Branching topology of the human embryo transcriptome revealed by Entropy Sort Feature Weighting.

Analysis of single cell transcriptomics (scRNA-seq) data is typically performed after subsetting to highly variable genes (HVGs). Here, we show that Entropy Sorting provides an alternative mathematical framework for feature selection. On synthetic datasets, continuous Entropy Sort Feature Weighting (cESFW) outperforms HVG selection in distinguishing cell-state-specific genes. We apply cESFW to six merged scRNA-seq datasets spanning human early embryo development. Without smoothing or augmenting the raw counts matrices, cESFW generates a high-resolution embedding displaying coherent developmental progression from eight-cell to post-implantation stages and delineating 15 distinct cell states. The embedding highlights sequential lineage decisions during blastocyst development, while unsupervised clustering identifies branch point populations obscured in previous analyses. The first branching region, where morula cells become specified for inner cell mass or trophectoderm, includes cells previously asserted to lack a developmental trajectory. We quantify the relatedness of different pluripotent stem cell cultures to distinct embryo cell types and identify marker genes of naïve and primed pluripotency. Finally, by revealing genes with dynamic lineage-specific expression, we provide markers for staging progression from morula to blastocyst.

ERK signalling eliminates Nanog and maintains Oct4 to drive the formative pluripotency transition.

Naïve epiblast cells in the embryo and pluripotent stem cells in vitro undergo developmental progression to a formative state competent for lineage specification. During this transition, transcription factors and chromatin are rewired to encode new functional features. Here, we examine the role of mitogen-activated protein kinase (ERK1/2) signalling in pluripotent state transition. We show that a primary consequence of ERK activation in mouse embryonic stem cells is elimination of Nanog, which precipitates breakdown of the naïve state gene regulatory network. Variability in pERK dynamics results in heterogeneous loss of Nanog and metachronous state transition. Knockdown of Nanog allows exit without ERK activation. However, transition to formative pluripotency does not proceed and cells collapse to an indeterminate identity. This outcome is due to failure to maintain expression of the central pluripotency factor Oct4. Thus, during formative transition ERK signalling both dismantles the naïve state and preserves pluripotency. These results illustrate how a single signalling pathway can both initiate and secure transition between cell states.

Alpha-Gal Syndrome and Cardiac Surgery.

Galactose-alpha-1,3-galactose (alpha-gal) is a carbohydrate expressed by all mammals except for humans and certain old-world primates. It can be found in a plethora of products derived from mammals, including milk, organs, skeletal muscle and gelatin, in addition to products prepared with mammalian cells or constituents. In the late 2000s, an association between tick bites and the development of immunoglobulin E antibodies to the alpha-gal carbohydrate was discovered. The term "alpha-gal syndrome" (AGS) was then coined to describe allergic reactions to mammalian meat or other alpha-gal-containing products derived from mammals. Symptoms are often delayed several hours from consumption and can be urticarial and/or gastrointestinal. Medications and bioprosthetic inserts derived from mammals were also noted to cause allergic reactions in affected patients. Cardiac surgery, in particular, is considered high risk, given that unfractionated heparin has a bovine or porcine origin and is administered in large doses for cardiopulmonary bypass. Bioprosthetic valves have similar origins and risks. Awareness of AGS in cardiac surgery patients can lead to decreased risk preoperatively and inform management perioperatively and postoperatively. In this narrative review, we have reviewed the published literature relevant to AGS in patients undergoing cardiac surgery and shared our treatment approach.

Latarjet procedure restores range of motion at six months postoperatively: a prospective cohort study utilizing motion capture analysis.

