Engineering a "muco-trapping" ACE2-immunoglobulin hybrid with picomolar affinity as an inhaled, pan-variant immunotherapy for COVID-19.

Soluble angiotensin-converting enzyme 2 (ACE2) can act as a decoy molecule that neutralizes severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) by blocking spike (S) proteins on virions from binding ACE2 on host cells. Based on structural insights of ACE2 and S proteins, we designed a "muco-trapping" ACE2-Fc conjugate, termed ACE2-(G4S)6-Fc, comprised of the extracellular segment of ACE2 (lacking the C-terminal collectrin domain) that is linked to mucin-binding IgG1-Fc via an extended glycine-serine flexible linker. ACE2-(G4S)6-Fc exhibits substantially greater binding affinity and neutralization potency than conventional full length ACE2-Fc decoys or similar truncated ACE2-Fc decoys without flexible linkers, possessing picomolar binding affinity and strong neutralization potency against pseudovirus and live virus. ACE2-(G4S)6-Fc effectively trapped fluorescent SARS-CoV-2 virus like particles in fresh human airway mucus and was stably nebulized using a commercial vibrating mesh nebulizer. Intranasal dosing of ACE2-(G4S)6-Fc in hamsters as late as 2 days postinfection provided a 10-fold reduction in viral load in the nasal turbinate tissues by Day 4. These results strongly support further development of ACE2-(G4S)6-Fc as an inhaled immunotherapy for COVID-19, as well as other emerging viruses that bind ACE2 for cellular entry.

Free PEG Suppresses Anaphylaxis to PEGylated Nanomedicine in Swine.

Covalent conjugation of poly(ethylene glycol) (PEG) is frequently employed to enhance the pharmacokinetics and biodistribution of various protein and nanoparticle therapeutics. Unfortunately, some PEGylated drugs can induce elevated levels of antibodies that can bind PEG, i.e., anti-PEG antibodies (APA), in some patients. APA in turn can reduce the efficacy and increase the risks of allergic reactions, including anaphylaxis. There is currently no intervention available in the clinic that specifically mitigates allergic reactions to PEGylated drugs without the use of broad immunosuppression. We previously showed that infusion of high molecular weight free PEG could safely and effectively suppress the induction of APA in mice and restore prolonged circulation of various PEGylated therapeutics. Here, we explored the effectiveness of free PEG as a prophylaxis against anaphylaxis induced by PEG-specific allergic reactions in swine. Injection of PEG-liposomes (PL) resulted in anaphylactoid shock (pseudoanaphylaxis) within 1-3 min in both naïve and PL-sensitized swine. In contrast, repeated injection of free PEG alone did not result in allergic reactions, and injection of free PEG effectively suppressed allergic reactions to PL, including in previously PL-sensitized swine. These results strongly support the further investigation of free PEG for reducing APA and allergic responses to PEGylated therapeutics.

Duodenitis eosinofílica asociada a alergia alimentaria debutando como dolor visceral agudo en un adulto con vitíligo: reporte de un caso

La duodenitis eosinofílica tiene una prevalencia entre 5,1 a 8,2 por 100000 personas. Se desconocen los mecanismos moleculares subyacentes de la enfermedad, pero la hipersensibilidad (alergias estacionales y alimentarias) juega un papel importante en su patogénesis, la predisposición alérgica se encuentra en el 25-35% de los casos. El diagnóstico incluye manifestaciones clínicas, hallazgos imagenológicos y evidencia histológica de infiltración eosinofílica >20 eosinófilos por campo de alto poder. Realizamos un informe de caso clínico y revisión de literatura. Hombre de 25 años con vitíligo que consulta a urgencias refiriendo síntomas de dispepsia, vómitos y dolor abdominal de máxima intensidad, en el examen médico se localiza dolor abdominal superior, con paraclínicos normales excepto un recuento de eosinófilos >2000 células/ul, la ecografía abdominal fue normal, la endoscopia superior reveló pangastritis eritematosa y duodenitis con pliegues rígidos y engrosados, la colonoscopia mostró hemorroides grado I. Coproscópico seriado negativo para parásitos, IgE total, IgA e IgG en rango normal, se reportó IgG positivo a Toxoplasma gondii, perfil de autoinmunidad negativo. En los siguientes 4 días aumenta el dolor abdominal y el recuento de eosinófilos, con endoscopia control y tomografía abdomino-pélvica contrastada que muestran duodeno edematizado con reflujo biliar severo, reporte histopatológico con duodenitis crónica atrófica y con pruebas para alergenos alimentarios positivo a cereales (centeno, soja, cebada), Manihot esculenta, plátano verde, tomate, leche de vaca, naranja y piña. Se indicó dieta restrictiva e inhibidor de la bomba de protones (pantoprazol), control ambulatorio a los 45 días de resolución de los síntomas con recuento de eosinófilos en sangre normal. Se presenta un caso de duodenitis eosinofílica relacionada con alergia alimentaria con mecanismos IgE independientes en un varón joven con vitíligo, que debutó con cuadro clínico inusual de dolor visceral agudo y reflujo biliar, que se resolvió con dieta de eliminación y pantoprazol sin uso de corticoides.

