A Deep Learning Approach to Antibiotic Discovery.

Due to the rapid emergence of antibiotic-resistant bacteria, there is a growing need to discover new antibiotics. To address this challenge, we trained a deep neural network capable of predicting molecules with antibacterial activity. We performed predictions on multiple chemical libraries and discovered a molecule from the Drug Repurposing Hub-halicin-that is structurally divergent from conventional antibiotics and displays bactericidal activity against a wide phylogenetic spectrum of pathogens including Mycobacterium tuberculosis and carbapenem-resistant Enterobacteriaceae. Halicin also effectively treated Clostridioides difficile and pan-resistant Acinetobacter baumannii infections in murine models. Additionally, from a discrete set of 23 empirically tested predictions from >107 million molecules curated from the ZINC15 database, our model identified eight antibacterial compounds that are structurally distant from known antibiotics. This work highlights the utility of deep learning approaches to expand our antibiotic arsenal through the discovery of structurally distinct antibacterial molecules.

HSP70 binds to specific non-coding RNA and regulates human RNA polymerase III.

Molecular chaperones are critical for protein homeostasis and are implicated in several human pathologies such as neurodegeneration and cancer. While the binding of chaperones to nascent and misfolded proteins has been studied in great detail, the direct interaction between chaperones and RNA has not been systematically investigated. Here, we provide the evidence for widespread interaction between chaperones and RNA in human cells. We show that the major chaperone heat shock protein 70 (HSP70) binds to non-coding RNA transcribed by RNA polymerase III (RNA Pol III) such as tRNA and 5S rRNA. Global chromatin profiling revealed that HSP70 binds genomic sites of transcription by RNA Pol III. Detailed biochemical analyses showed that HSP70 alleviates the inhibitory effect of cognate tRNA transcript on tRNA gene transcription. Thus, our study uncovers an unexpected role of HSP70-RNA interaction in the biogenesis of a specific class of non-coding RNA with wider implications in cancer therapeutics.

Discovery of a structural class of antibiotics with explainable deep learning.

The discovery of novel structural classes of antibiotics is urgently needed to address the ongoing antibiotic resistance crisis1-9. Deep learning approaches have aided in exploring chemical spaces1,10-15; these typically use black box models and do not provide chemical insights. Here we reasoned that the chemical substructures associated with antibiotic activity learned by neural network models can be identified and used to predict structural classes of antibiotics. We tested this hypothesis by developing an explainable, substructure-based approach for the efficient, deep learning-guided exploration of chemical spaces. We determined the antibiotic activities and human cell cytotoxicity profiles of 39,312 compounds and applied ensembles of graph neural networks to predict antibiotic activity and cytotoxicity for 12,076,365 compounds. Using explainable graph algorithms, we identified substructure-based rationales for compounds with high predicted antibiotic activity and low predicted cytotoxicity. We empirically tested 283 compounds and found that compounds exhibiting antibiotic activity against Staphylococcus aureus were enriched in putative structural classes arising from rationales. Of these structural classes of compounds, one is selective against methicillin-resistant S. aureus (MRSA) and vancomycin-resistant enterococci, evades substantial resistance, and reduces bacterial titres in mouse models of MRSA skin and systemic thigh infection. Our approach enables the deep learning-guided discovery of structural classes of antibiotics and demonstrates that machine learning models in drug discovery can be explainable, providing insights into the chemical substructures that underlie selective antibiotic activity.

n-Type Fullerene-Carbon Dots: Synthesis and Electrochemical and Photophysical Properties.

