Proof-of-concept studies with a computationally designed Mpro inhibitor as a synergistic combination regimen alternative to Paxlovid.

As the SARS-CoV-2 virus continues to spread and mutate, it remains important to focus not only on preventing spread through vaccination but also on treating infection with direct-acting antivirals (DAA). The approval of Paxlovid, a SARS-CoV-2 main protease (Mpro) DAA, has been significant for treatment of patients. A limitation of this DAA, however, is that the antiviral component, nirmatrelvir, is rapidly metabolized and requires inclusion of a CYP450 3A4 metabolic inhibitor, ritonavir, to boost levels of the active drug. Serious drug-drug interactions can occur with Paxlovid for patients who are also taking other medications metabolized by CYP4503A4, particularly transplant or otherwise immunocompromised patients who are most at risk for SARS-CoV-2 infection and the development of severe symptoms. Developing an alternative antiviral with improved pharmacological properties is critical for treatment of these patients. By using a computational and structure-guided approach, we were able to optimize a 100 to 250 µM screening hit to a potent nanomolar inhibitor and lead compound, Mpro61. In this study, we further evaluate Mpro61 as a lead compound, starting with examination of its mode of binding to SARS-CoV-2 Mpro. In vitro pharmacological profiling established a lack of off-target effects, particularly CYP450 3A4 inhibition, as well as potential for synergy with the currently approved alternate antiviral, molnupiravir. Development and subsequent testing of a capsule formulation for oral dosing of Mpro61 in B6-K18-hACE2 mice demonstrated favorable pharmacological properties, efficacy, and synergy with molnupiravir, and complete recovery from subsequent challenge by SARS-CoV-2, establishing Mpro61 as a promising potential preclinical candidate.

Efectividad de los protocolos de fisioterapia para pacientes con dolor lumbar crónico. Una revisión sistemática / Effectiveness of physiotherapy protocols for patients with chronic low back pain: A systematic review

Introducción: El dolor lumbar crónico es una de las principales causas de incapacidad laboral en el mundo. Requiere un abordaje interdisciplinario para la evolución del paciente. Hasta el momento, no existe consenso en el manejo del dolor lumbar crónico, lo que generó la inquietud de esta revisión sistemática. Objetivo: Identificar la efectividad de los protocolos de fisioterapia en el manejo del dolor lumbar crónico. Metodología: Se realizó una búsqueda sistemática en las bases de datos Pubmed, ScienceDirect, Scopus, Oxford, Wiley, Cochrane Library Plus, PEDro, Epistemonikos, Hinari y LILACS, Google Scholar, Teseo y PROSPERO, desde el inicio de las bases hasta agosto de 2021. Los criterios de selección se definieron según la intervención y el tema del artículo. Resultados: Se incluyeron 26 estudios en la síntesis cualitativa, se excluyeron artículos que no cumplieran con los criterios de inclusión. Se encontró efecto en el control del dolor y la disminución de la discapacidad y las principales intervenciones son: fortalecimiento muscular del Core y miembros inferiores, estiramiento de miembros inferiores, movilidad lumbopélvica y educación o escuela de espalda. La frecuencia en el tratamiento osciló entre 2 y 3 veces por semana durante 5 semanas. Conclusiones: Se encontró mayor efectividad en el tiempo de control del dolor y la disminución de la discapacidad, relacionados principalmente con el fortalecimiento muscular del Core y las estrategias educativas.(AU)

Introduction: Chronic low back pain is one of the main causes of incapacity for work in the world. It requires an interdisciplinary approach for the evolution of the patient. Until now, there is no consensus on the management of chronic low back pain, which generated the concern of this systematic review. Aim: To identify the effectiveness of physiotherapy protocols in the management of chronic low back pain. Methodology: A systematic search was carried out in the Pubmed, ScienceDirect, Scopus, Oxford, Wiley, Cochrane Library Plus, PEDro, Epistemonikos, Hinari and LILACS, Google Scholar, Teseo and PROSPERO databases, from the beginning of the databases until August, 2021. The selection criteria were defined according to the intervention and topic of the article. Results: Twenty-six studies were included in the qualitative synthesis, articles that did not meet the inclusion criteria were excluded. An effect was found in the control of pain and the reduction of disability and the main interventions are: muscular strengthening of the core and lower limbs, stretching of the lower limbs, lumbopelvic mobility and education or back school. The treatment frequency ranged from 2 to 3 times per week for 5 weeks. Conclusions: Greater effectiveness was found in pain control time and disability reduction, mainly related to core muscle strengthening and educational strategies.(AU)

DPYD genotyping and 5-fluoropyrimidine toxicity: An overview of systematic reviews protocol / Genotipado del gen DPYD y toxicidad de 5-fluoropirimidinas: Protocolo de una revisión de revisiones sistemáticas

Introduction: The increased risk of severe and life-threatening toxicity in patients with dihydropyridine dehydrogenase (DPD) deficiency, under treatment with fluoropyrimidines, has been widely studied. An up-to-date overview of systematic reviews summarizing existing literature can add value by highlighting most relevant information and supports decision-making regarding treatment in DPD deficient patients. The main objective of this overview of systematic reviews is to identify published systematic reviews on the association between germline variations in the DPYD gene and fluoropyrimidine toxicity.Methods and analysis: This protocol was developed following the Preferred Reported Items for Systematic Review and Meta-analysis Protocols (PRISMA-P) checklist, and the overview of systematic reviews will be reported in accordance with the PRISMA statement. PubMed, Embase, Scopus, and the Cochrane Library will be searched from inception to 2023. Systematic reviews irrespective of study designs that analyze the association between germline variations in the DPYD and fluoropyrimidine toxicity will be considered. Methodological quality will be assessed using AMSTAR2 checklist (Measurement Tool to Assess Systematic Reviews 2). Two independent investigators will perform the study selection, quality assessment, and data collection. Discrepancies will be solved by a third investigator.(AU)

