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DNA-Encoded Libraries (DELs) allow the parallel screening of millions of compounds for various applications, including de novo discovery or affinity maturation campaigns. However, library construction and HIT resynthesis can be cumbersome, especially when library members present an unknown stereochemistry. We introduce a permutational encoding strategy suitable for the construction of highly pure single-stranded single-pharmacophore DELs, designed to distinguish isomers at the sequencing level (e.g., stereoisomers, regio-isomers, and peptide sequences). This approach was validated by synthesizing a mock 921,600-member 4-amino-proline single-stranded DEL ("DEL1"). While screening DEL1 against different targets, high-throughput sequencing results showed selective enrichment of the most potent stereoisomers, with enrichment factors that outperform conventional encoding strategies. The versatility of our methodology was additionally validated by encoding 24 scaffolds derived from different permutations of the amino acid sequence of a previously described cyclic peptide targeting Fibroblast Activation Protein (FAP-2286). The resulting library ("DEL2") was interrogated against human FAP, showing selective enrichment of five cyclic peptides. We observed a direct correlation between enrichment factors and on-DNA binding affinities. The presented encoding methodology accelerates drug discovery by facilitating library synthesis and streamlining HIT resynthesis while enhancing enrichment factors at the DEL sequencing level. This facilitates the identification of HIT candidates prior to medicinal chemistry and affinity maturation campaigns.
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ADN de Cadena Simple , ADN de Cadena Simple/química , ADN de Cadena Simple/genética , Biblioteca de Genes , Descubrimiento de Drogas/métodos , Estereoisomerismo , Humanos , Péptidos Cíclicos/química , Bibliotecas de Moléculas Pequeñas/química , Bibliotecas de Moléculas Pequeñas/farmacología , Secuencia de AminoácidosRESUMEN
Prostate-specific membrane antigen (PSMA)-targeted radio ligand therapeutics (RLTs), such as [177Lu]Lu-PSMA-617 (Pluvicto), have been shown to accumulate in salivary glands and kidneys, potentially leading to undesired side effects. As unwanted accumulation in normal organs may derive from the cross-reactivity of PSMA ligands to glutamate carboxypeptidase III (GCPIII), it may be convenient to block this interaction with GCPIII-selective ligands. Parallel screening of a DNA-encoded chemical library (DEL) against GCPIII and PSMA allowed the identification of GCPIII binders. Structure-activity relationship (SAR) studies resulted in the identification of nanomolar GCPIII ligands with up to 1000-fold selectivity over PSMA. We studied the ability of GCPIII ligands to counteract the binding of [177Lu]Lu-PSMA-617 to human salivary glands by autoradiography and could demonstrate a partial radioprotection.
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Dipéptidos , Compuestos Heterocíclicos con 1 Anillo , Lutecio , Humanos , Antígenos de Superficie , Autorradiografía , Dipéptidos/química , Dipéptidos/metabolismo , Glutamato Carboxipeptidasa II , Compuestos Heterocíclicos con 1 Anillo/química , Compuestos Heterocíclicos con 1 Anillo/metabolismo , Ligandos , Lutecio/química , Lutecio/metabolismo , Antígeno Prostático Específico , Radioisótopos/química , Radioisótopos/metabolismo , Radiofármacos/química , Radiofármacos/metabolismo , Radiofármacos/farmacocinética , Glándulas Salivales/metabolismo , Relación Estructura-Actividad , Distribución TisularRESUMEN
Meningitis and ventriculitis, due to carbapenem-resistant Enterobacterales, are frequently associated with significant morbidity and mortality. In the case of multi-drug-resistant pathogens, it is necessary to consider the limited susceptibility profile as well as the penetration of the antimicrobials into the brain. Limited data are available regarding the treatment of central nervous system infections caused by carbapenem-resistant Enterobacterales. We report a study of a patient treated with meropenem-vaborbactam in the case of post-neurosurgical meningitis due to carbapenemase-producing Klebsiella pneumoniae (CPKP).
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DNA-encoded chemical libraries (DELs) are powerful drug discovery tools, enabling the parallel screening of millions of DNA-barcoded compounds. We investigated how the DEL input affects the hit discovery rate in DEL screenings. Evaluation of selection fingerprints revealed that the use of approximately 105 copies of each library member is required for the confident identification of nanomolar hits, using generally applicable methodologies.