The covalent incorporation of C60 and C70 derivatives of the well-known n-type organic semiconductor PCBM ([6,6]-phenyl-C61-butyric acid methyl ester) onto carbon dots (CD) is described. Morphological and structural characterization reveal combined features of both pristine starting materials (CD and PCBM). Electrochemical investigations evidenced the existence of additional reduction processes to that of CD or PCBM precursors, showing rich electron-acceptor capabilities, with multistep processes in an affordable and narrow electrochemical window (ca. 1.5 V). Electronic communication in the obtained nanoconjugated species were derived from steady-state absorption and emission spectroscopies, which showed bathochromically shifted absorptions and emissions well entering the red region. Finally, the lower fluorescence quantum yield of CD-PCBM nanoconjugates, compared with CD, and the fast decay of the observed emission of CD, support the existence of an electronic communication between both CD and PCBM units in the excited state.

Identifying and Filling the Chemobiological Gaps of Gut Microbial Metabolites.

Human gut microbial metabolites are currently undergoing much research due to their involvement in multiple biological processes that are important for health, including immunity, metabolism, nutrition, and the nervous system. Metabolites exert their effect through interaction with host and bacterial proteins, suggesting the use of "metabolite-mimetic" molecules as drugs and nutraceutics. In the present work, we retrieve and analyze the full set of published interactions of these compounds with human and microbiome-relevant proteins and find patterns in their structure, chemical class, target class, and biological origins. In addition, we use virtual screening to expand (more than 4-fold) the interactions, validate them with retrospective analyses, and use bioinformatic tools to prioritize them based on biological relevance. In this way, we fill many of the chemobiological gaps observed in the published data. By providing these interactions, we expect to speed up the full clarification of the chemobiological space of these compounds by suggesting many reliable predictions for fast, focused experimental testing.

Lung Volumes in a Mouse Model of Pulmonary Allergic Inflammation.

PURPOSE: Air trapping, often attested in humans by elevated residual volume (RV) and ratio of RV on total lung capacity (RV/TLC), is frequently observed in asthma. Confirming these alterations in experimental asthma would be important for translational purposes. Herein, lung volumes were investigated in a mouse model of pulmonary allergic inflammation. METHODS: Eight- to 10-week-old male C57BL/6 and BALB/c mice were exposed once daily to intranasal house dust mite (HDM) for 10 consecutive days. All readouts were measured 24 h after the last exposure. Lung volumes were assessed with the flexiVent using a new automated method consisting of degassing the lungs followed by a full-range pressure-volume maneuver. The weight and the volume of the lungs were also measured ex vivo and a lobe was further processed for histological analyses. RESULTS: HDM exposure led to tissue infiltration with inflammatory cells, goblet cell hyperplasia, thickening of the airway epithelium, and elevated ex vivo lung weight and volume. It also decreased TLC and vital capacity but without affecting RV and RV/TLC. These observations were similar between the two mouse strains. CONCLUSION: Alterations of lung volumes in a murine model of pulmonary allergic inflammation are inconsistent with observations made in human asthma. These discrepancies reflect the different means whereby lung volumes are measured between species. The invasive method used herein enables RV to be measured more precisely and without the confounding effect of air trapping, suggesting that changes in RV and RV/TLC using this method in mice should be interpreted differently than in humans.

Integration of persistence in the 5P-medicine approach for age-related chronic diseases.

5P medicine is defined as Personalized, Predictive, Preventive, Participatory, and Population-based. 5P medicine may be improved by including a factor that could provide information about the therapeutic value of a particular drug treatment and measure its effectiveness in clinical practice. We propose that this factor may be treatment persistence, and that its addition to 5P medicine would allow to define a new improved 6P medicine. Persistence is the length of time between initiation and the last dose, which immediately precedes discontinuation, that is, a definitive suspension of the treatment. By including this sixth P, the persistence, we would be able to present the value of a treatment for each individual patient with its own characteristics, state of the disease, with more than one age-related diseases and patient journey. Persistence is a concept of the value of a treatment that includes the three main stakeholders of the pharmacotherapeutic process: Patient, Physician, and Pharmacist. Persistence is becoming a useful measure to evaluate the long-term effectiveness of therapies in real-world setting in chronic diseases. Drug treatments with longer persistence are more likely to provide better disease control and to be amenable to dose adjustment in order to optimize treatment cost in age-related chronic diseases. Long-term persistence could be a measure of a drug´s real-world performance and has been shown to aid in clinical decision-making.