Introducción: El incremento del riesgo de toxicidad grave y potencialmente mortal en pacientes con deficiencia de dihidropiridina deshidrogenasa (DPD) en tratamiento con fluoropirimidinas ha sido ampliamente estudiado. Una revisión actualizada de las revisiones sistemáticas publicadas, que agrupe la literatura existente, puede añadir valor al resaltar la información más relevante y respaldar la toma de decisiones con respecto al tratamiento en pacientes con deficiencia de DPD. El objetivo principal de esta revisión de revisiones sistemáticas es identificar revisiones sistemáticas publicadas sobre la asociación entre variaciones en el linaje germinal del gen DPYD y la toxicidad de las fluoropirimidinas. Métodos y análisis: Este protocolo se ha desarrollado siguiendo la lista de verificación de los Protocolos para Revisiones Sistemáticas y Metaanálisis Preferidos (PRISMA-P), y la revisión de las revisiones sistemáticas se comunicará de acuerdo con la declaración PRISMA. Se realizará una búsqueda en PubMed, Embase, Scopus y la Biblioteca Cochrane desde su inicio hasta 2023. Se considerarán aquellas revisiones sistemáticas, independientemente de los diseños de estudio, que analicen la asociación entre variaciones en el linaje germinal del gen DPYD y la toxicidad de las fluoropirimidinas. La calidad metodológica se evaluará utilizando la lista de verificación AMSTAR2 (Herramienta de Medición para Evaluar Revisiones Sistemáticas 2). Dos investigadores independientes realizarán la selección de estudios, la evaluación de la calidad y la recopilación de datos. Las discrepancias se resolverán mediante un tercer investigador.(AU)

Genotipado del gen DPYD y toxicidad de 5-fluoropirimidinas: Protocolo de una revisión de revisiones sistemáticas / DPYD genotyping and 5-fluoropyrimidine toxicity: An overview of systematic reviews protocol

Introduction: The increased risk of severe and life-threatening toxicity in patients with dihydropyridine dehydrogenase (DPD) deficiency, under treatment with fluoropyrimidines, has been widely studied. An up-to-date overview of systematic reviews summarizing existing literature can add value by highlighting most relevant information and supports decision-making regarding treatment in DPD deficient patients. The main objective of this overview of systematic reviews is to identify published systematic reviews on the association between germline variations in the DPYD gene and fluoropyrimidine toxicity.Methods and analysis: This protocol was developed following the Preferred Reported Items for Systematic Review and Meta-analysis Protocols (PRISMA-P) checklist, and the overview of systematic reviews will be reported in accordance with the PRISMA statement. PubMed, Embase, Scopus, and the Cochrane Library will be searched from inception to 2023. Systematic reviews irrespective of study designs that analyze the association between germline variations in the DPYD and fluoropyrimidine toxicity will be considered. Methodological quality will be assessed using AMSTAR2 checklist (Measurement Tool to Assess Systematic Reviews 2). Two independent investigators will perform the study selection, quality assessment, and data collection. Discrepancies will be solved by a third investigator.(AU)

Introducción: El incremento del riesgo de toxicidad grave y potencialmente mortal en pacientes con deficiencia de dihidropiridina deshidrogenasa (DPD) en tratamiento con fluoropirimidinas ha sido ampliamente estudiado. Una revisión actualizada de las revisiones sistemáticas publicadas, que agrupe la literatura existente, puede añadir valor al resaltar la información más relevante y respaldar la toma de decisiones con respecto al tratamiento en pacientes con deficiencia de DPD. El objetivo principal de esta revisión de revisiones sistemáticas es identificar revisiones sistemáticas publicadas sobre la asociación entre variaciones en el linaje germinal del gen DPYD y la toxicidad de las fluoropirimidinas. Métodos y análisis: Este protocolo se ha desarrollado siguiendo la lista de verificación de los Protocolos para Revisiones Sistemáticas y Metaanálisis Preferidos (PRISMA-P), y la revisión de las revisiones sistemáticas se comunicará de acuerdo con la declaración PRISMA. Se realizará una búsqueda en PubMed, Embase, Scopus y la Biblioteca Cochrane desde su inicio hasta 2023. Se considerarán aquellas revisiones sistemáticas, independientemente de los diseños de estudio, que analicen la asociación entre variaciones en el linaje germinal del gen DPYD y la toxicidad de las fluoropirimidinas. La calidad metodológica se evaluará utilizando la lista de verificación AMSTAR2 (Herramienta de Medición para Evaluar Revisiones Sistemáticas 2). Dos investigadores independientes realizarán la selección de estudios, la evaluación de la calidad y la recopilación de datos. Las discrepancias se resolverán mediante un tercer investigador.(AU)

Validated medication deprescribing instruments for patients with palliative care needs: a systematic review / Instrumentos validados de desprescripción de medicamentos para los pacientes que reciben cuidados paliativos: una revisión sistemática