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Prehospital field triage often fails to accurately identify the need for emergent surgical or non-surgical procedures, resulting in inefficient resource utilization and increased costs. This study aimed to analyze prehospital factors associated with the need for emergent procedures (such as surgery or interventional angiography) within 6 h of hospital admission. Additionally, our goal was to develop a prehospital triage tool capable of estimating the likelihood of requiring an emergent procedure following hospital admission. We conducted a retrospective observational study, analyzing both prehospital and in-hospital data obtained from the Lombardy Trauma Registry. We conducted a multivariable logistic regression analysis to identify independent predictors of emergency procedures within the first 6 h from admission. Subsequently, we developed and internally validated a triage score composed of factors associated with the probability of requiring an emergency procedure. The study included a total of 3985 patients, among whom 295 (7.4%) required an emergent procedure within 6 h. Age, penetrating injury, downfall, cardiac arrest, poor neurological status, endotracheal intubation, systolic pressure, diastolic pressure, shock index, respiratory rate and tachycardia were identified as predictors of requiring an emergency procedure. A triage score generated from these predictors showed a good predictive power (AUC of the ROC curve: 0.81) to identify patients requiring an emergent surgical or non-surgical procedure within 6 h from hospital admission. The proposed triage score might contribute to predicting the need for immediate resource availability in trauma patients.
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Class IA phosphoinositide 3-kinase alpha (PI3Kα) is an important drug target because it is one of the most frequently mutated proteins in human cancers. However, small molecule inhibitors currently on the market or under development have safety concerns due to a lack of selectivity. Therefore, other chemical scaffolds or unique mechanisms of catalytic kinase inhibition are needed. Here, we report the cryo-electron microscopy structures of wild-type PI3Kα, the dimer of p110α and p85α, in complex with three Y-shaped ligands [cpd16 (compound 16), cpd17 (compound 17), and cpd18 (compound 18)] of different affinities and no inhibitory effect on the kinase activity. Unlike ATP-competitive inhibitors, cpd17 adopts a Y-shaped conformation with one arm inserted into a binding pocket formed by R770 and W780 and the other arm lodged in the ATP-binding pocket at an angle that is different from that of the ATP phosphate tail. Such a special interaction induces a conformation of PI3Kα resembling that of the unliganded protein. These observations were confirmed with two isomers (cpd16 and cpd18). Further analysis of these Y-shaped ligands revealed the structural basis of differential binding affinities caused by stereo- or regiochemical modifications. Our results may offer a different direction toward the design of therapeutic agents against PI3Kα.
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Fosfatidilinositol 3-Quinasa , Fosfatidilinositol 3-Quinasas , Humanos , Fosfatidilinositol 3-Quinasas/metabolismo , Ligandos , Microscopía por Crioelectrón , Adenosina Trifosfato/metabolismoRESUMEN
DNA-Encoded Chemical Libraries (DELs) have emerged as efficient and cost-effective ligand discovery tools, which enable the generation of protein-ligand interaction data of unprecedented size. In this article, we present an approach that combines DEL screening and instance-level deep learning modeling to identify tumor-targeting ligands against carbonic anhydrase IX (CAIX), a clinically validated marker of hypoxia and clear cell renal cell carcinoma. We present a new ligand identification and hit-to-lead strategy driven by machine learning models trained on DELs, which expand the scope of DEL-derived chemical motifs. CAIX-screening datasets obtained from three different DELs were used to train machine learning models for generating novel hits, dissimilar to elements present in the original DELs. Out of the 152 novel potential hits that were identified with our approach and screened in an in vitro enzymatic inhibition assay, 70% displayed submicromolar activities (IC50 < 1 µM). To generate lead compounds that are functionalized with anticancer payloads, analogues of top hits were prioritized for synthesis based on the predicted CAIX affinity and synthetic feasibility. Three lead candidates showed accumulation on the surface of CAIX-expressing tumor cells in cellular binding assays. The best compound displayed an in vitro KD of 5.7 nM and selectively targeted tumors in mice bearing human renal cell carcinoma lesions. Our results demonstrate the synergy between DEL and machine learning for the identification of novel hits and for the successful translation of lead candidates for in vivo targeting applications.