Exceptional Electron-Rich Heteroaromatic Pentacycle for Ultralow Band Gap Conjugated Polymers and Photothermal Therapy.

Stable redox-active conjugated molecules with exceptional electron-donating abilities are key components for the design and synthesis of ultralow band gap conjugated polymers. While hallmark electron-rich examples such as pentacene derivatives have been thoroughly explored, their poor air stability has hampered their broad incorporation into conjugated polymers for practical applications. Herein, we describe the synthesis of the electron-rich, fused pentacyclic pyrazino[2,3-b:5,6-b']diindolizine (PDIz) motif and detail its optical and redox behavior. The PDIz ring system exhibits a lower oxidation potential and a reduced optical band gap than the isoelectronic pentacene while retaining greater air stability in both solution and the solid state. The enhanced stability and electron density, together with readily installed solubilizing groups and polymerization handles, allow for the use of the PDIz motif in the synthesis of a series of conjugated polymers with band gaps as small as 0.71 eV. The tunable absorbance throughout the biologically relevant near-infrared I and II regions enables the use of these PDIz-based polymers as efficient photothermal therapeutic reagents for laser ablation of cancer cells.

Clinical and Electroencephalographic Predictors of Seizures and Status Epilepticus in 12,450 Critically Ill Adults: A Retrospective Cohort Study.

OBJECTIVES: Status epilepticus (SE) is associated with significantly higher morbidity and mortality than isolated seizures. Our objective was to identify clinical diagnoses and rhythmic and periodic electroencephalogram patterns (RPPs) associated with SE and seizures. DESIGN: Retrospective cohort study. SETTING: Tertiary-care hospitals. SUBJECTS: Twelve thousand four hundred fifty adult hospitalized patients undergoing continuous electroencephalogram (cEEG) monitoring in selected participating sites in the Critical Care EEG Monitoring Research Consortium database (February 2013 to June 2021). INTERVENTIONS: Not applicable. MEASUREMENTS AND MAIN RESULTS: We defined an ordinal outcome in the first 72 hours of cEEG: no seizures, isolated seizures without SE, or SE (with or without isolated seizures). Composite groups included isolated seizures or SE (AnySz) and no seizure or isolated seizures. In this cohort (mean age: 60 ± 17 yr), 1,226 patients (9.8%) had AnySz and 439 patients (3.5%) had SE. In a multivariate model, factors independently associated with SE were cardiac arrest (9.2% with SE; adjusted odds ratio, 8.8 [6.3-12.1]), clinical seizures before cEEG (5.7%; 3.3 [2.5-4.3]), brain neoplasms (3.2%; 1.6 [1.0-2.6]), lateralized periodic discharges (LPDs) (15.4%; 7.3 [5.7-9.4]), brief potentially ictal rhythmic discharges (BIRDs) (22.5%; 3.8 [2.6-5.5]), and generalized periodic discharges (GPDs) (7.2%; 2.4 [1.7-3.3]). All above variables and lateralized rhythmic delta activity (LRDA) were also associated with AnySz. Factors disproportionately increasing odds of SE over isolated seizures were cardiac arrest (7.3 [4.4-12.1]), clinical seizures (1.7 [1.3-2.4]), GPDs (2.3 [1.4-3.5]), and LPDs (1.4 [1.0-1.9]). LRDA had lower odds of SE compared with isolated seizures (0.5 [0.3-0.9]). RPP modifiers did not improve SE prediction beyond RPPs presence/absence ( p = 0.8). CONCLUSIONS: Using the largest existing cEEG database, we identified specific predictors of SE (cardiac arrest, clinical seizures prior to cEEG, brain neoplasms, LPDs, GPDs, and BIRDs) and seizures (all previous and LRDA). These findings could be used to tailor cEEG monitoring for critically ill patients.

