CD19 CAR T cells for B cell malignancies: a systematic review and meta-analysis focused on clinical impacts of CAR structural domains, manufacturing conditions, cellular product, doses, patient's age, and tumor types.

CD19-targeted chimeric antigen receptors (CAR) T cells are one of the most remarkable cellular therapies for managing B cell malignancies. However, long-term disease-free survival is still a challenge to overcome. Here, we evaluated the influence of different hinge, transmembrane (TM), and costimulatory CAR domains, as well as manufacturing conditions, cellular product type, doses, patient's age, and tumor types on the clinical outcomes of patients with B cell cancers treated with CD19 CAR T cells. The primary outcome was defined as the best complete response (BCR), and the secondary outcomes were the best objective response (BOR) and 12-month overall survival (OS). The covariates considered were the type of hinge, TM, and costimulatory domains in the CAR, CAR T cell manufacturing conditions, cell population transduced with the CAR, the number of CAR T cell infusions, amount of CAR T cells injected/Kg, CD19 CAR type (name), tumor type, and age. Fifty-six studies (3493 patients) were included in the systematic review and 46 (3421 patients) in the meta-analysis. The overall BCR rate was 56%, with 60% OS and 75% BOR. Younger patients displayed remarkably higher BCR prevalence without differences in OS. The presence of CD28 in the CAR's hinge, TM, and costimulatory domains improved all outcomes evaluated. Doses from one to 4.9 million cells/kg resulted in better clinical outcomes. Our data also suggest that regardless of whether patients have had high objective responses, they might have survival benefits from CD19 CAR T therapy. This meta-analysis is a critical hypothesis-generating instrument, capturing effects in the CD19 CAR T cells literature lacking randomized clinical trials and large observational studies.

[GMK rotating hinge prosthesis. A valid option for complex revision knee prosthetic surgery]. / Prótesis bisagra rotatoria GMK. Una opción válida para la cirugía de revisión protésica compleja de rodilla.

INTRODUCTION: revision joint replacement surgery presents a surgical challenge. The use of rotating hinge prostheses is an option in patients with femorotibial bone defects, ligament insufficiency, or significant deformities. The aim of this study was to evaluate the clinical, functional, and radiological outcomes of a series of patients who underwent surgery using the GMK Hinge (Medacta®) rotational hinge model. MATERIAL AND METHODS: a descriptive, retrospective, and analytical study was conducted on a series of 36 patients, with a mean age of 72.5 years (47-85), operated on by the same surgical team between January 2015 and January 2022. The etiology of revision was chronic infection in 38.9% of cases, instability in 33.3%, aseptic loosening in 19.4%, and stiffness in 8.4%. The Knee Society Score (KSS) and the Forgotten Joint Score (FJS) were used to assess functional outcomes. The degree of femorotibial bone defect was evaluated using the Anderson Orthopaedic Research Institute (AORI) classification. Postoperative complications are also recorded. RESULTS: a total of 36 patients, 17 males and 19 females, were included, with a mean follow-up of 30 months (12-66). Twelve patients had type 1 defects, ten had 2A defects, ten had 2B defects, and two had type 3 defects on the femoral side, with the use of wedges required for asymmetrical defects (21 patients). The predominant tibial defect was type 1 without the need for wedges. The majority achieved a satisfactory outcome on the KSS scale (72.2 ± 9.4), with significant differences compared to the previous KSS (54.3 ± 8.9). A score of 31 (12-67) was also obtained on the FJS scale. Postoperative complications were present in 16.7% of patients. CONCLUSIONS: complex prosthetic revision surgery using a rotating hinge prosthesis represents a suitable therapeutic option, yielding appropriate clinical and functional outcomes, albeit not without complications.