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DNA-encoded chemical libraries (DELs) consist of large chemical compound collections individually linked to DNA barcodes, facilitating pooled construction and screening. However, screening campaigns often fail if the molecular arrangement of the building blocks is not conducive to an efficient interaction with a protein target. Here we postulated that the use of rigid, compact and stereo-defined central scaffolds for DEL synthesis may facilitate the discovery of very specific ligands capable of discriminating between closely related protein targets. We synthesized a DEL comprising 3,735,936 members, featuring the four stereoisomers of 4-aminopyrrolidine-2-carboxylic acid as central scaffolds. The library was screened in comparative selections against pharmaceutically relevant targets and their closely related protein isoforms. Hit validation results revealed a strong impact of stereochemistry, with large affinity differences between stereoisomers. We identified potent isozyme-selective ligands against multiple protein targets. Some of these hits, specific to tumour-associated antigens, demonstrated tumour-selective targeting in vitro and in vivo. Collectively, constructing DELs with stereo-defined elements contributed to high library productivity and ligand selectivity.
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BACKGROUND: Changing trunk inclination affects lung function in patients with ARDS. However, its impacts on PEEP titration remain unknown. The primary aim of this study was to assess, in mechanically ventilated patients with COVID-19 ARDS, the effects of trunk inclination on PEEP titration. The secondary aim was to compare respiratory mechanics and gas exchange in the semi-recumbent (40° head-of-the-bed) and supine-flat (0°) positions following PEEP titration. METHODS: Twelve patients were positioned both at 40° and 0° trunk inclination (randomized order). The PEEP associated with the best compromise between overdistension and collapse guided by Electrical Impedance Tomography (PEEPEIT) was set. After 30 min of controlled mechanical ventilation, data regarding respiratory mechanics, gas exchange, and EIT parameters were collected. The same procedure was repeated for the other trunk inclination. RESULTS: PEEPEIT was lower in the semi-recumbent than in the supine-flat position (8 ± 2 vs. 13 ± 2 cmH2O, p < 0.001). A semi-recumbent position with optimized PEEP resulted in higher PaO2:FiO2 (141 ± 46 vs. 196 ± 99, p = 0.02) and a lower global inhomogeneity index (46 ± 10 vs. 53 ± 11, p = 0.008). After 30 min of observation, a loss of aeration (measured by EIT) was observed only in the supine-flat position (-153 ± 162 vs. 27 ± 203 mL, p = 0.007). CONCLUSIONS: A semi-recumbent position is associated with lower PEEPEIT and results in better oxygenation, less derecruitment, and more homogenous ventilation compared to the supine-flat position.
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Glutamato Carboxipeptidasa II , Urea , Humanos , Ligandos , Antígenos de Superficie , Línea Celular TumoralRESUMEN
BACKGROUND: Impairment of ventilation and perfusion (V/Q) matching is a common mechanism leading to hypoxemia in patients with acute respiratory failure requiring intensive care unit (ICU) admission. While ventilation has been thoroughly investigated, little progress has been made to monitor pulmonary perfusion at the bedside and treat impaired blood distribution. The study aimed to assess real-time changes in regional pulmonary perfusion in response to a therapeutic intervention. METHODS: Single-center prospective study that enrolled adult patients with ARDS caused by SARS-Cov-2 who were sedated, paralyzed, and mechanically ventilated. The distribution of pulmonary perfusion was assessed through electrical impedance tomography (EIT) after the injection of a 10-ml bolus of hypertonic saline. The therapeutic intervention consisted in the administration of inhaled nitric oxide (iNO), as rescue therapy for refractory hypoxemia. Each patient underwent two 15-min steps at 0 and 20 ppm iNO, respectively. At each step, respiratory, gas exchange, and hemodynamic parameters were recorded, and V/Q distribution was measured, with unchanged ventilatory settings. RESULTS: Ten 65 [56-75] years old patients with moderate (40%) and severe (60%) ARDS were studied 10 [4-20] days after intubation. Gas exchange improved at 20 ppm iNO (PaO2/FiO2 from 86 ± 16 to 110 ± 30 mmHg, p = 0.001; venous admixture from 51 ± 8 to 45 ± 7%, p = 0.0045; dead space from 29 ± 8 to 25 ± 6%, p = 0.008). The respiratory system's elastic properties and ventilation distribution were unaltered by iNO. Hemodynamics did not change after gas initiation (cardiac output 7.6 ± 1.9 vs. 7.7 ± 1.9 L/min, p = 0.66). The EIT pixel perfusion maps showed a variety of patterns of changes in pulmonary blood flow, whose increase positively correlated with PaO2/FiO2 increase (R2 = 0.50, p = 0.049). CONCLUSIONS: The assessment of lung perfusion is feasible at the bedside and blood distribution can be modulated with effects that are visualized in vivo. These findings might lay the foundations for testing new therapies aimed at optimizing the regional perfusion in the lungs.