More airway smooth muscle in males versus females in a mouse model of asthma: A blessing in disguise?

NEW FINDINGS: What is the central question of this study? The lung response to inhaled methacholine is reputed to be greater in male than in female mice. The underpinnings of this sex disparity are ill defined. What is the main finding and its importance? We demonstrated that male airways exhibit a greater content of airway smooth muscle than female airways. We also found that, although a more muscular airway tree in males might contribute to their greater responsiveness to inhaled methacholine than females, it might also curb the heterogeneity in small airway narrowing. ABSTRACT: Mouse models are helpful in unveiling the mechanisms underlying sex disparities in asthma. In comparison to their female counterparts, male mice are hyperresponsive to inhaled methacholine, a cardinal feature of asthma that contributes to its symptoms. The physiological details and the structural underpinnings of this hyperresponsiveness in males are currently unknown. Herein, BALB/c mice were exposed intranasally to either saline or house dust mite once daily for 10 consecutive days to induce experimental asthma. Twenty-four hours after the last exposure, respiratory mechanics were measured at baseline and after a single dose of inhaled methacholine that was adjusted to trigger the same degree of bronchoconstriction in both sexes (it was twice as high in females). Bronchoalveolar lavages were then collected, and the lungs were processed for histology. House dust mite increased the number of inflammatory cells in bronchoalveolar lavages to the same extent in both sexes (asthma, P = 0.0005; sex, P = 0.96). The methacholine response was also markedly increased by asthma in both sexes (e.g., P = 0.0002 for asthma on the methacholine-induced bronchoconstriction). However, for a well-matched bronchoconstriction between sexes, the increase in hysteresivity, an indicator of airway narrowing heterogeneity, was attenuated in males for both control and asthmatic mice (sex, P = 0.002). The content of airway smooth muscle was not affected by asthma but was greater in males (asthma, P = 0.31; sex, P < 0.0001). These results provide further insights regarding an important sex disparity in mouse models of asthma. The increased amount of airway smooth muscle in males might contribute functionally to their greater methacholine response and, possibly, to their decreased propensity for airway narrowing heterogeneity.

Unusually High Affinity of the PLK Inhibitors RO3280 and GSK461364 to HSA and Its Possible Pharmacokinetic Implications.

The binding processes of two Polo-like kinase inhibitors, RO3280 and GSK461364, to the human serum albumin (HSA) protein as well as the protonation equilibria of both compounds have been studied combining absorbance and fluorescence spectroscopy experiments together with density functional theory calculations. We found that the charge states of RO3280 and GSK461364 are +2 and +1, respectively, at the physiological pH. Nevertheless, RO3280 binds to HSA in the charge state +1 prior to a deprotonation pre-equilibrium. Binding constants to site I of HSA of 2.23 × 106 and 8.80 × 104 M-1 were determined for RO3280 and GSK461364, respectively, at 310 K. The binding processes of RO3280 and GSK461364 to HSA are entropy- and enthalpy-driven, respectively. The positive enthalpy found for the RO3280-HSA complex formation could be related to a proton pre-equilibrium of RO3280.

The effect of responsive neurostimulation (RNS) on neuropsychiatric and psychosocial outcomes in drug-resistant epilepsy.