Background: Eosinophilic duodenitis has a prevalence of 5.1 to 8.2 per 100000 persons. The underlying molecular mechanisms are unknown, but hypersensitivity (seasonal and food allergies, asthma, eczema) response plays a major role in its pathogenesis, allergic predisposition can be found up-to 25-35% of cases. The diagnosis includes clinical manifestation, imaging findings and histological evidence of eosinophilic infiltration >20 eosinophils per high-power field. This is a clinical case report. a 25-years old man with vitiligo consult to emergency department referring dyspepsia symptoms, vomiting and abdominal pain of maximal intensity, in the medical exam upper abdominal pain was found, blood laboratories were unremarkable except a high net eosinophil-count >2000 cells/ul, abdominal ultrasound were normal, upper endoscopy revealed duodenitis with rigid and thickened folds, colonoscopy show hemorrhoids grade I. Coproscopy exam was negative for parasites, total IgE, IgA and IgG were in normal range, a positive IgG to Toxoplasma gondii was reported, autoimmunity panel was negative. In the following 4 days the abdominal pain and eosinophils count increase, a new abdomin-pelvic tomography was done showing thickened duodenum with a new endoscopy showing marked edema in duodenum with severe biliary reflux with biopsies describing an atrophic chronic duodenitis. Allergy tests -skin prick and patch tests- were done resulting positive to cereals (rye, soy, barley), Manihot esculenta, green banana, tomato, cow milk, orange and pineapple. A restrictive diet and protons pump inhibitor was indicated, ambulatory control at 45 days after show symptoms resolution with a normal blood eosinophils count. Here is reported a case of eosinophilic duodenitis related to food allergy in a young man with vitiligo debuting with an unusual clinical presentation of acute visceral pain and biliary reflux which resolved with elimination diet and pantoprazole without use of corticoids, with both, IgE and non-IgE mechanisms playing important roles explaining food sensitization.

Experimental and Analytical Framework for "Mix-and-Read" Assays Based on Split Luciferase.

The use of immunodetection assays including the widely used enzyme-linked immunosorbent assay (ELISA) in applications such as point-of-care detection is often limited by the need for protein immobilization and multiple binding and washing steps. Here, we describe an experimental and analytical framework for the development of simple and modular "mix-and-read" enzymatic complementation assays based on split luciferase that enable sensitive detection and quantification of analytes in solution. In this assay, two engineered protein binders targeting nonoverlapping epitopes on the target analyte were each fused to nonactive fragments of luciferase to create biosensor probes. Binding proteins to two model targets, lysozyme and Sso6904, were isolated from a combinatorial library of Sso7d mutants using yeast surface display. In the presence of the analyte, probes were brought into close proximity, reconstituting enzymatic activity of luciferase and enabling detection of low picomolar concentrations of the analyte by chemiluminescence. Subsequently, we constructed an equilibrium binding model that relates binding affinities of the binding proteins for the target, assay parameters such as the concentrations of probes used, and assay performance (limit of detection and concentration range over which the target can be quantified). Overall, our experimental and analytical framework provides the foundation for the development of split luciferase assays for detection and quantification of various targets.

[Eosinophilic duodenitis associated to food allergy debuting as acute visceral pain in an adult with vitiligo: a case report]. / Duodenitis eosinofílica asociada a alergia alimentaria debutando como dolor visceral agudo en un adulto con vitíligo: reporte de un caso.