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COVID-19 , Síndrome de Dificultad Respiratoria , Insuficiencia Respiratoria , Adulto , Humanos , Persona de Mediana Edad , Anciano , Circulación Pulmonar , Estudios Prospectivos , Intercambio Gaseoso Pulmonar , COVID-19/complicaciones , SARS-CoV-2 , Síndrome de Dificultad Respiratoria/tratamiento farmacológico , Síndrome de Dificultad Respiratoria/etiología , Óxido Nítrico , Hipoxia , Insuficiencia Respiratoria/tratamiento farmacológico , Administración por InhalaciónRESUMEN
BACKGROUND: The role of upper airways microbiota and its association with ventilator-associated pneumonia (VAP) development in mechanically ventilated (MV) patients is unclear. Taking advantage of data collected in a prospective study aimed to assess the composition and over-time variation of upper airway microbiota in patients MV for non-pulmonary reasons, we describe upper airway microbiota characteristics among VAP and NO-VAP patients. METHODS: Exploratory analysis of data collected in a prospective observational study on patients intubated for non-pulmonary conditions. Microbiota analysis (trough 16S-rRNA gene profiling) was performed on endotracheal aspirates (at intubation, T0, and after 72 h, T3) of patients with VAP (cases cohort) and a subgroup of NO-VAP patients (control cohort, matched according to total intubation time). RESULTS: Samples from 13 VAP patients and 22 NO-VAP matched controls were analyzed. At intubation (T0), patients with VAP revealed a significantly lower microbial complexity of the microbiota of the upper airways compared to NO-VAP controls (alpha diversity index of 84 ± 37 and 160 ± 102, in VAP and NO_VAP group, respectively, p-value < 0.012). Furthermore, an overall decrease in microbial diversity was observed in both groups at T3 as compared to T0. At T3, a loss of some genera (Prevotella 7, Fusobacterium, Neisseria, Escherichia-Shigella and Haemophilus) was found in VAP patients. In contrast, eight genera belonging to the Bacteroidetes, Firmicutes and Fusobacteria phyla was predominant in this group. However, it is unclear whether VAP caused dysbiosis or dysbiosis caused VAP. CONCLUSIONS: In a small sample size of intubated patients, microbial diversity at intubation was less in patients with VAP compared to patients without VAP.
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BACKGROUND: Return of spontaneous circulation (ROSC) is achieved in 25% of out-of-hospital cardiac arrest (OHCA) patients. Mechanical chest compression (mechCPR) may maintain better perfusion during transport, allowing hospital treatments like extracorporeal circulation life support (ECLS). We aim to assess the effectiveness of a pre-hospital protocol introduction. METHODS: Observational, retrospective study assessing all OHCA patients aged 12-75, with no-flow time <20 min in a metropolitan area (Milan, Italy, 2013-2016). PRIMARY OUTCOMES: ROSC and Cerebral Performance Category score (CPC) ≤2 at hospital discharge. Logistic regressions with multiple comparison adjustments balanced with propensity scores calculated with inverse probability of treatment weighting were performed. RESULTS: 1366 OHCA were analysed; 305 received mechCPR, 1061 manual chest compressions (manCPR), and 108 ECLS. ROSC and CPC ≤2 were associated with low-flow minutes (odds ratio [95% confidence interval] 0.90 [0.88-0.91] and 0.90 [0.87-0.93]), shockable rhythm (2.52 [1.71-3.72] and 10.68 [5.63-20.28]), defibrillations number (1.15 [1.07-1.23] and 1.15 [1.04-1.26]), and mechCPR (1.86 [1.17-2.96] and 2.06 [1.11-3.81]). With resuscitation times >13 min, mechCPR achieved more frequently ROSC compared to manCPR. Among ECLS patients, 70% had time exceeding protocol: 8 (7.5%) had CPC ≤2 (half of them with low-flow times between 45 and 90 min), 2 (1.9%) survived with severe neurological disabilities, and 13 brain-dead (12.0%) became organ donors. CONCLUSIONS: MechCPR patients achieved ROSC more frequently than manual CPR patients; mechCPR was a crucial factor in an ECLS protocol for refractory OHCA. ECLS offered a chance of survival to patients who would otherwise die.
