests distinct patterns of joint loading and locomotor behavior. Our analysis of cortical bone in the hip and trabecular bone in the ankle, knee, and hip joints suggests that P . robustus habitually adopted a high frequency of ankle, knee, and hip flexion, as required for climbing, while Australopithecus from a c. 3.4 Ma level at the site of Sterkfontein displays a more modern human-like structural pattern across the lower limb joints consistent with comparatively more frequent terrestrial bipedalism. These results reveal that geologically younger P . robustus likely used arboreality more frequently than older Sterkfontein Australopithecus . Together with differences in masticatory behavior, this line of evidence indicates that these two hominin taxa occupied distinct ecological niches.
Response by Chen and Duan to Letter Regarding Article, “Oral Pathobionts Aggravate Myocardial Infarction Through Mobilization of B2 Cells”
Effect of lactic acid bacteria inoculation and urea on fermentation quality and aerobic stability of sugarcane top silage
Oak masting breaks down in a highly fragmented, pollen-limited landscape
Masting, the production of variable and synchronous seed crops, is common among wind pollinated trees, and periodic pollen limitation is thought to be an important component of the process of masting. However, little is known either about the dynamics of mast seed production or pollen limitation in isolated trees. We tracked seed production of valley oak ( Quercus lobata ) over 11 years in a highly fragmented landscape in California’s Central Valley in which many trees lacked conspecific neighbors within 500 m. We found that oaks with closer neighbors produced more acorns on average than oaks with fewer neighbors. Consistent with theories linking mast seeding and pollination, the isolation effect was most apparent in the highest seed production years. While individual trees showed substantial interannual variation in seed production, we observed little synchrony in seed production among individuals compared to intact oak populations throughout California. Our results indicate that highly fragmented populations suffer signs of pollen limitation and do not produce synchronous seed crops. Fragmentation, alongside climate change, is a dimension of global change that interrupts the typical seed production dynamics of trees.
Prehospital Heparin Administration in Patients With STEMI Undergoing Primary PCI: HEPARIN-STEMI Randomized Controlled Trial
BACKGROUND: Primary percutaneous coronary intervention (PCI) is the preferred reperfusion strategy for patients with ST-segment–elevation myocardial infarction (STEMI). We investigated the benefits and safety of pretreatment with unfractionated heparin (UFH) in patients with STEMI referred to primary PCI. METHODS: In HEPARIN-STEMI (Pretreatment With Unfractionated Heparin for ST Elevation Myocardial Infarction)—a single-center, open-label, randomized controlled trial—patients with STEMI with ≤6 hours symptom duration were assigned to receive either a 70- to 100-IE/kg bolus of UFH at first prehospital medical contact plus a supplemental dose before PCI, adjusted to activated clothing time ≥250 seconds, or to a control group receiving standard UFH at the time of PCI. The primary efficacy end point was TIMI (Thrombolysis in Myocardial Infarction) flow grade 2–3 in the infarct-related artery at initial coronary angiography. The primary safety end point was BARC (Bleeding Academic Research Consortium) type 3–5 bleeding during the index hospital stay. RESULTS: From March 2022 to February 2025, 298 patients were randomized to UFH pretreatment and 295 to the control group. The groups were comparable in age, sex, risk factors, previous cardiovascular events, and median delay from symptoms to coronary angiography (145 versus 150 minutes; P =0.814). The median time from UFH pretreatment to coronary angiography was 60 minutes (25th–75th interquartile range, 47–55 minutes). TIMI flow grade 2–3 in the infarct-related artery was documented in 43% of patients with UFH pretreatment and 27% of patients in the control group (relative risk, 1.59 [95% CI, 1.27–1.98]; P <0.001), with no significant difference in BARC type 3–5 bleeding (2.4% versus 2.0%; relative risk, 1.16 [95% CI, 0.39–3.45]; P =0.789). CONCLUSIONS: In patients with STEMI undergoing primary PCI, in a mature STEMI network, pretreatment with UFH at first prehospital medical contact was associated with an absolute 16% increase in infarct-related artery patency without an increased risk of bleeding. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT05247424.