BACKGROUND: Eosinophilic duodenitis has a prevalence of 5.1 to 8.2 per 100000 persons. The underlying molecular mechanisms are unknown, but hypersensitivity (seasonal and food allergies, asthma, eczema) response plays a major role in its pathogenesis, allergic predisposition can be found up-to 25-35% of cases. The diagnosis includes clinical manifestation, imaging findings and histological evidence of eosinophilic infiltration >20 eosinophils per high-power field. This is a clinical case report. a 25-years old man with vitiligo consult to emergency department referring dyspepsia symptoms, vomiting and abdominal pain of maximal intensity, in the medical exam upper abdominal pain was found, blood laboratories were unremarkable except a high net eosinophil-count >2000 cells/ul, abdominal ultrasound were normal, upper endoscopy revealed duodenitis with rigid and thickened folds, colonoscopy show hemorrhoids grade I. Coproscopy exam was negative for parasites, total IgE, IgA and IgG were in normal range, a positive IgG to Toxoplasma gondii was reported, autoimmunity panel was negative. In the following 4 days the abdominal pain and eosinophils count increase, a new abdomin-pelvic tomography was done showing thickened duodenum with a new endoscopy showing marked edema in duodenum with severe biliary reflux with biopsies describing an atrophic chronic duodenitis. Allergy tests -skin prick and patch tests- were done resulting positive to cereals (rye, soy, barley), Manihot esculenta, green banana, tomato, cow milk, orange and pineapple. A restrictive diet and protons pump inhibitor was indicated, ambulatory control at 45 days after show symptoms resolution with a normal blood eosinophils count. Here is reported a case of eosinophilic duodenitis related to food allergy in a young man with vitiligo debuting with an unusual clinical presentation of acute visceral pain and biliary reflux which resolved with elimination diet and pantoprazole without use of corticoids, with both, IgE and non-IgE mechanisms playing important roles explaining food sensitization.

Anoniquia Congénita Asociada a Herencia Autosómica Dominante, Síndrome de Cooks

Resumen El síndrome de Cook fue descrito por primera vez por Cook y colaboradores en 1985. Este se caracteriza por una historia familiar de hipoplasia congénita de las uñas de las manos en los dígitos 1,2 y 3, ausencia de las uñas en los dígitos 4 y 5, braquidactilia del digito 5 de las manos y ausencia complete de las uñas de los pies. Además, puede existir una hipoplasia o ausencia de las falanges distales en los pies y las manos. La oficina de enfermedades raras del Instituto Nacional de Salud, considera este síndrome como una "enfermedad rara". Presentamos el caso de un recién nacido con anoniquia congénita en ambas manos y pies en el digito 2 asociado a hipoplasia ungueal en dígitos 1 y 3 respetando dígitos 4 y 5. La radiografía de los dedos no muestra anormalidades en las falanges. Este caso podría representar una variante del síndrome de Cook o una nueva enfermedad aun no descrita debido a la existencia de una historia familiar importante con similares deformidades en la madre, la abuela y la hermana.

Abstract Cooks syndrome, which was first reported by Cooks et al in 1985. It is characterized by family history of bilateral congenital nail hypoplasia of digits 1,2 and 3, with absence of nails in digits 4, 5, and brachydactyly of digit five of the hands and complete absence of all toenails. In addition, there is hypoplasia or absence of distal phalanges of the hands and feet. According to the Office of rare Diseases of the National Institutes of Health, this syndrome is considered as a "rare disease". We present a newborn child with a history of congenital anonychia in digit 2 in both hands and feet and nail hypoplasia in digits 1 and 3 sparing digits 4 and 5. Radiography of the fingers shows no abnormalities in the phalanges. This case could represent a variant of Cooks syndrome or a new disease not yet described because of the existence of an important family history with similar deformities in the mother, grandmother and sister.

Engineering sperm-binding IgG antibodies for the development of an effective nonhormonal female contraception.

Many women risk unintended pregnancy because of medical contraindications or dissatisfaction with contraceptive methods, including real and perceived side effects associated with the use of exogenous hormones. We pursued direct vaginal delivery of sperm-binding monoclonal antibodies (mAbs) that can limit progressive sperm motility in the female reproductive tract as a strategy for effective nonhormonal contraception. Here, motivated by the greater agglutination potencies of polyvalent immunoglobulins but the bioprocessing ease and stability of immunoglobulin G (IgG), we engineered a panel of sperm-binding IgGs with 6 to 10 antigen-binding fragments (Fabs), isolated from a healthy immune-infertile woman against a unique surface antigen universally present on human sperm. These highly multivalent IgGs (HM-IgGs) were at least 10- to 16-fold more potent and faster at agglutinating sperm than the parent IgG while preserving the crystallizable fragment (Fc) of IgG that mediates trapping of individual spermatozoa in mucus. The increased potencies translated into effective (>99.9%) reduction of progressively motile sperm in the sheep vagina using as little as 33 µg of the 10-Fab HM-IgG. HM-IgGs were produced at comparable yields and had identical thermal stability to the parent IgG, with greater homogeneity. HM-IgGs represent not only promising biologics for nonhormonal contraception but also a promising platform for engineering potent multivalent mAbs for other biomedical applications.