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Reanimación Cardiopulmonar , Oxigenación por Membrana Extracorpórea , Paro Cardíaco Extrahospitalario , Humanos , Paro Cardíaco Extrahospitalario/terapia , Reanimación Cardiopulmonar/métodos , Estudios Retrospectivos , Italia/epidemiologíaRESUMEN
PURPOSE: Recently, Pluvicto™ ([177Lu]Lu-PSMA-617), a small-molecule prostate-specific membrane antigen (PSMA) radioligand therapeutic, has been approved by the FDA in metastatic castration-resistant prostate cancer. Pluvicto™ and other PSMA-targeting radioligand therapeutics (RLTs) have shown side effects due to accumulation in certain healthy tissues, such as salivary glands and kidney. Until now, the molecular mechanism underlying the undesired accumulation of PSMA-targeting RLTs had not been elucidated. METHODS: We compared the sequence of PSMA with the entire human proteome to identify proteins closely related to the target. We have identified glutamate carboxypeptidase III (GCPIII), N-acetylated alpha-linked acidic dipeptidase like 1 (NAALADL-1), and transferrin receptor 1 (TfR1) as extracellular targets with the highest similarity to PSMA. The affinity of compound 1 for PSMA, GCPIII, NAALADL-1, and TfR1 was measured by fluorescence polarization. The expression of the putative anti-target GCPIII was assessed by immunofluorescence on human salivary glands and kidney, using commercially available antibodies. RESULTS: A fluorescent derivative of Pluvicto™ (compound 1) bound tightly to PSMA and to GCPIII in fluorescence polarization experiments, while no interaction was observed with NAALADL-1 and TfR1. Immunofluorescence analysis revealed abundant expression of GCPIII both in healthy human kidney and salivary glands. CONCLUSION: We conclude that the membranous expression of GCPIII in kidney and salivary gland may be the underlying cause for unwanted accumulation of Pluvicto™ and other Glu-ureido PSMA radio pharmaceuticals in patients.
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Neoplasias de la Próstata Resistentes a la Castración , Radiofármacos , Masculino , Humanos , Radiofármacos/uso terapéutico , Dipéptidos/uso terapéutico , Antígeno Prostático Específico , Neoplasias de la Próstata Resistentes a la Castración/metabolismo , Glutamato Carboxipeptidasa II/metabolismo , Antígenos de Superficie/metabolismo , Radioisótopos/uso terapéutico , Glándulas Salivales/diagnóstico por imagen , Glándulas Salivales/metabolismo , Riñón/metabolismo , Lutecio/uso terapéuticoRESUMEN
Natural Killer Group 2D (NKG2D) is a homo-dimeric transmembrane protein which is typically expressed on the surface of natural killer (NK) cells, natural killer T (NKT) cells, gamma delta T (γδT) cells, activated CD8 positive T-cells and activated macrophages. Bispecific molecules, capable of bridging NKG2D with a target protein expressed on the surface of tumor cells, may be used to redirect the cytotoxic activity of NK-cells towards antigen-positive malignant T-cells. In this work, we report the discovery of a novel NKG2D small molecule binder [KD =(410±60) nM], isolated from a DNA-Encoded Chemical Library (DEL). The discovery of small organic NKG2D ligands may facilitate the generation of fully synthetic bispecific adaptors, which may serve as an alternative to bispecific antibody products and which may benefit from better tumor targeting properties.