INTRODUCCIÓN: la cirugía de revisión protésica constituye un reto quirúrgico. La utilización de prótesis tipo bisagra rotatoria es una opción en pacientes con defectos óseos femorotibiales, insuficiencia ligamentosa o importantes deformidades. El objetivo del presente estudio es evaluar los resultados clínicos, funcionales y radiológicos de una serie de pacientes intervenidos mediante un modelo de bisagra rotacional GMK Hinge (Medacta®). MATERIAL Y MÉTODOS: estudio descriptivo retrospectivo y analítico que incluyó una serie de 36 pacientes, con edad media de 72.5 años (47-85) intervenidos entre Enero de 2015 y Enero de 2022 por el mismo equipo quirúrgico. La etiología de revisión fue infección crónica en 38.9%, inestabilidad en 33.3%, aflojamiento aséptico en 19.4% y rigidez en 8.4%. Para la evaluación de resultados funcionales se utiliza la escala Knee Society Score (KSS), así como la escala Forgotten Joint Score (FJS). El grado de defecto óseo femorotibial se evaluó mediante la clasificación de Anderson Orthopaedic Research Institute (AORI). También se registraron las complicaciones postquirúrgicas. RESULTADOS: se analizó un total de 36 pacientes, 17 varones y 19 mujeres, con seguimiento medio de 30 meses (12-66). Se encontraron doce pacientes con defectos tipo 1, diez con defectos 2A, diez con defectos 2B y dos con defecto tipo 3 en la vertiente femoral, siendo necesario la utilización de cuñas en defectos asimétricos (21 pacientes). El defecto tibial mayoritario fue el tipo 1 sin necesidad de cuñas. La mayoría obtuvo un resultado satisfactorio en la escala KSS (72.2 ± 9.4), con diferencias significativas respecto al KSS previo (54.3 ± 8.9). Se obtuvo también una puntuación de 31 (12-67) en la escala FJS. Presentaron complicaciones postoperatorias 16.7% de los pacientes. CONCLUSIONES: la cirugía de revisión protésica compleja mediante prótesis tipo bisagra rotacional constituye una correcta opción terapéutica, presentando resultados clínicos y funcionales adecuados, no exentos de complicaciones.

Lateral hinge fracture in medial opening wedge high tibial osteotomy: a narrative review.

Lateral hinge fractures (LHF) are one of the most common complications of medial opening wedge high tibial osteotomy (MOWHTO), and are the leading cause of construct instability displacement, non-union, and varus recurrence after this procedure. To date, Takeuchi's classification is the most popular classification to describe this complication, and it can help surgeons to make intra and postoperative decisions. Opening medial gap width is the most recognized factor related to LHF occurrence. Recognizing the implications of LHF in patients' clinical and radiographic results has led many authors to propose surgical tips and the use of osteosynthesis materials such as K-wires and screws for its prevention, which should be considered when identifying risk factors for LHF during preoperative planning. The evidence for determining the optimal management of LHF is scarce and mostly supported by experts' opinions and recommendations; therefore, studies are still needed to identify the most appropriate behavior when dealing with such a complication.

The p.Cys1281Tyr variant in the hinge module/flap region of thyroglobulin causes intracellular transport disorder and congenital hypothyroidism.

Congenital hypothyroidism (CH) due to thyroglobulin (TG) variants causes very low serum TG levels with normal or enlarged thyroid glands, depending on the severity of the defect, and with autosomal recessive inheritance. The purpose of this study was to functionally characterize p.Cys1281Tyr variant in the TG gene in order to increase our knowledge of the molecular mechanisms associated with CH. In order to find evidence that support the hypothesis that the p.Cys1281Tyr variant would affect the TG folding were performed amino acid prediction, 3D modeling and transient expression analysis in HEK293T cells. 18 of the 21″in silico" algorithms predict a deleterious effect of the p.Cys1281Tyr variant. The full-length 3D model p.Cys1281Tyr TG showed disulfide bond cleavage between the cysteines at positions 1249 and 1281 and rearrangement of the TG structure, while transient expression analysis indicated that p.Cys1281Tyr causes retention of the protein inside the cell. Consequently, these results show that this pathogenic variant makes it impossible for TG to fulfill its function in the biosynthesis process of thyroid hormones, causing CH. In conclusion, our results confirm the pathophysiological importance of misfolding of TG as a consequence of p.Cys1281Tyr variant located in the hinge module/flap region of TG.