Challenges and opportunities for antiviral monoclonal antibodies as COVID-19 therapy.

To address the COVID-19 pandemic, there has been an unprecedented global effort to advance potent neutralizing mAbs against SARS-CoV-2 as therapeutics. However, historical efforts to advance antiviral monoclonal antibodies (mAbs) for the treatment of other respiratory infections have been met with categorical failures in the clinic. By investigating the mechanism by which SARS-CoV-2 and similar viruses spread within the lung, along with available biodistribution data for systemically injected mAb, we highlight the challenges faced by current antiviral mAbs for COVID-19. We summarize some of the leading mAbs currently in development, and present the evidence supporting inhaled delivery of antiviral mAb as an early intervention against COVID-19 that could prevent important pulmonary morbidities associated with the infection.

Covid-19, una mirada desde la pediatría / Covid-19, a look from pediatrics

El COVID-19 fue predominantemente más prevalente entre adultos mayores de 15 años en las primeras etapas del brote y la proporción de casos confirmados entre niños fue relativamente menor. Sin embargo, debido a la creciente propagación mundial del SARS-CoV-2, tenemos nuevos desafíos para la prevención y el control de la epidemia de COVID-19 entre los niños. Ya que en los más pequeños no se pueden emplear medidas de prevención (barbijos), la clínica inespecífica que presentan, las dificultades para el diagnóstico, la deficiente comunicación entre médico-paciente y familiar que han contribuido al desafío de desarrollar medidas para proteger a esta población, al igual que al personal de salud que manejan casos pediátricos. Al mismo tiempo, los niños con comorbilidades, s on vulnerables a la infección por SARS-CoV-2. La presente revisión intenta mostrar esta enfermedad desde el punto de vista pediátrico, para orientar en su diagnóstico y manejo.

COVID-19 was predominantly more prevalent among adults over the age of 15 in the early stages of the outbreak, and the proportion of confirmed cases among children was relatively lower. However, because younger children cannot wear chinstraps and no other preventive measures have been taken in this group. Children have certain peculiarities and we cannot clearly demonstrate their state of health, which has contributed to the serious challenge of protecting, diagnosing and treating this population. Due to the increasing worldwide spread of SARS-CoV-2, we have new challenges for the prevention and control of the COVID-19 epidemic among children. At the same time, children with comorbidities are vulnerable to SARS-CoV-2 infection. The present review tries to show this disease from the pediatric point of view, to guide its diagnosis and management.

Challenges & opportunities for phage-based in situ microbiome engineering in the gut.

The gut microbiome is a promising target for the development of GI tract therapies, yet it has been under-exploited due, in part, to a lack of tools to control and manipulate complex microbial communities. To date, the most common approach in harnessing bacteria for therapeutic purposes has been to deliver ex vivo engineered bacteria-effectively taking a bacterial cell therapy-based approach. An alternative approach involves taking advantage of the rich microbial ecosystem in the gut by genetically modifying the microbiome in situ through the use of engineered bacteriophages-akin to human gene therapies delivered by viral vectors. In this review, we present the challenges and opportunities associated with engineering bacteriophages to control and manipulate the gut microbiome.

Simultaneous Soluble Secretion and Surface Display of Proteins in Saccharomyces cerevisiae Using Inefficient Ribosomal Skipping.

Combinatorial library screening platforms, such as yeast surface display, typically identify several candidate proteins that need further characterization and validation using soluble recombinant protein. However, recombinant production of these candidate proteins involves tedious and time-consuming subcloning steps. This, in turn, limits the number of candidate proteins that can be characterized. To address this bottleneck, we have developed a platform that exploits inefficient ribosomal skipping by the F2A peptide for simultaneous soluble secretion and cell surface display of protein in the yeast Saccharomyces cerevisiae. Here we provide detailed protocols utilizing this F2A-based yeast display system. We discuss specific recommendations for the purification of the secreted protein. Additionally, we provide suggestions for testing the functionality and binding specificity of the soluble secreted proteins using flow cytometry analysis.

An Engineered Sso7d Variant Enables Efficient Magnetization of Yeast Cells.