BACKGROUND: There is a common concern that range of motion (ROM) is negatively affected by the Latarjet procedure. We hypothesize that the Latarjet procedure results in full recuperation of ROM postoperatively and significantly improved patient reported outcome measures. METHODS: Patient data were prospectively collected from a randomized controlled trial to analyze outcomes after open Latarjet procedure. Inclusion criteria involved a minimum follow-up of six months and unilateral shoulder instability. Study outcome was assessed by postoperative ROM at six months postoperatively and compared to the preoperative ROM of the ipsilateral shoulder as well as the ROM of the unaffected contralateral shoulder. All ROM measurements were performed utilizing a motion capture system to ensure consistent and reliable measurements. RESULTS: The study included a total of 84 patients. ROM was measured in external rotation with the shoulder adducted (ER1), external rotation with the shoulder abducted 90 degrees (ER2), internal rotation with the arm abducted 90 degrees (IR2), and active forward elevation (AE). The average difference in ROM between the operated arm vs. the contralateral healthy arm at six months postoperatively was 3.4 degrees in ER1 (p=0.19), 4.2 degrees in ER2 (p=0.086), 2.2 degrees in IR2 (p=0.36), and 2.4 degrees in AE (p=0.045). Sub-analysis of patients with and without sling use revealed no significant difference in ROM between the operated shoulder and contralateral shoulder at six months in either group, with the exception of ER2 in the sling group. In this latter group, ROM was 71 degrees in the operated arm and 79 degrees in the contralateral arm (p=0.0094). Average preoperative pain score was 25.7 (21.4-30.1, 95%CI) vs. 13.0 postoperatively at six months (9.50-16.5, 95%CI) (p <0.00001). Average preoperative SANE instability was 42.9 (38.4-47.3, 95%CI) vs. 86.2 postoperatively at six months (83.6-88.7, 95%CI) (p <0.00001). Average preoperative Rowe score was 38.5 (34.3-42.7, 95%CI) vs. 84.3 at six postoperative months (81.1-87.4, 95%CI) (p<0.00001). CONCLUSIONS: Latarjet procedure performed for anterior instability utilizing a capsular repair result in complete ROM recovery in ER1, ER2, and IR2 at six months postoperatively, with only a slight discrepancy in active elevation. Sling use after the Latarjet procedure results in no benefit over postoperative recovery without the use of a sling. Sling use negatively affects the ROM in ER2, taking as reference the contralateral arm of the same patient, when compared to patients that did not use a sling postoperatively.

A feasibility cadaver study for placing screws in various pelvic osseous fracture pathways using a robotic arm.

INTRODUCTION: The use of a robotic system for the placement of pedicle screws in spine surgeries is well documented in the literature. However, there is only a single report in the United States describing the use of a robotic system to place two screws in osseous fixation pathways (OFPs) commonly used in the treatment of pelvic and acetabular fractures in a simulated bone model. The purpose of this study was to demonstrate the use of a robotic system to place screws in multiple, clinically relevant OFPs in a cadaveric model and to quantitatively measure accuracy of screw placement relative to the preoperative plan. METHODS: A single cadaveric specimen was obtained for the purpose of this study. All surrounding soft tissues were left intact. Screws were placed in OFPs, namely iliosacral (IS), trans-sacral (TS), Lateral Compression-II (LC-II), antegrade anterior column (AC) and antegrade posterior column (PC) of the right hemipelvis using standard, fluoroscopically assisted percutaneous or mini-open technique. Following the placement of screws into the right hemipelvis using standard techniques, screws were planned and placed in the same OFPs of the contralateral hemipelvis using the commercially available ExcelsiusGPS® robotic system (Globus Medical Inc., Audubon, PA). After robotic-assisted screw placement, a post-procedure CT scan was obtained to evaluate actual screw placement against the pre-procedure plan. A custom-made image analysis program was devised to measure screw tip/tail offset and angular offset on axial and sagittal planes. RESULTS: For different OFPs, the mean tip offset, tail offset and angular offsets were 1.6 ± 0.9 mm (Range 0.0-3.6 mm), 1.4 ± 0.4 mm (Range 0.3-2.5 mm) and 1.1 ± 0.4° (Range 0.5-2.1), respectively. CONCLUSION: In this feasibility study, surgeons were able to place screws into the clinically relevant fracture pathways of the pelvis using ExcelsiusGPS® for robotic-assisted surgery. The measured accuracy was encouraging; however, further investigation is needed to demonstrate that robotic-assisted surgery can be used to successfully place the screws in the bony corridors of the pelvis to treat traumatic pelvic injuries.

"Shoe Shop" Lacing Technique: A New Biceps-Augmented Knotless Suture for Arthroscopic Rotator Cuff Repair.