Resultados de la técnica septum bisagra en desviación de la punta nasal / Septum hinge technique outcomes in nasal tip deviation

Introducción: La desviación de la punta nasal suele producir alteración estética y funcional nasal. Generalmente, asocia alteraciones morfológicas de los cartílagos alares, además de dismorfia del cartílago septal. Objetivo: Presentar una técnica quirúrgica alternativa para el tratamiento de la laterorrinia en tercio inferior nasal y sus resultados. Material y Método: Se trataron 27 pacientes con una laterorrinia en punta nasal con la técnica del septum bisagra, incluyendo la colocación de uno o dos injertos de expansión. Describimos el protocolo de anamnesis y exploración que seguimos en estos pacientes y la descripción detallada de la técnica quirúrgica. Resultados: En 19 pacientes se utilizó un injerto de expansión unilateral para completar la técnica y en ocho de forma bilateral. Se obtuvo una puntuación media en la escala visual analógica (EVA) de ventilación de 8,3, con una mejoría de seis puntos, y en la EVA de aspecto estético de 8,1, mejorando en 4,6 puntos. Conclusión: la utilización de la técnica del septum bisagra es beneficiosa para el tratamiento de la desviación de la punta nasal, tanto a nivel funcional como estético. Presenta ciertas diferencias frente a otras técnicas descritas. La indicación se debe adecuar a cada paciente de manera individualizada.

Introduction: Deviation of nasal tip usually produces aesthetic disturbance and nasal ventilation decrease. It is usually associated with alar cartilages morphologic disturbances and dysmorphia of the septal cartilage. Aim: To present an alternative surgical technique for treating laterorrhinia in the nasal inferior third and its outcomes. Material and Method: 27 patients with nasal tip laterorrhinia were treated with the hinge septum technique, including the placement of one or two spreader grafts. We describe the anamnesis and exploration protocol that we carried out in these patients and a detailed description of the surgical procedure. Results: Unilateral spreader graft was used in 19 patients to complete the technique, and bilateral spreader graft was used in eight. The average score in visual analogue scale (VAS) related to nasal flow was 8.3, which means an improvement of six points, and in VAS related to aesthetic appearance the score was 8.1, improving 4.6 points. Conclusion: The use of the hinge septum technique is useful to treat the deviation of the nasal tip in a functional and aesthetic way. There are several differences compared to other described techniques. The indication has to be suitable for each patient individually.

Features and applications of Ent35-MccV hybrid bacteriocin: current state and perspectives.

Bacteriocins are peptides of ribosomal synthesis that are active against bacteria related to the producing strain. They have been widely used in the food industry as biopreservatives. The generation of hybrid peptides by combining the genes that encode two different bacteriocins has made it possible to study the mechanisms of action of the bacteriocins that compose them and also develop new peptides with improved biotechnological applications. Hybrid bacteriocins may be obtained in several ways. In our laboratory, by combining enterocin CRL35 and microcin V (Ent35-MccV), we obtained a broad-spectrum peptide that is active against both Gram-positive and Gram-negative bacteria. Ent35-MccV is sensitive to the action of intestinal proteases and is heat resistant, which makes it a good candidate for use as a biopreservative. For this reason, the peptide was tested in skim milk and beef burgers as food models. We also obtained more potent variants of the hybrid by modifying the central amino acid of the hinge region that connects the two bacteriocins. This review also discusses future applications and perspectives regarding the Ent35-MccV and other hybrid peptides.Key Points• Ent35-MccV is a new broad-spectrum bacteriocin.• The mechanism of action of bacteriocins can be studied using hybrid peptides.• Genetic engineering allows obtaining improved bacteriocin derivatives.• Hybrid peptides can be used in the food, pharmaceutical, and veterinary applications.

Obtaining an Ent35-MccV derivative with mutated hinge region that exhibits increased activity against Listeria monocytogenes and Escherichia coli.

The present paper describes the generation of derivatives from the hybrid peptide called Ent35-MccV, active against Gram-positive and Gram-negative bacteria. This peptide has a triple glycine hinge region between enterocin CRL35 and microcin V. In order to obtain variants of Ent35-MccV with greater biotechnological potential, a saturation mutagenesis was carried out in the hinge region. As a result, we obtained a bank of E. coli strains expressing different mutated hybrid bacteriocins in the central position of the hinge region. From all these variants, we found that the one bearing a tyrosine in the central region of the hinge (Ent35-GYG-MccV) is 2-fold more active against E. coli and 4-fold more active against Listeria than the original peptide Ent35-MccV. This derivative was purified and characterized. The development and evaluation of alternative hinges for Ent35-MccV represents a step forward in the bioengineering of antimicrobial peptides. This approach fosters the rational design of peptides with enhanced antimicrobial activity.