Magnetization using cheap and minimally toxic materials, such as iron oxide nanoparticles can enable easy separation of cells from culture medium and is relevant to several industrial applications. Here, we show that cell surface expression of a mutant protein that binds iron oxide can enable efficient magnetization of yeast cells. We screened a combinatorial library of mutants derived from the Sso7d protein scaffold to isolate proteins that exhibit preferential binding to iron oxide. One of the isolated mutants, SsoFe2, was chosen for further characterization. Yeast cells expressing SsoFe2 as fusions to a cell wall protein-but not other Sso7d mutants with similar overall protein charge or amino acid composition-preferentially bind iron oxide when present in a solution with high protein concentration and in the presence of 1000-fold excess of competitor yeast cells. Moreover, coexpression of cell surface SsoFe2 enables efficient magnetic capture and separation of yeast cells expressing an enzyme (glucose oxidase) on the cell surface from yeast culture medium, and solutions with high protein concentration or containing other metal oxides. Therefore, SsoFe2-enabled magnetization can enable a range of industrial and biotechnology applications, where easy separation of cells or organelles from complex media is desirable.

Inefficient Ribosomal Skipping Enables Simultaneous Secretion and Display of Proteins in Saccharomyces cerevisiae.

The need for recombinant expression of soluble protein slows the validation of engineered proteins isolated from combinatorial libraries and limits the number of protein variants evaluated. To overcome this bottleneck, we describe a system for simultaneous cell surface display and soluble secretion of proteins in Saccharomyces cerevisiae based on inefficient ribosomal skipping. Ribosomal skipping mediated by "self-cleaving" 2A peptides produces two proteins from a single open reading frame. Incorporation of the F2A peptide sequence-with ∼50% efficiency of ribosomal skipping-between the protein of interest and the yeast cell wall protein Aga2 results in simultaneous expression of both the solubly secreted protein and the protein-Aga2 fusion that is tethered to the yeast cell surface. We show that binding proteins derived from the Sso7d scaffold and the homodimeric enzyme glucose oxidase can be simultaneously secreted solubly and expressed as yeast cell surface fusions using the F2A-based system. Furthermore, a combinatorial library of Sso7d mutants can be screened to isolate binders with higher affinity for a model target (lysozyme), and the pool of higher affinity binders can be characterized in soluble form. Significantly, we show that both N- and C-terminal fusions to Aga2 can be simultaneously secreted solubly and displayed on the cell surface; this is particularly advantageous because protein functionality can be affected by the specific position of Aga2 in the protein fusion. We expect that the F2A-based yeast surface display and secretion system will be a useful tool for protein engineering and enable efficient characterization of individual clones isolated from combinatorial libraries.

Neurosífilis / Neurosyphilis

Durante muchas décadas la sífilis y neurosifilis han sido consideradas condiciones poco frecuentes. Con el advenimiento del virus de inmunodeficiencia humana la incidencia de estas enfermedades se ha incrementado. La neurosifilis puede estar presente tanto en estadios tempranos como tardíos de sífilis; sus manifestaciones clínicas son variadas y dependerán de la respuesta del huésped y la duración de la exposición a esta espiroqueta; estas pueden ir desde meningitis asintomática, meningoencefalitis hasta eventos cerebrales vasculares y condiciones más crónicas como tabes dorsalis y/o demencia sifilítica. La esencia del enfoque diagnóstico es un alto índice de sospecha en pacientes con factores de riesgo. La sola presencia de pruebas no treponémicas no son diagnósticos de neurosifilis sino serán necesarios la confirmación con pruebas treponémicas junto con anormalidades en liquido cefalorraquídeo y la presencia de VDRL o RPR en el mismo. La piedra angular en el tratamiento de sífilis y neurosifilis continúan siendo dosis altas de penicilina y alternativamente doxicilina o ceftriaxona.

For decades syphilis and neurosyphilis were considered infrequent conditions; however with the advent of the human immunodeficiency virus the incidence of both diseases have increased. Neurosyphilis could be present in early or late stages of syphilis; the clinical manifestations are varied and will depend on the host response and the length of exposure to the spirochete; this could range from asymptomatic meningitis, to meningoencephalitis, strokes and more chronic conditions such as tabes dorsalis or syphilitic dementia. The key diagnostic approach is a high index of suspicion in patients with risk factors. The only presence of non treponemal studies is not diagnostic of neurosyphilis; it will be necessary to confirm it with treponemal serology and abnormalities in the cerebrospinal fluid (CSF) and positive VDRL and RPR in CSF. The cornerstone of treatment of neurosyphilis is still high doses penicillin and alternatively doxycycline or ceftriaxone.