Objectives: Patients with life-limiting illnesses are prone to unnecessary polypharmacy. Deprescribing tools may contribute to minimizing negative outcomes. Thus, the aims of the study were to identify validated instruments for deprescribing inappropriate medications for patients with palliative care needs and to assess the impact on clinical, humanistic, and economic outcomes. Methods: A systematic review was conducted in LILACS, PUBMED, EMBASE, COCHRANE, and WEB OF SCIENCE databases (until May 2021). A manual search was performed in the references of enrolled articles. The screening, eligibility, extraction, and bias risk assessment were carried out by 2 independent researchers. Experimental and observational studies were eligible for inclusion. Results: Out of the 5791 studies retrieved, after excluding duplicates (n = 1050), conducting title/abstract screening (n = 4741), and full reading (n = 41), only 1 study met the inclusion criteria. In this included study, a randomized controlled trial was conducted, which showed a high level of bias risk overall. Adults 75 years or older (n = 130) with limited life expectancy and polypharmacy were allocated to 2 groups [intervention arm (deprescribing); and control arm (usual care)]. Deprescribing was performed with the aid of the STOPPFrail tool. The mean number of inappropriate medications and monthly medication costs were significantly lower in the intervention arm. No statistically significant differences were found in terms of unscheduled hospital presentations, falls, fractures, mortality, and quality of life. Conclusions: Despite the availability of several instruments to support deprescribing in patients with palliative care needs, only 1 of them has undergone validation and robust assessment for effectiveness in clinical practice. The STOPPFrail tool appears to reduce the number of inappropriate medications for older people with limited life expectancy (and probably palliative care needs)...(AU)

Objetivo: Los pacientes con enfermedades terminales son propensos a la polifarmacia innecesaria. Las herramientas de desprescripción pueden contribuir a minimizar los resultados negativos. Por lo tanto, los objetivos del estudio fueron identificar instrumentos validados para la desprescripción de medicamentos inapropiados en pacientes con necesidades de cuidados paliativos y evaluar el impacto en los resultados clínicos, humanísticos y económicos. Métodos: Se realizó una revisión sistemática en las bases de datos LILACS, PUBMED, EMBASE, COCHRANE y WEB OF SCIENCE (hasta mayo de 2021). Se realizó una búsqueda manual en las referencias de los artículos incluidos. La selección, elegibilidad, extracción y evaluación del riesgo de sesgo se llevaron a cabo por dos investigadores independientes. Se aceptó la inclusión de estudios observacionales y experimentales. Resultados: De los 5791 estudios recuperados, después de excluir duplicados (n = 1050), realizar la selección de títulos/resúmenes (n = 4741) y la lectura completa (n = 41), solo un estudio cumplió con los criterios de inclusión. En este estudio incluido, se realizó un ensayo controlado aleatorizado, que mostró un alto nivel de riesgo de sesgo en general. A los adultos de 75 años o más (n = 130) con esperanza de vida limitada y polifarmacia se les asignaron dos grupos [grupo de intervención (desprescripción) y grupo de control (atención habitual)]. Se realizó la desprescripción con la ayuda de la herramienta STOPPFrail. El número promedio de medicamentos inapropiados y los costos mensuales de los medicamentos fueron significativamente más bajos en el grupo de intervención. No se encontraron diferencias estadísticamente significativas en términos de presentaciones hospitalarias no programadas, caídas, fracturas, mortalidad y calidad de vida. Conclusiones: A pesar de la disponibilidad de varias herramientas para apoyar la deprescripción en pacientes con necesidades de cuidados paliativos...(AU)

Instrumentos validados de desprescripción de medicamentos para los pacientes que reciben cuidados paliativos: una revisión sistemática / Validated medication deprescribing instruments for patients with palliative care needs: a systematic review

Objectives: Patients with life-limiting illnesses are prone to unnecessary polypharmacy. Deprescribing tools may contribute to minimizing negative outcomes. Thus, the aims of the study were to identify validated instruments for deprescribing inappropriate medications for patients with palliative care needs and to assess the impact on clinical, humanistic, and economic outcomes. Methods: A systematic review was conducted in LILACS, PUBMED, EMBASE, COCHRANE, and WEB OF SCIENCE databases (until May 2021). A manual search was performed in the references of enrolled articles. The screening, eligibility, extraction, and bias risk assessment were carried out by 2 independent researchers. Experimental and observational studies were eligible for inclusion. Results: Out of the 5791 studies retrieved, after excluding duplicates (n = 1050), conducting title/abstract screening (n = 4741), and full reading (n = 41), only 1 study met the inclusion criteria. In this included study, a randomized controlled trial was conducted, which showed a high level of bias risk overall. Adults 75 years or older (n = 130) with limited life expectancy and polypharmacy were allocated to 2 groups [intervention arm (deprescribing); and control arm (usual care)]. Deprescribing was performed with the aid of the STOPPFrail tool. The mean number of inappropriate medications and monthly medication costs were significantly lower in the intervention arm. No statistically significant differences were found in terms of unscheduled hospital presentations, falls, fractures, mortality, and quality of life. Conclusions: Despite the availability of several instruments to support deprescribing in patients with palliative care needs, only 1 of them has undergone validation and robust assessment for effectiveness in clinical practice. The STOPPFrail tool appears to reduce the number of inappropriate medications for older people with limited life expectancy (and probably palliative care needs)...(AU)