OBJECTIVE: The impact of responsive neurostimulation (RNS) on neuropsychiatric and psychosocial outcomes has not been extensively evaluated outside of the original clinical trials and post-approval studies. The goal of this study was to ascertain the potential real-world effects of RNS on cognitive, psychiatric, and quality of life (QOL) outcomes in relation to seizure outcomes by examining 50 patients undergoing RNS implantation for drug-resistant epilepsy (DRE). METHODS: We performed a retrospective review of all patients treated at our institution with RNS for DRE with at least 12 months of follow-up. In addition to baseline demographic and disease-related characteristics, we collected cognitive (Full-Scale Intelligence Quotient, Verbal Comprehension, and Perceptual Reasoning Index), psychiatric (Beck Depression and Anxiety Inventory Scores), and QOL (QOLIE-31) outcomes at 6 and 12 months after RNS implantation and correlated them with seizure outcomes. RESULTS: Fifty patients (median age 39.5 years, 64% female) were treated with RNS for DRE in our institution from 2005 to 2020. Of the 37 of them who had well-documented pre and post-implantation seizure diaries, the 6-month median seizure frequency reduction was 88%, the response rate (50% or greater seizure frequency reduction) was 78%, and 32% of patients were free of disabling seizures in this timeframe. There was no statistically significant difference at a group level in any of the evaluated cognitive, psychiatric, and QOL outcomes at 6 and 12 months post-implantation compared to the pre-implantation baseline, irrespective of seizure outcomes, although a subset of patients experienced a decline in mood or cognitive variables. SIGNIFICANCE: Responsive neurostimulation does not appear to have a statistically significant negative or positive impact on neuropsychiatric and psychosocial status at the group level. We observed significant variability in outcome, with a minority of patients experiencing worse behavioral outcomes, which seemed related to RNS implantation. Careful outcome monitoring is required to identify the subset of patients experiencing a poor response and to make appropriate adjustments in care.

Sensitive physiological readouts to evaluate countermeasures for lipopolysaccharide-induced lung alterations in mice.

Despite decades of research, studies investigating the physiological alterations caused by an acute bout of inflammation induced by exposing the lung to lipopolysaccharide have yielded inconsistent results. This can be attributed to small effects and/or a lack of fitted physiological testing. Herein, a comprehensive investigation of lung mechanics was conducted on 270 male C57BL/6 mice at 24, 48, or 96 h after an intranasal exposure to saline or lipopolysaccharide at either 1 or 3 mg/kg (30 mice per group). Traditional techniques that probe the lung using small-amplitude perturbations (i.e., oscillometry) were used, together with less conventional and new techniques that probe the lung using maneuvers of large amplitudes. The latter include a partial and a full-range pressure-volume maneuvers to measure quasi-static elastance, compliance, total lung volume, vital capacity, and residual volume. The results demonstrate that lung mechanics assessed by oscillometry was only slightly affected by lipopolysaccharide, confirming previous findings. In contradistinction, lipopolysaccharide markedly altered mechanics when the lung was probed with maneuvers of large amplitudes. With the dose of 3 mg/kg at the peak of inflammation (48 h postexposure), lipopolysaccharide increased quasi-static elastance by 26.7% (P < 0.0001) and decreased compliance by 34.5% (P < 0.0001). It also decreased lung volumes, including total lung capacity, vital capacity, and residual volume by 33.3%, 30.5%, and 43.3%, respectively (all P < 0.0001). These newly reported physiological alterations represent sensitive outcomes to efficiently evaluate countermeasures (e.g., drugs) in the context of several lung diseases.

Anterior nucleus of the thalamus deep brain stimulation vs temporal lobe responsive neurostimulation for temporal lobe epilepsy.