Advancements in rotator cuff tear repair have led to innovative techniques for complex cases. In this article, we introduce the "shoe shop" lacing technique, a knotless, side-to-side, and tendon-to-bone suture method augmented with the long head of the biceps tendon (LHBT) for anterior margin-deficient massive rotator cuff tears. This approach offers simplicity, durability, and potential advantages in biomechanics. The LHBT integration and knotless sutures make it a promising solution for challenging tear patterns. This technique provides an attractive option for arthroscopic repair, improving outcomes in cases where anterior cable reinforcement is essential.

Downregulation of Fidgetin-Like 2 Increases Microglial Function: The Relationship Between Microtubules, Morphology, and Activity.

The microtubule cytoskeleton regulates microglial morphology, motility, and effector functions. The microtubule-severing enzyme, fidgetin-like 2 (FL2), negatively regulates cell motility and nerve regeneration, making it a promising therapeutic target for central nervous system injury. Microglia perform important functions in response to inflammation and injury, but how FL2 affects microglia is unclear. In this study, we investigated the role of FL2 in microglial morphology and injury responses in vitro. We first determined that the pro-inflammatory stimulus, lipopolysaccharide (LPS), induced a dose- and time-dependent reduction in FL2 expression associated with reduced microglial ramification. We then administered nanoparticle-encapuslated FL2 siRNA to knockdown FL2 and assess microglial functions compared to negative control siRNA and vehicle controls. Time-lapse live-cell microscopy showed that FL2 knockdown increased the velocity of microglial motility. After incubation with fluorescently labeled IgG-opsonized beads, FL2 knockdown increased phagocytosis. Microglia were exposed to low-dose LPS after nanoparticle treatment to model injury-induced cytokine secretion. FL2 knockdown enhanced LPS-induced cytokine secretion of IL-1α, IL-1ß, and TNFα. These results identify FL2 as a regulator of microglial morphology and suggest that FL2 can be targeted to increase or accelerate microglial injury responses.

Structural Elucidation and Absolute Stereochemistry for Pharma Compounds Using MicroED.

Microcrystal electron diffraction (microED) is an emerging technique for rapid crystallographic analysis of small molecule micro- and nanocrystals. In this report, we evaluate the applicability of microED to pharmaceutical compounds through the analysis of 30 samples obtained from the process and medicinal chemistry groups at Amgen Inc. Using only 40 h of microscope time, 15 of 30 crystal structures were elucidated. From these crystal structures, all chiral compounds had the correct absolute stereochemistry assigned by dynamical refinement of continuous rotation electron diffraction data, confirming dynamical refinement as a promising tool for the absolute stereochemistry determination of pharmaceutically relevant compounds.

Multi-scale signaling and tumor evolution in high-grade gliomas.

Although genomic anomalies in glioblastoma (GBM) have been well studied for over a decade, its 5-year survival rate remains lower than 5%. We seek to expand the molecular landscape of high-grade glioma, composed of IDH-wildtype GBM and IDH-mutant grade 4 astrocytoma, by integrating proteomic, metabolomic, lipidomic, and post-translational modifications (PTMs) with genomic and transcriptomic measurements to uncover multi-scale regulatory interactions governing tumor development and evolution. Applying 14 proteogenomic and metabolomic platforms to 228 tumors (212 GBM and 16 grade 4 IDH-mutant astrocytoma), including 28 at recurrence, plus 18 normal brain samples and 14 brain metastases as comparators, reveals heterogeneous upstream alterations converging on common downstream events at the proteomic and metabolomic levels and changes in protein-protein interactions and glycosylation site occupancy at recurrence. Recurrent genetic alterations and phosphorylation events on PTPN11 map to important regulatory domains in three dimensions, suggesting a central role for PTPN11 signaling across high-grade gliomas.