Objetivo: Los pacientes con enfermedades terminales son propensos a la polifarmacia innecesaria. Las herramientas de desprescripción pueden contribuir a minimizar los resultados negativos. Por lo tanto, los objetivos del estudio fueron identificar instrumentos validados para la desprescripción de medicamentos inapropiados en pacientes con necesidades de cuidados paliativos y evaluar el impacto en los resultados clínicos, humanísticos y económicos. Métodos: Se realizó una revisión sistemática en las bases de datos LILACS, PUBMED, EMBASE, COCHRANE y WEB OF SCIENCE (hasta mayo de 2021). Se realizó una búsqueda manual en las referencias de los artículos incluidos. La selección, elegibilidad, extracción y evaluación del riesgo de sesgo se llevaron a cabo por dos investigadores independientes. Se aceptó la inclusión de estudios observacionales y experimentales. Resultados: De los 5791 estudios recuperados, después de excluir duplicados (n = 1050), realizar la selección de títulos/resúmenes (n = 4741) y la lectura completa (n = 41), solo un estudio cumplió con los criterios de inclusión. En este estudio incluido, se realizó un ensayo controlado aleatorizado, que mostró un alto nivel de riesgo de sesgo en general. A los adultos de 75 años o más (n = 130) con esperanza de vida limitada y polifarmacia se les asignaron dos grupos [grupo de intervención (desprescripción) y grupo de control (atención habitual)]. Se realizó la desprescripción con la ayuda de la herramienta STOPPFrail. El número promedio de medicamentos inapropiados y los costos mensuales de los medicamentos fueron significativamente más bajos en el grupo de intervención. No se encontraron diferencias estadísticamente significativas en términos de presentaciones hospitalarias no programadas, caídas, fracturas, mortalidad y calidad de vida. Conclusiones: A pesar de la disponibilidad de varias herramientas para apoyar la deprescripción en pacientes con necesidades de cuidados paliativos...(AU)

Guía: Principios básicos de la neurorrehabilitación del paciente con daño cerebral adquirido. Recomendaciones de la Sociedad Española de Neurorrehabilitación / Guidelines: Basic principles of neurorehabilitation for patients with acquired brain injury. Recommendations of the Spanish Society of Neurorehabilitation

Introducción: Guía para la práctica clínica en neurorrehabilitación de personas adultas con daño cerebral adquirido de la Sociedad Española de Neurorrehabilitación. Documento basado en la revisión de guías de práctica clínica internacionales publicadas entre 2013-2020. Desarrollo: Se establecen recomendaciones según el nivel de evidencia que ofrecen los estudios revisados referentes a aspectos consensuados entre expertos dirigidos a definir la población, características específicas de la intervención o la exposición bajo investigación. Conclusiones: Deben recibir neurorrehabilitación todos aquellos pacientes que, tras un daño cerebral adquirido, hayan alcanzado una mínima estabilidad clínica. La neurorrehabilitación debe ofrecer tanto tratamiento como sea posible en términos de frecuencia, duración e intensidad (al menos 45-60 minutos de cada modalidad de terapia específica que el paciente precise). La neurorrehabilitación requiere un equipo transdisciplinar coordinado, con el conocimiento, la experiencia y las habilidades para trabajar en equipo tanto con pacientes como con sus familias. En la fase aguda, y para los casos más graves, se recomiendan programas de rehabilitación en unidades hospitalarias, procediéndose a tratamiento ambulatorio tan pronto como la situación clínica lo permita y se puedan mantener los criterios de intensidad. La duración del tratamiento debe basarse en la respuesta terapéutica y en las posibilidades de mejoría, en función del mayor grado de evidencia disponible. Al alta deben ofrecerse servicios de promoción de la salud, actividad física, apoyo y seguimiento para garantizar que se mantengan los beneficios alcanzados, detectar posibles complicaciones o valorar posibles cambios en la funcionalidad que hagan necesario el acceso a nuevos programas de tratamiento.(AU)

Introduction: We present the Spanish Society of Neurorehabilitation's guidelines for adult acquired brain injury (ABI) rehabilitation. These recommendations are based on a review of international clinical practice guidelines published between 2013 and 2020. Development: We establish recommendations based on the levels of evidence of the studies reviewed and expert consensus on population characteristics and the specific aspects of the intervention or procedure under research. Conclusions: All patients with ABI should receive neurorehabilitation therapy once they present a minimal level of clinical stability. Neurorehabilitation should offer as much treatment as possible in terms of frequency, duration, and intensity (at least 45–60 min of each specific form of therapy that is needed). Neurorehabilitation requires a coordinated, multidisciplinary team with the knowledge, experience, and skills needed to work in collaboration both with patients and with their families. Inpatient rehabilitation interventions are recommended for patients with more severe deficits and those in the acute phase, with outpatient treatment to be offered as soon as the patient's clinical situation allows it, as long as intensity criteria can be maintained. The duration of treatment should be based on treatment response and the possibilities for further improvement, according to the best available evidence. At discharge, patients should be offered health promotion, physical activity, support, and follow-up services to ensure that the benefits achieved are maintained, to detect possible complications, and to assess possible changes in functional status that may lead the patient to need other treatment programmes.(AU)

Complicaciones tras retirada de barra de Nussen pectus excavatum. Análisis y propuesta de unprotocolo de seguridad / Complications after Nuss bar removal procedure for pectus excavatum. Analysis and proposal of a safety protocol