Hinge axis - location, clinical use and controversies

The hinge axis is an imaginary line around which the condyles can rotate without translation. Terminal hinge position is the most retruded hinge position and it is significant because it is a learnable, repeatable and recordable position that coincides with the position of centric relation. There are many schools of thought regarding hinge axis. The proponents of Gnathology say that there is one transverse hinge axis common to both condyles which can be accurately located. The proponents of transographics claim that each condyle has a different transverse hinge axis and that a transograph is the only instrument that can duplicate this. Still others claim that an exact duplication of jaw movement is not possible on any machine. The aim of this article is to throw light on location, clinical use and controversies of hinge axis.

The functional aortic annulus in the 3D era: focus on transcatheter aortic valve replacement for the perioperative echocardiographer.

The functional aortic annulus represents a sound clinical framework for understanding the components of the aortic root complex. Recent three-dimensional imaging analysis has demonstrated that the aortic annulus frequently is elliptical rather than circular. Comprehensive three-dimensional quantification of this aortic annular geometry by transesophageal echocardiography and/or multidetector computed tomography is essential to guide precise prosthesis sizing in transcatheter aortic valve replacement to minimize paravalvular leak for optimal clinical outcome. Furthermore, three-dimensional transesophageal echocardiography accurately can quantify additional parameters of the functional aortic annulus such as coronary height for complete sizing profiles for all valve types in transcatheter aortic valve replacement. Although it is maturing rapidly as a clinical imaging modality, its role in transcatheter aortic valve replacement is seen best as complementary to multidetector computed tomography in a multidisciplinary heart team model.

Oclusión dental: ¿doctrina mecanicista o lógica morfofisiológica? / Dental occlusion: mechanistic doctrine or morphophysiological logical?

Las escuelas de oclusión han creado un constructo mecanicista que busca explicar, bajo un modelo reduccionista y determinista, una dinámica cráneo-cervical y estomatognática compleja. Estos modelos de oclusión le dedican más importancia a la morfología dental y sus geometrías interpretativas que a la morfofisiología estomatognática. La configuración musculo-esquelética cráneo-cervical tiene el poder ganado de influir concomitantemente en la ubicación espacial de la mandíbula e implícitamente en las relaciones interoclusales. La visión actual de la oclusión sigue basándose en observaciones empíricas de un siglo de antigüedad que carecen de soporte apropiado en el marco del nivel de evidencia. En la dimensión funcional los modelos de oclusión conservan los mismos vacíos que existían desde su estructuración en el siglo pasado, particularmente en sus representaciones espaciales estáticas, uniáxicas y anti-dinámicas que desestiman la individualidad de cada sujeto. Cada especialidad puede tener tantas razones como puntos de vista diferentes de "maloclusión" así como formas de tratarla.

Occlusion schools have created a mechanistic construct that seeks to explain, under a reductionist and deterministic model, a craneal-cervical and stomatognathic complex dynamic. These occlusion models dedicate more importance to dental morphology and its interpretative geometries than a stomatognathic morphophysiology. Craneocervical musculoskeletal configuration has the gained power to concomitantly influence the jaw location in the space and implicitly in the interocclusal relations. The current vision of the occlusion is based on empirical observations of almost a century that lack support in the level of evidence framework. In the functional dimension occlusion models maintain the same gaps that existed from its origins since the last century, particularly in its static, uniaxic and anti-dynamic spatial representations that dismiss the individuality of each subject. Each specialty can have as many reasons as different points of view about "malocclusion" as well as techniques to treat it.