OBJECTIVE: Based on the promising results of randomized controlled trials, deep brain stimulation (DBS) and responsive neurostimulation (RNS) are used increasingly in the treatment of patients with drug-resistant epilepsy. Drug-resistant temporal lobe epilepsy (TLE) is an indication for either DBS of the anterior nucleus of the thalamus (ANT) or temporal lobe (TL) RNS, but there are no studies that directly compare the seizure benefits and adverse effects associated with these therapies in this patient population. We, therefore, examined all patients who underwent ANT-DBS or TL-RNS for drug-resistant TLE at our center. METHODS: We performed a retrospective review of patients who were treated with either ANT-DBS or TL-RNS for drug-resistant TLE with at least 12 months of follow-up. Along with the clinical characteristics of each patient's epilepsy, seizure frequency was recorded throughout each patient's postoperative clinical course. RESULTS: Twenty-six patients underwent ANT-DBS implantation and 32 patients underwent TL-RNS for drug-resistant TLE. The epilepsy characteristics of both groups were similar. Patients who underwent ANT-DBS demonstrated a median seizure reduction of 58% at 12-15 months, compared to a median seizure reduction of 70% at 12-15 months in patients treated with TL-RNS (p > .05). The responder rate (percentage of patients with a 50% decrease or more in seizure frequency) was 54% for ANT-DBS and 56% for TL-RNS (p > .05). The incidence of complications and stimulation-related side effects did not significantly differ between therapies. SIGNIFICANCE: We demonstrate in our single-center experience that patients with drug-resistant TLE benefit similarly from either ANT-DBS or TL-RNS. Selection of either ANT-DBS or TL-RNS may, therefore, depend more heavily on patient and provider preference, as each has unique capabilities and configurations. Future studies will consider subgroup analyses to determine if specific patients have greater seizure frequency reduction from one form of neuromodulation strategy over another.

Evaluating the Need for Prolonged Telemetry Monitoring in Patients With Isolated Sternal Fractures.

INTRODUCTION: Isolated sternal fractures (ISFs) often result from deceleration or chest wall trauma. Current guidelines recommend screening ISF patients for blunt cardiac injury (BCI) with electrocardiogram (ECG) and troponin. If either is abnormal, 24-h telemetry monitoring is recommended. This study sought to determine if ISF patients with abnormal ECG will manifest any cardiac-related complications within 6 h of hospital arrival. METHODS: A retrospective study was performed at a single level I trauma center. Patients with diagnosed sternal fracture and an Abbreviated Injury Scale <2 for head/neck, face, abdomen, and extremities were included. Patients with multiple rib fractures or hemopneumothorax were excluded. Demographic data, ECG, troponin, and echocardiogram results were collected. The primary outcome was cardiac-related complications or procedures. Complications included hypotension, arrhythmia, and hemodynamic instability. Procedures included sternal stabilization, cardiac catheterization, or sternotomy/thoracotomy. Descriptive statistics were performed. RESULTS: One hundred twenty-nine ISF patients were evaluated, 68 (52.7%) had an ECG abnormality. Eight patients had elevated troponin (6.2%). One patient (0.78%) suffered a cardiac-related complication (arrhythmia); however, this was 82 h into hospitalization. Two patients suffered noncardiac complications (urinary tract infection and acute kidney injury) (1.55%). Three patients had echocardiogram abnormality (2.33%), but no patients sustained a BCI or underwent a BCI-related procedure. CONCLUSIONS: After ISF, <1% of patients suffered a cardiac-related complication and none had BCI. These findings suggest 24-h monitoring for patients with ISF and abnormal ECG may be unnecessarily long. A prospective multicenter study to evaluate the validity of these results is needed prior to change of practice.

Systematic Analysis and Prediction of the Target Space of Bioactive Food Compounds: Filling the Chemobiological Gaps.

Food compounds and their molecular interactions are crucial for health and provide new chemotypes and targets for drug and nutraceutic design. Here, we retrieve and analyze the complete set of published interactions of food compounds with human proteins using the FooDB as a compound set and ChEMBL as a source of interactions. The data are analyzed in terms of 19 target classes and 19 compound classes, showing a small fraction of target assignment for the compounds (1.6%) and unraveling multiple gaps in the chemobiological space for these molecules. By using well-established cheminformatic approaches [similarity ensemble approach (SEA) combined with the maximum Tanimoto coefficient to the nearest bioactive, "SEA + TC"], we achieve a much enhanced target assignment (64.2%), filling many of the gaps with target hypothesis for fast focused testing. By publishing these data sets and analyses, we expect to provide a set of resources to speed up the full clarification of the chemobiological space of food compounds, opening new opportunities for drug and nutraceutic design.

Bevacizumab and aflibercept in second-line metastatic colorectal cancer: 12 years of experience.