Objetivo: La retirada de la barra de Nuss puede provocar diversascomplicaciones, algunas leves y otras potencialmente mortales. Su incidencia puede verse reducida con una preparación quirúrgica adecuaday siguiendo ciertos pasos de seguridad. El presente estudio tiene porobjeto analizar nuestra experiencia con las complicaciones acontecidasdurante la retirada de la barra, así como nuestro protocolo de seguridadpara la prevención y el manejo de dichas complicaciones.Material y métodos:Estudio de cohortes observacional llevado acabo a partir del análisis retrospectivo de todos los pacientes sometidos acirugía de retirada de barra de Nuss entre noviembre de 2013 y marzo de2022 en un hospital universitario. Se analizaron las siguientes variables:demografía de los pacientes, presencia de comorbilidades, tiempo desdela colocación de la barra hasta su retirada, y complicaciones operatoriasy postoperatorias. El estudio se realizó conforme a las directrices de laPROCESS Guideline. Resultados: Se incluyó a 40 pacientes, 37 de ellos varones. En 17pacientes se retiró una barra, y en 22, dos. La edad media en el momento de la cirugía fue de 17,5 años (percentil 25-75%: 16,75 - 19,25).El tiempo transcurrido desde la colocación hasta la retirada fue de 26meses (percentil 25-75%: 23,75 - 30,25). Se registraron 10 complicaciones en 9 pacientes (22,5%), 6 de clase I según la clasificación deClavien-Dindo (67%), 2 de clase II (22%), 1 de clase IIIb y 1 de claseIV. La complicación hemorrágica motivó la creación de un protocolo deseguridad para disminuir la incidencia de las complicaciones. Conclusión: La retirada de la barra de Nuss es un procedimientoseguro, habitualmente con escasas complicaciones, aunque en ocasionespueden ser graves. Para evitarlas, es importante contar con un protocoloque garantice la seguridad.(AU)

Objective: The Nuss bar removal procedure may bring about different complications. Some are mild while others can be life-threatening.An adequate surgery setup and the fulfilment of some security stepsmay reduce their incidence. This study aims to analyze our experiencewith the complications that occurred during bar removal and our safetyprotocol for the prevention and management of these complications.Materials and methods: Observational cohort study from a retrospective chart review of all patients who underwent Nuss bar removalfrom November 2013 to March 2022 at a University hospital. Variablesanalyzed include patients’ demographics; presence of comorbidities;time elapsed from bar placement to removal, and the occurrence ofoperative and postoperative complications. Study written under the´PROCESS Guideline’. Results: Fourty (40) patients were included in the study; 37 weremale. One bar was removed in 17 patients and two in 22 patients. Medianage at surgery: 17.5 years (Percentile 25-75%: 16.75 - 19.25). Timeelapsed from placement to removal: 26 months (Percentile 25 - 75%:23.75 - 30.25). Complications: 10 in 9 patients (22.5%); 6 Clavien-Dindoclass I (67%); 2 class II (22%); 1 class IIIb, 1 class IV. The hemorrhagiccomplication motivated the development of a safety protocol to reduceincidence of complications. Conclusion: Nuss bar removal is a safe procedure with usuallyscant complications. Nonetheless, these may be serious sometimes. Toprevent them, a protocol for a safe procedure is important.(AU)

Recomendaciones SER sobre el tratamiento del síndrome de Behçet refractario / SER recommendations on treatment of refractory Behçet's syndrome

Objetivo: Elaborar recomendaciones multidisciplinares, basadas en la evidencia disponible y el consenso de expertos, para el manejo terapéutico de los pacientes con síndrome de Behçet refractario (difícil de tratar, resistente grave, recidivante grave) al tratamiento convencional. Métodos: Un panel de expertos identificó preguntas clínicas de investigación relevantes para el objetivo del documento. Estas preguntas fueron reformuladas en formato PICO –paciente, intervención, comparación, outcome o desenlace–. A continuación, se realizaron revisiones sistemáticas; la evaluación de la calidad de la evidencia se realizó siguiendo la metodología del grupo internacional de trabajo Grading of Recommendations, Assessment, Development, and Evaluation. Tras esto, el panel multidisciplinar formuló las recomendaciones. Resultados: Se seleccionaron 4 preguntas PICO relativas a la eficacia y seguridad de los tratamientos farmacológicos sistémicos en los pacientes con síndrome de Behçet con manifestaciones clínicas refractarias a terapia convencional, relacionadas con los fenotipos mucocutáneo y/o articular, vascular, neurológico-parenquimatoso y gastrointestinal. Se formularon un total de 7 recomendaciones estructuradas por pregunta, con base en la evidencia encontrada y el consenso de expertos. Conclusiones: El tratamiento de las manifestaciones clínicas más graves del síndrome de Behçet carece de evidencia científica sólida y no existen documentos de recomendaciones específicas para los pacientes con enfermedad refractaria a la terapia convencional. Con el fin de aportar una respuesta a esta necesidad, se presenta el primer documento de recomendaciones de la Sociedad Española de Reumatología específicas para el abordaje terapéutico de estos pacientes, que servirá de ayuda en la toma de decisiones clínica y la reducción de la variabilidad en la atención.(AU)