Targeted Mutagenesis and Combinatorial Library Screening Enables Control of Protein Orientation on Surfaces and Increased Activity of Adsorbed Proteins.

While nonspecific adsorption is widely used for immobilizing proteins on solid surfaces, the random nature of protein adsorption may reduce the activity of immobilized proteins due to occlusion of the active site. We hypothesized that the orientation a protein assumes on a given surface can be controlled by systematically introducing mutations into a region distant from its active site, thereby retaining activity of the immobilized protein. To test this hypothesis, we generated a combinatorial protein library by randomizing six targeted residues in a binding protein derived from highly stable, nonimmunoglobulin Sso7d scaffold; mutations were targeted in a region that is distant from the binding site. This library was screened to isolate binders that retain binding to its cognate target (chicken immunoglobulin Y, cIgY) as well as exhibit adsorption on unmodified silica at pH 7.4 and high ionic strength conditions. A single mutant, Sso7d-2B5, was selected for further characterization. Sso7d-2B5 retained binding to cIgY with an apparent dissociation constant similar to that of the parent protein; both mutant and parent proteins saturated the surface of silica with similar densities. Strikingly, however, silica beads coated with Sso7d-2B5 could achieve up to 7-fold higher capture of cIgY than beads coated with the parent protein. These results strongly suggest that mutations introduced in Sso7d-2B5 alter its orientation relative to the parent protein, when adsorbed on silica surfaces. Our approach also provides a generalizable strategy for introducing mutations in proteins so as to improve their activity upon immobilization, and has direct relevance to development of protein-based biosensors and biocatalysts.

Combinatorial Pairwise Assembly Efficiently Generates High Affinity Binders and Enables a "Mix-and-Read" Detection Scheme.

We show that a combinatorial library constructed by random pairwise assembly of low affinity binders can efficiently generate binders with increased affinity. Such a library based on the Sso7d scaffold, from a pool of low affinity binders subjected to random mutagenesis, contained putative high affinity clones for a model target (lysozyme) at higher frequency than a library of monovalent mutants generated by random mutagenesis alone. Increased binding affinity was due to intramolecular avidity generated by linking binders targeting nonoverlapping epitopes; individual binders of KD ∼ 1.3 µM and 250 nM produced a bivalent binder with apparent KD ∼ 2 nM. Furthermore, the bivalent protein retained thermal stability (TM = 84.5 °C) and high recombinant expression yields in E. coli. Finally, when binders comprising the bivalent protein are fused to two of the three fragments of tripartite split-green fluorescent protein (GFP), target-dependent reconstitution of fluorescence occurs, thereby enabling a "mix-and-read" assay for target quantification.

Assessment of long-term cognitive impairment after off-pump coronary-artery bypass grafting and related risk factors.

OBJECTIVES: To assess cognitive impairment after off-pump coronary-artery bypass grafting, with a particular emphasis on long-term follow-up and related risk factors. DESIGN: Prospective study. SETTING: Virgen de la Victoria University Hospital, Málaga, Spain. PARTICIPANTS: Participants were 36 patients undergoing off-pump coronary-artery bypass grafting. MEASUREMENTS: Changes in the neuropsychological test battery administered from before to after surgery (1, 6, and 12 months). Postoperative cognitive impairment was defined by a significant decrease. RESULTS: A significantly multidomain (attention-executive functions, P < .01; immediate and delayed memory, P < .001; and verbal fluency, P < .05) postoperative cognitive impairment was shown, being maximum at 6 months (more than 50% of patients) and still presented at 12 months (more than 30% of patients), but partially recovered. Related risk factors as smoking (P < .01), diabetes mellitus (P < .01), peripheral arteriopathy (P < .01), obesity (P < .05), lower hematocrit (P < .01), and hemoglobin (P < .05) levels and diastolic blood pressure (P < .05) were identified as predictors of cognitive impairment. Better New York Heart Association class (P < .01) and less severity of angina (P < .01) were associated with partial postoperative recovering. CONCLUSION: A multidomain long-term postoperative cognitive impairment and a partial neurocognitive recovering were detected after off-pump coronary-artery bypass grafting and were associated with several nonspecific surgery factors. These findings may be useful when counseling patients before surgery and suggest the importance of long-term neurocognitive evaluation.