PURPOSE: To evaluate and compare the efficacy and safety of bevacizumab and aflibercept in second-line treatment in metastatic colorectal cancer (mCRC) in real-life clinical practice. METHODS: Retrospective observational study of patients treated with second-line bevacizumab (BFIR) and aflibercept (AFIR) in mCRC, associated with a FOLFIRI scheme, in the last 12 years (January 2009-January 2021) in a tertiary hospital. Patients with prior oxaliplatin-based treatment were included. VARIABLES MEASURED: previous chemotherapy, treatment time (TT), progression-free survival (PFS), overall survival (OS). To assess toxicity, adverse effects that caused delay in cycle administration were recorded. The lost cycles/month of treatment (CP/MT) were also calculated. RESULTS: Eighty-four patients [40 (47.6%) AFIR and 44 (52.4%) BFIR]. Average age: 60.2 ± 10.7 years. In 79.8% the previous scheme was FOLFOX type. Efficacy of AFIR vs BFIR: median HR of TT (95% CI) = 0.816 (0.527-1.266); p = 0.365, PFS HR (95% CI) = 0.674 (0.389-1.117); p = 0.159, OS HR (95% CI) = 0.566 (0.342-0.936); p = 0.026. The main reason for the delay in administration was neutropenia (28.7% AFIR vs 24.7% BFIR), and the greatest difference found was thrombopenia (13.9% AFIR vs 2.5% BFIR), without observing large differences between the rest of adverse reactions. Mean CP/MT: 0.49 ± 0.46 cycles with AFIR and 0.33 ± 0.27 with BFIR; p = 0.046. CONCLUSION: Although no statistically significant differences have been found in TT or PFS, it would be more advisable to use BFIR scheme due to its better results in OS and toxicity profile.

RESUMEN: OBJETIVO: Evaluar y comparar la eficacia y seguridad de bevacizumab y aflibercept en segunda línea de tratamiento en el cáncer colorrectal metastásico (CCRm) en la práctica clínica real. MéTODOS: Estudio observacional retrospectivo de los pacientes tratados con bevacizumab (BFIR) y aflibercept (AFIR) en segunda línea en CCRm, asociado a un esquema FOLFIRI, en los últimos 12 años (septiembre 2009-enero 2021) en un hospital de tercer nivel. Se incluyeron pacientes con tratamiento previo basado en oxaliplatino. Variables medidas: esquema previo, tiempo de tratamiento (TT), supervivencia libre de progresión (SLP), supervivencia global (SG). Para valorar toxicidad, se registraron los efectos adversos que provocaron retraso en la administración del ciclo. También se calcularon los ciclos perdidos/mes de tratamiento (CP/MT). RESULTADOS: 84 pacientes [40 (47,6%) AFIR y 44 (52,4%) BFIR]. Media de edad: 60,2 ± 10,7 años. En el 79,8% el esquema previo fue tipo FOLFOX. Eficacia de AFIR vs BFIR: HR de mediana de TT (IC95%) = 0,816 (0,527­1,266); p = 0,365, HR de SLP (IC95%) = 0,674 (0,389­1,117); p = 0,159, HR de SG (IC95%) = 0,566 (0,342­0,936); p = 0,026. El principal motivo de retraso en la administración fue neutropenia (28,7% AFIR vs 24,7% BFIR), y el que más diferencia hubo entre ambos la trombopenia (13,9% AFIR vs 2,5% BFIR), sin observarse grandes diferencias entre el resto de reacciones adversas. Media de CP/MT: 0,49 ± 0,46 ciclos con AFIR y 0,33 ± 0,27 con BFIR; p = 0,046. CONCLUSIONES: Aunque no se han encontrado diferencias estadísticamente significativas en TT ni en SLP, sería más recomendable utilizar el esquema BFIR por sus mejores resultados en SG y perfil de toxicidad.