Objective: To develop multidisciplinary recommendations based on available evidence and expert consensus for the therapeutic management of patients with refractory Behçet's syndrome (difficult to treat, severe resistant, severe relapse) to conventional treatment. Methods: A group of experts identified clinical research questions relevant to the objective of the document. These questions were reformulated in PICO format –patient, intervention, comparison and outcome–. Systematic reviews of the evidence were conducted; the quality of the evidence was evaluated following the methodology of the international working group Grading of Recommendations, Assessment, Development, and Evaluation. After that, the multidisciplinary panel formulated the specific recommendations. Results: Four PICO questions were selected regarding the efficacy and safety of systemic pharmacological treatments in patients with Behçet's syndrome with clinical manifestations refractory to conventional therapy related to mucocutaneous and/or articular, vascular, neurological parenchymal and gastrointestinal phenotypes. A total of 7 recommendations were made, structured by question, based on the identified evidence and expert consensus. Conclusions: The treatment of most severe clinical manifestations of Behçet's syndrome lacks solid scientific evidence and, besides, there are no specific recommendation documents for patients with refractory disease. With the aim of providing a response to this need, here we present the first official recommendations of the Spanish Society of Rheumatology for the management of these patients. They are devised as a tool for assistance in clinical decision making, therapeutic homogenisation and to reduce variability in the care of these patients.(AU)

Prospective, randomized study comparing two different regimens of split-dose polyethylene glycol and their effect on endoscopic outcomes.

BACKGROUND: Different split regimens of polyethylene glycol are routinely used and no guidelines are available to select an optimal protocol of ingestion. This study aims to compare the efficacy and side effect profile of two different regimens of polyethylene glycol bowel preparation solution: PEG (3 + 1) vs. PEG (2 + 2). METHODS: 240 patients above the age of 18 years were included in the study between June 1st and November 31st, 2023. Patients were randomly assigned either to Group A, consisting of 115 patients receiving a 3 L of PEG the night before the colonoscopy, and 1 L the same morning of the procedure. Or to group B, where 125 patients ingested 2 L the night before the procedure, and the remaining 2 L the same morning. The cleansing efficacy was evaluated by the attending endoscopist using the Boston Bowel Preparation Scale, through a score assigned for each segment of the colon (0-3). Side effects, tolerability, and willingness to retake the same preparation were listed by an independent investigator using a questionnaire administered before the procedure. RESULTS: A higher percentage of patients had gastric fullness with the 3 + 1 vs. 2 + 2 preparation (58.3% vs. 31.2%; p <.001). A higher Boston bowel preparation score was seen in patients who took the 2 + 2 vs. 3 + 1 preparation (7.87 vs. 7.23). Using the 2 + 2 preparation was significantly associated with higher Boston bowel preparation scores vs. the 3 + 1 preparation (OR = 1.37, p =.001, 95% CI 1.14, 1.64). After adjustment over other variables (age, gender, comorbidities, previous abdominal surgeries, presence of adenoma, and time between last dose and colonoscopy), results remained the same (aOR = 1.34, p =.003, 95% CI 1.10, 1.62). CONCLUSION: While both (2 + 2) and (3 + 1) regimens of polyethylene glycol are a good choice for a successful colonoscopy, we recommend the use of (2 + 2) regimen for its superior efficacy in bowel cleansing.

INDIVIDUAL ARTICLE: Efficacy of a Prebiotic Skincare Regimen on Improving Mild Atopic Dermatitis and Severe Xerosis in Diverse Ethnically Patients.

Atopic Dermatitis (AD) is a chronic relapsing inflammatory skin disease associated with a significant patient burden on quality-of-life. Given skin barrier including skin microbiome changes are linked to AD pathogenesis, prebiotic emollients are shown to improve disease symptoms and maintain skin barrier integrity, normalizing skin microbiota. In this study, we evaluated the efficacy and safety of a prebiotic skincare routine in improving AD and xerosis, and ultimately quality-of-life in ethnically diverse patients. A total of 140 subjects from different racial/ethnic backgrounds, aged 3-80 years old with skin phototypes I-VI, and presenting with mild-AD or severe xerosis completed study. Expert grading, instrumentation, self-assessment questionnaires, plus clinical imaging demonstrated that a prebiotic cleanser and moisturizer routine significantly reduced skin conditions severity, strengthened skin barrier properties in both lesional and normal skin, and improved patients' quality-of-life while providing itch relief as soon as 4 weeks. The results of this research indicate that a prebiotic cleanser and moisturizer regimen offers benefits for diverse patient’s daily skincare routine by effectively managing AD and xerosis severity and symptoms, normalizing skin microbiota, plus preserving skin barrier integrity to prevent long-term sequelae. J Drugs Dermatol. 2024;23:3(Suppl 2):s12-22.

Flow diversion of ruptured intracranial aneurysms: a single-center study with a standardized antithrombotic treatment protocol.

BACKGROUND: The use of antithrombotic medication following acute flow diversion for a ruptured intracranial aneurysm (IA) is challenging with no current guidelines. We investigated the incidence of treatment-related complications and patient outcomes after flow diversion for a ruptured IA before and after the implementation of a standardized antithrombotic medication protocol. METHODS: We conducted a single-center retrospective study including consecutive patients treated for acutely ruptured IAs with flow diversion during 2015-2023. We divided the patients into two groups: those treated before the implementation of the protocol (pre-protocol) and those treated after the implementation of the protocol (post-protocol). The primary outcomes were hemorrhagic and ischemic complications. A secondary outcome was clinical outcome using the modified Ranking Scale (mRS). RESULTS: Totally 39 patients with 40 ruptured IAs were treated with flow diversion (69% pre-protocol, 31% post-protocol). The patient mean age was 55 years, 62% were female, 63% of aneurysms were in the posterior circulation, 92% of aneurysms were non-saccular, and 44% were in poor grade on admission. Treatment differences included the use of glycoprotein IIb/IIIa inhibitors (pre-group 48% vs. post-group 100%), and the use of early dual antiplatelets (pre-group 44% vs. 92% post-group). The incidence of ischemic complications was 37% and 42% and the incidence of hemorrhagic complications was 30% and 33% in the pre- and post-groups, respectively, with no between-group differences. There were three (11%) aneurysm re-ruptures in the pre-group and none in the post-group. There were no differences in mortality or mRS 0-2 between the groups at 6 months. CONCLUSION: We found no major differences in the incidence of ischemic or hemorrhagic complications after the implementation of a standardized antithrombotic protocol for acute flow diversion for ruptured IAs. There is an urgent need for more evidence-based guidelines to optimize antithrombotic treatment after flow diversion in the setting of subarachnoid hemorrhage.