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Subfamilia K de Receptores Similares a Lectina de Células NK , Bibliotecas de Moléculas Pequeñas , Subfamilia K de Receptores Similares a Lectina de Células NK/metabolismo , Ligandos , Bibliotecas de Moléculas Pequeñas/farmacología , Bibliotecas de Moléculas Pequeñas/metabolismo , Células Asesinas Naturales , ADN/metabolismoRESUMEN
BACKGROUND: External chest-wall compression (ECC) is sometimes used in ARDS patients despite lack of evidence. It is currently unknown whether this practice has any clinical benefit in patients with COVID-19 ARDS (C-ARDS) characterized by a respiratory system compliance (Crs) < 35 mL/cmH2O. OBJECTIVES: To test if an ECC with a 5 L-bag in low-compliance C-ARDS can lead to a reduction in driving pressure (DP) and improve gas exchange, and to understand the underlying mechanisms. METHODS: Eleven patients with low-compliance C-ARDS were enrolled and underwent 4 steps: baseline, ECC for 60 min, ECC discontinuation and PEEP reduction. Respiratory mechanics, gas exchange, hemodynamics and electrical impedance tomography were recorded. Four pigs with acute ARDS were studied with ECC to understand the effect of ECC on pleural pressure gradient using pleural pressure transducers in both non-dependent and dependent lung regions. RESULTS: Five minutes of ECC reduced DP from baseline 14.2 ± 1.3 to 12.3 ± 1.3 cmH2O (P < 0.001), explained by an improved lung compliance. Changes in DP by ECC were strongly correlated with changes in DP obtained with PEEP reduction (R2 = 0.82, P < 0.001). The initial benefit of ECC decreased over time (DP = 13.3 ± 1.5 cmH2O at 60 min, P = 0.03 vs. baseline). Gas exchange and hemodynamics were unaffected by ECC. In four pigs with lung injury, ECC led to a decrease in the pleural pressure gradient at end-inspiration [2.2 (1.1-3) vs. 3.0 (2.2-4.1) cmH2O, P = 0.035]. CONCLUSIONS: In C-ARDS patients with Crs < 35 mL/cmH2O, ECC acutely reduces DP. ECC does not improve oxygenation but it can be used as a simple tool to detect hyperinflation as it improves Crs and reduces Ppl gradient. ECC benefits seem to partially fade over time. ECC produces similar changes compared to PEEP reduction.
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DNA-encoded chemical libraries (DELs) are useful tools for the discovery of small molecule ligands to protein targets of pharmaceutical interest. Compared with single-pharmacophore DELs, dual-pharmacophore DELs simultaneously display two chemical moieties on both DNA strands, and allow for the construction of highly diverse and pure libraries, with a potential for targeting larger protein surfaces. Although methods for the encoding of simple, fragment-like dual-display libraries have been established, more complex libraries require a different encoding strategy. Here, we present a robust and convenient "large encoding design" (LED), which facilitates the PCR-amplification of multiple codes distributed among two partially complementary DNA strands. We experimentally implemented multiple coding regions and we compared the new DNA encoding scheme with previously reported dual-display DEL modalities in terms of amplifiability and performance in test selections against two target proteins. With the LED methodology in place, we foresee the construction and screening of DELs of unprecedented sizes and designs.
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COVID-19/terapia , Posicionamiento del Paciente/métodos , Respiración Artificial/métodos , Síndrome de Dificultad Respiratoria/terapia , Mecánica Respiratoria , Anciano , COVID-19/complicaciones , Estudios Cruzados , Femenino , Hemodinámica , Humanos , Masculino , Persona de Mediana Edad , Intercambio Gaseoso Pulmonar , Síndrome de Dificultad Respiratoria/etiología , SARS-CoV-2RESUMEN
AIMS: To estimate if chronic anticoagulant (CAC) treatment is associated with morbidity and mortality outcomes of patients hospitalized for SARS-CoV-2 infection. METHODS: In this European multicentric cohort study, we included 1186 patients of whom 144 were on CAC (12.1%) with positive coronavirus disease 2019 testing between 1 February and 30 July 2020. The average treatment effect (ATE) analysis with a propensity score-matching (PSM) algorithm was used to estimate the impact of CAC on the primary outcomes defined as in-hospital death, major and minor bleeding events, cardiovascular complications (CCI), and acute kidney injury (AKI). We also investigated if different dosages of in-hospital heparin were associated with in-hospital survival. RESULTS: In unadjusted populations, primary outcomes were significantly higher among CAC patients compared with non-CAC patients: all-cause death (35% vs. 18% Pâ<â0.001), major and minor bleeding (14% vs. 8% Pâ=â0.026; 25% vs. 17% Pâ=â0.014), CCI (27% vs. 14% Pâ<â0.001), and AKI (42% vs. 19% Pâ<â0.001). In ATE analysis with PSM, there was no significant association between CAC and primary outcomes except for an increased incidence of AKI (ATE +10.2%, 95% confidence interval 0.3-20.1%, Pâ=â0.044). Conversely, in-hospital heparin, regardless of dose, was associated with a significantly higher survival compared with no anticoagulation. CONCLUSIONS: The use of CAC was not associated with the primary outcomes except for the increase in AKI. However, in the adjusted survival analysis, any dose of in-hospital anticoagulation was associated with significantly higher survival compared with no anticoagulation.