Six months multicentre pilot open label single-arm study to evaluate patient experience, acceptability and satisfaction of switching certolizumab pegol from a prefilled syringe or autoinjection pen to an AVA® e-Device in rheumatoid arthritis, psoriatic arthritis and axial spondyloarthritis patients.

WHAT IS KNOWN AND OBJECTIVE: The study aimed to assess acceptability and patient experience of Certolizumab (CZP) self-injection with AVA® and clarify patient device preference after switching CZP from the syringe or auto-injection pen to AVA® in rheumatoid arthritis (RA), psoriatic arthritis (PsA) and axial spondyloarthritis (axSpA) patients. METHOD: A multicentre open-label, cross-sectional and prospective study among four Spanish hospitals was performed. Adult RA, PsA, axSpA patients treated for at least 6 months with the CZP syringe or pen were recruited. At the first visit, patients completed Pre-AVA® questionnaire. Patients were instructed on proper administration of CZP by AVA®. After 2 and 6 months of CZP self-injections using the AVA®, patient experience, adherence, preference and safety of each administration was assessed using post-AVA® questionnaire. RESULTS AND DISCUSSION: Thirty four patients were included (28 women). All patients self-administered CZP AVA® the full dose of CZP was injected. Patients reported >90% adherence to CZP AVA® assessed with the injection log. Pain at the injection site was reduced after switching to AVA®. Twenty nine patients preferred CZP AVA® and five patients preferred the CZP pen. No safety-related findings related to AVA® CZP administration were identified. WHAT IS NEW AND CONCLUSION: The AVA® is an advantageous delivery option for CZP in patients with RA, PsA, axSpA.

Association of Epileptiform Abnormality on Electroencephalography with Development of Epilepsy After Acute Brain Injury.

BACKGROUND/OBJECTIVES: Epileptiform abnormalities (EA) on continuous electroencephalography (cEEG) are associated with increased risk of acute seizures; however, data on their association with development of long-term epilepsy are limited. We aimed to investigate the association of EA in patients with acute brain injury (ABI): ischemic or hemorrhagic stroke, traumatic brain injury, encephalitis, or posterior reversible encephalopathy syndrome, and subsequent development of epilepsy. METHODS: This was a retrospective, single-center study of patients with ABI who had at least 6 hours of cEEG during the index admission between 1/1/2017 and 12/31/2018 and at least 12 months of follow-up. We compared patients with EAs; defined as lateralized periodic discharges (LPDs), lateralized rhythmic delta activity (LRDA), generalized periodic discharges (GPDs), and sporadic interictal epileptiform discharges (sIEDs) to patients without EAs on cEEG. The primary outcome was the new development of epilepsy, defined as the occurrence of spontaneous clinical seizures following hospital discharge. Secondary outcomes included time to development of epilepsy and use of anti-seizure medications (ASMs) at the time of last follow-up visit. RESULTS: One hundred and one patients with ABI met study inclusion criteria. Thirty-one patients (30.7%) had EAs on cEEG. The median (IQR) time to cEEG was 2 (1-5) days. During a median (IQR) follow-up period of 19.1 (16.2-24.3) months, 25.7% of patients developed epilepsy; the percentage of patients who developed epilepsy was higher in those with EAs compared to those without EAs (41.9% vs. 18.6%, p = 0.025). Patients with EAs were more likely to be continued on ASMs during follow-up compared to patients without EAs (67.7% vs. 38.6%, p = 0.009). Using multivariable Cox regression analysis, after adjusting for age, mental status, electrographic seizures on cEEG, sex, ABI etiology, and ASM treatment on discharge, patients with EAs had a significantly increased risk of developing epilepsy compared to patients without EA (hazard ratio 3.39; 95% CI 1.39-8.26; p = 0.007). CONCLUSIONS: EAs on cEEG in patients with ABI are associated with a greater than three-fold increased risk of new-onset epilepsy. cEEG findings in ABI may therefore be a useful risk stratification tool for assessing long-term risk of seizures and serve as a biomarker for new-onset epilepsy.