A standardized treatment protocol for pilonidal disease can influence the health mindset of adolescents.

PURPOSE: Pilonidal disease (PD) significantly impacts patients' quality of life and requires regular maintenance behaviors to achieve cure. Health mindset is a psychological construct which can influence health behaviors and outcomes, with a growth mindset being associated with better outcomes than a fixed. We propose that participation in a standardized treatment protocol can affect the health mindset for adolescents with pilonidal disease. METHODS: PD patients' demographics, recurrence, and comorbidities were prospectively collected from 2019 to 2022. We assessed patients' mindset score at initial presentation using the validated Three-Item Mindset Scale (1-6) then reassessed during follow-up. t-test was used to compare baseline and follow-up mindset scores and stratified by recurrence or comorbidities. p ≤ 0.05 was considered significant. RESULTS: A total of 207 PD patients (108 males, 99 females) with mean age 18.2 ± 3.7 years were followed for 351 ± 327 days. Mean baseline mindset score (4.76 ± 1.27) was significantly lower than mean follow-up mindset score (5.03 ± 1.18, p = 0.049). Baseline mindset score was significantly lower among patients with PD recurrence (4.00 ± 0.66) compared to those without recurrence (4.8 ± 1.29, p = 0.05). Among patients with PD recurrence, mean baseline mindset score (4.00 ± 0.66) was significantly lower than mean follow-up mindset score (5.27 ± 0.93, p = 0.0038). Patient comorbidity did not affect the baseline or follow-up mindset score. CONCLUSIONS: Participation in a standardized treatment protocol is associated with the development of a stronger growth mindset over time for patients with PD. Furthermore, a growth mindset was linked to lower recurrence rate than a fixed mindset. Further investigations into how treatment approaches can work in concert with health mindset are proposed.

COMPARISON OF THREE MIDAZOLAM-BASED SEDATION PROTOCOLS IN BUDGERIGARS (MELOPSITTACUS UNDULATUS) AND BLACK-CHEEKED LOVEBIRDS (AGAPORNIS NIGRIGENIS).

This randomized, crossover study evaluated three sedation protocols administered subcutaneously in nine budgerigars (Melopsittacus undulatus) and nine black-cheeked lovebirds (Agapornis nigrigenis). All protocols included midazolam (5 mg/kg), combined with butorphanol (5 mg/kg) (BM), medetomidine (20 lg/kg) (MM), or alfaxalone (13 mg/kg) (AM). Mortalities from suspected cardiorespiratory arrest were observed when AM was used in lovebirds, even after reduction of alfaxalone dosage to 3 mg/kg, and therefore this protocol was excluded from further use in this species. Induction and recovery times were recorded and their quality assessed. Sedation depth and heart and respiratory rates were measured every 5 min and radiographic positioning was attempted at 10 and 20 min. At 30 min, midazolam and medetomidine were reversed with flumazenil (0.05 mg/kg, SC), and atipamezole (0.2 mg/kg, SC), respectively. MM consistently provided deep sedation in both species, with successful radiographic positioning at every attempt. As expected, heart rate was often lower with MM than with other protocols, but no associated complications were noted. In budgerigars, BM had the lowest radiographic positioning success rate (10 min: 5/9, 20 min: 3/9), whereas in lovebirds it provided significantly deeper sedation (P < 0.001), allowing radiographic positioning in all subjects. In both species, BM provided the shortest recovery times. AM resulted in reliable radiographic positioning of all budgerigars at 10 min, but not at 20 min (5/ 9), and provided consistently poor recoveries. This study highlights how differently two psittacine species of similar size may react to the same sedation protocols. AM sedation cannot be fully reversed and produced significant undesirable effects, several of which have been previously reported with alfaxalone administration to avian species. The authors therefore caution against using alfaxalone-midazolam combinations in budgerigars and black-cheeked lovebirds. Both BM and MM provided reliable sedation in these species, and appear to be suitable alternatives to AM.

Identification of a hyperinflammatory sepsis phenotype using protein biomarker and clinical data in the ProCESS randomized trial.