Larval development of Brachidontes solisianus (Bivalvia, Mytilidae): with notes on differences between its hinge system and that of the mollusk Perna perna

This work, which is part of a study program on meroplankton larvae, aims to gain more in-depth knowledge about planktonic larvae. This study began with the mollusk Brachidontes solisianus (Bivalvia - Mytilidae), which is abundant on the rocky shores of the Cabo Frio region (state of Rio de Janeiro, Brazil). Brachidontes solisianus larvae were grown under controlled conditions for a period of 26 days and were fed with Isochrysis galbana and Tetraselmis chui. The temperature was kept at 26 °C and the saltiness at 28‰. Images of the larvae were taken daily with a light camera and measured with a micrometric lens until settlement occurred. The average size of the first D-shaped veliger stage was 90 µm in length and 70 µm in height, while the size in the last stage before settlement (pediveliger) was 273 µm in length and 257 µm in height. The comparative study of the hinge system involved the most abundant intertidal species of the study area: Brachidontes solisianus and Perna perna. The B. solisianus species were found to have more visible denticles at the extremities of the provinculum, whereas the denticles of the P. perna species occur along the entire provinculum.

Este trabalho faz parte de um programa de estudo sobre larvas meroplanctônicas que tem como objetivo o reconhecimento mais preciso das larvas no plâncton. Este estudo foi iniciado com a espécie Brachidontes solisianus (Bivalvia - Mytilidae) que é muito abundante nos costões rochosos da região de Cabo Frio. O desenvolvimento larvar foi realizado sob condições controladas durante 26 dias. A alimentação foi feita com Isochrysis galbana e Tetraselmis chui. A temperatura e a salinidade foram mantidas a 26° C e 28 ‰ , respectivamente. Diariamente, as larvas foram desenhadas em câmara clara e medidas com ocular micrométrica até a fixação. A primeira fase de véliger em forma de "D" ou Prodissoconcha I, mediu em média, 90 µm de comprimento por 70 µm de altura e a última, antes da fase de fixação (Pedivéliger), mediu 273 µm de comprimento e 257 µm de altura. No estudo comparativo das charneiras, duas espécies foram consideradas: Brachidontes solisianus e Perna perna. Observou-se que a espécie B. solisianus apresenta dentes mais evidentes nas extremidades do provinculum, enquanto na espécie P. perna aparecem ao longo de todo o provinculum.

Larval development of Brachidontes solisianus (Bivalvia, Mytilidae): with notes on differences between its hinge system and that of the mollusk Perna perna

This work, which is part of a study program on meroplankton larvae, aims to gain more in-depth knowledge about planktonic larvae. This study began with the mollusk Brachidontes solisianus (Bivalvia - Mytilidae), which is abundant on the rocky shores of the Cabo Frio region (state of Rio de Janeiro, Brazil). Brachidontes solisianus larvae were grown under controlled conditions for a period of 26 days and were fed with Isochrysis galbana and Tetraselmis chui. The temperature was kept at 26 °C and the saltiness at 28‰. Images of the larvae were taken daily with a light camera and measured with a micrometric lens until settlement occurred. The average size of the first D-shaped veliger stage was 90 µm in length and 70 µm in height, while the size in the last stage before settlement (pediveliger) was 273 µm in length and 257 µm in height. The comparative study of the hinge system involved the most abundant intertidal species of the study area: Brachidontes solisianus and Perna perna. The B. solisianus species were found to have more visible denticles at the extremities of the provinculum, whereas the denticles of the P. perna species occur along the entire provinculum.

Este trabalho faz parte de um programa de estudo sobre larvas meroplanctônicas que tem como objetivo o reconhecimento mais preciso das larvas no plâncton. Este estudo foi iniciado com a espécie Brachidontes solisianus (Bivalvia - Mytilidae) que é muito abundante nos costões rochosos da região de Cabo Frio. O desenvolvimento larvar foi realizado sob condições controladas durante 26 dias. A alimentação foi feita com Isochrysis galbana e Tetraselmis chui. A temperatura e a salinidade foram mantidas a 26° C e 28 ‰ , respectivamente. Diariamente, as larvas foram desenhadas em câmara clara e medidas com ocular micrométrica até a fixação. A primeira fase de véliger em forma de "D" ou Prodissoconcha I, mediu em média, 90 µm de comprimento por 70 µm de altura e a última, antes da fase de fixação (Pedivéliger), mediu 273 µm de comprimento e 257 µm de altura. No estudo comparativo das charneiras, duas espécies foram consideradas: Brachidontes solisianus e Perna perna. Observou-se que a espécie B. solisianus apresenta dentes mais evidentes nas extremidades do provinculum, enquanto na espécie P. perna aparecem ao longo de todo o provinculum.