Sepsis is a heterogeneous syndrome and phenotypes have been proposed using clinical data. Less is known about the contribution of protein biomarkers to clinical sepsis phenotypes and their importance for treatment effects in randomized trials of resuscitation. The objective is to use both clinical and biomarker data in the Protocol-Based Care for Early Septic Shock (ProCESS) randomized trial to determine sepsis phenotypes and to test for heterogeneity of treatment effect by phenotype comparing usual care to protocolized early, goal-directed therapy(EGDT). In this secondary analysis of a subset of patients with biomarker sampling in the ProCESS trial (n = 543), we identified sepsis phenotypes prior to randomization using latent class analysis of 20 clinical and biomarker variables. Logistic regression was used to test for interaction between phenotype and treatment arm for 60-day inpatient mortality. Among 543 patients with severe sepsis or septic shock in the ProCESS trial, a 2-class model best fit the data (p = 0.01). Phenotype 1 (n = 66, 12%) had increased IL-6, ICAM, and total bilirubin and decreased platelets compared to phenotype 2 (n = 477, 88%, p < 0.01 for all). Phenotype 1 had greater 60-day inpatient mortality compared to Phenotype 2 (41% vs 16%; p < 0.01). Treatment with EGDT was associated with worse 60-day inpatient mortality compared to usual care (58% vs. 23%) in Phenotype 1 only (p-value for interaction = 0.05). The 60-day inpatient mortality was similar comparing EGDT to usual care in Phenotype 2 (16% vs. 17%). We identified 2 sepsis phenotypes using latent class analysis of clinical and protein biomarker data at randomization in the ProCESS trial. Phenotype 1 had increased inflammation, organ dysfunction and worse clinical outcomes compared to phenotype 2. Response to EGDT versus usual care differed by phenotype.

Gut dysbiosis is linked to metabolic syndrome in obese Egyptian women: potential treatment by probiotics and high fiber diets regimen.

Metabolic syndrome (MetS) is defined as a cluster of glucose intolerance, hypertension, dyslipidemia, and central obesity with insulin resistance. The role of gut microbiota in metabolic disorders is increasingly considered. To investigate the effects of probiotic supplements and hypocaloric high fiber regimen on MetS in obese Egyptian women. A longitudinal follow-up intervention study included 58 obese Egyptian women, with a mean age of 41.62 ± 10.70 years. They were grouped according to the criteria of MetS into 2 groups; 23 obese women with MetS and 35 ones without MetS. They followed a hypocaloric high fiber regimen weight loss program, light physical exercise, and received a probiotic supplement daily for 3 months. For each participating woman, blood pressure, anthropometric measurements, basal metabolic rate (BMR), dietary recalls, laboratory investigations, and microbiota analysis were acquired before and after 3 months of follow-up. After intervention by the probiotic and hypocaloric high fiber regimen and light exercise, reduction ranged from numerical to significant difference in the anthropometric parameters, blood pressure, and BMR was reported. All the biochemical parameters characterized by MetS decreased significantly at p ≤ 0.05-0.01. Before the intervention, results revealed abundant of Bacteroidetes bacteria over Firmicutes with a low Firmicutes/Bacteroidetes ratio. After the intervention, Log Lactobacillus, Log Bifidobacteria, and Log Bacteroidetes increased significantly in both groups, while Log Firmicutes and the Firmicutes/Bacteroidetes Ratio revealed a significant decrease. In conclusion, this study's results highlight a positive trend of probiotics supplementation with hypocaloric high-fiber diets in amelioration of the criteria of the Mets in obese Egyptian women.

Two-Stage Treatment Protocol of Fungal Periprosthetic Hip and Knee Joint Infections: the Clinical Experience from a Single Center Experience.

PURPOSE OF THE STUDY: To evaluate the clinical results and safety of fungal periprosthetic joint Infections (fPJIs) using two-stage treatment protocol. MATERIAL AND METHODS: 8 patients with fPJIs (3 hips and 5 knees) using two-stage revision were reviewed retrospectively and followed up at least 2 years. The preoperative demographic data, two-stage treatment protocol, results of microbiology and histologic workup and postoperative follow-up results (reimplantation success rate and infection free time) were recorded. RESULTS: 7 patients got successful reimplantation, with a 75% reimplantation success rate. Two patients got knee arthrodesis eventually. All patients were infection free with a median follow-up of 4.0 ± 2.0 years (range, 2-7 years). Of them, Candida species were found in 7 patients, while non-Candida specimen was only isolated in 1 patient with Aspergillus. Only 2 patients had coexisting bacterial infection (Methicillin-resistant coagulase-negative Staphylococci and Proteus mirabilis respectively). The average interval between the initial surgery and diagnosis of fPJIs was 21.50±34.79 months (range, 4-104 months). The mean time of spacer implantation was 7.75±2.77 months (range, 6-14 months). None serious complication or above knee amputation was found. DISCUSSION: fPJIs are very rare and considerable challenge after total hip or knee arthroplasty. The goal of therapy is to eradicate local infection and maintain function. Candida species were the most common pathogen. The duration between spacer placement and staged reimplantation was highly variable, and generally dependent upon the results of joint aspirates and infl ammatory markers. The current study shows that the two-stage treatment protocol is recommended for fungal periprosthetic hip and knee joint infections. CONCLUSIONS: The two-stage treatment protocol is recommended for fungal periprosthetic hip and knee joint infections. The safety and effi cacy of biantibiotical impregnated (antifungal + antibiotics) cement spacer is confi rmed. Further evidence-based work is needed to determine the optimal drug dose and reimplantation time. KEY WORDS: two-stage treatment protocol, fungal periprosthetic infections, hip spacer, knee spacer.

Intentional Replantation: No Longer a Last Resort for Saving a Natural Tooth.

Intentional replantation (IR) is the intentional extraction of a tooth followed by its replacement back into its socket for the purpose of performing a root-end surgery or other necessary repairs. The procedure may be considered a favorable alternative to conventional microsurgery, especially when surgical access is restricted due to specific anatomical challenges. With advancements in magnification, bioceramics, and instrumentation, IR has become a well-established, scientifically supported treatment modality and is cost-effective when compared to single-implant placement. This article discusses the rationale and indications for IR, describes treatment protocols, and reports on its outcomes.