Insuficiente aplicación de Medicina Natural y Tradicional en afecciones relacionadas con la ortopedia y la traumatología

La Medicina Natural y Tradicional aplica sus diferentes modalidades en la práctica médica moderna, segura, económica, inocua y simple; y con pocos efectos colaterales resuelve grandes problemas de salud en situaciones especiales o de desastres con recursos limitados. De ahí que el egresado de programas de especialización de las ciencias médicas cuenta con sólidos conocimientos para su aplicación, especialmente en las afecciones osteomioarticulares, donde la especialidad de ortopedia y traumatología tiene un papel primordial para identificar las causas y consecuencias de la insuficiencia de su aplicación en pacientes portadores de afecciones relacionadas con esta especialidad. A través de un estudio crítico reflexivo basado en el análisis y la síntesis, así como de la constatación de la validez de los puntos de vista asumidos como referentes en el proceso de superación del especialista de ortopedia y traumatología, se pudo mostrar cómo se ha concebido la superación profesional en el Hospital General Dr. Juan Bruno Zayas Alfonso, al integrar adecuadamente los conocimientos y las competencias. Esto se expresó en la elaboración e implementación de una estrategia de superación profesional, que permitió la actualización de relevantes conocimientos necesarios en el campo de la MNT para el desempeño de este profesional. Se concluyó que era insuficiente el nivel de conocimiento de los contenidos, como también los cursos ofertados para su desarrollo, lo que trajo como consecuencia una atención médica sin calidad.

Natural and traditional medicine applies its different modalities in modern, safe, economical, innocuous and simple medical practice; with few collateral effects, it solves major health problems in special or disaster situations with limited resources. Hence, the graduate of specialization programs in medical sciences possesses solid knowledge for its application, especially in osteomyoarticular conditions, in which the specialty of orthopedics and traumatology has a key role in identifying the causes and consequences of its unsatisfactory application in patients with conditions related to this specialty. Through a reflexive and critical study based on analysis and synthesis, as well as the verification of the validity of the viewpoints assumed as referents in the process of improvement of the orthopedics and traumatology specialist, it was possible to show how professional improvement has been conceived at Hospital General Dr. Juan Bruno Zayas Alfonso, by adequately integrating knowledge and competences. This was expressed through the elaboration and implementation of a professional improvement strategy, which allowed updating relevant knowledge necessary in the field of natural and traditional medicine for the performance of this professional. The level of knowledge about the contents was concluded to be insufficient, while the courses offered for its development were so, which resulted in a medical care without quality.

Estrategia de superación profesional para especialistas de Ortopedia y Traumatología en Medicina Natural y Tradicional

Introducción: La Medicina Natural y Tradicional (MNT) tiene como objetivo integrar conocimientos de sus modalidades a la práctica médica, a partir de una adecuada selección y fundamentación científica. Desde su desarrollo en el proceso de superación profesional en especialidades como la Ortopedia y Traumatología logra atención médica de calidad, se ajusta a las condiciones sociohistóricas actuales y al desarrollo de nuevos estilos de actuación, mejora las relaciones interpersonales y fomenta los valores ético-morales en íntima interrelación con la comunidad. Objetivo: Exponer fundamentos que sustentan el diseño y la aplicación de una estrategia de superación profesional en especialistas de Ortopedia y Traumatología para la aplicación de la Medicina Natural y Tradicional. Métodos: Se realizó un estudio pedagógico, prospectivo, que utilizó métodos teóricos y empíricos. Para la elaboración de la Estrategia de Superación Profesional se utilizó la modelación, que posibilitó el proceso de concreción-abstracción con sus interrelaciones y vínculos con la aplicación de la Medicina Natural y Tradicional. Se asumieron los criterios utilizados por la Dra. C. Yerina Figueredo. La población fue de 43 especialistas de Ortopedia y Traumatología del Hospital "Juan Bruno Zayas Alfonso", de Santiago de Cuba, entre julio y diciembre de 2021. Resultados: Se demostró alto nivel de satisfacción con la aplicación de la estrategia y la consulta de expertos evidenció mejora en el desempeño de estos profesionales. Conclusiones: La actualización en las modalidades de la Medicina Natural y Tradicional en la superación de los Especialistas de Ortopedia y Traumatología aportó un grupo de regularidades a la formación permanente y continuada, que enriquecen las ciencias de la educación médica.

Introduction: Natural and traditional medicine aims at integrating knowledge within its modalities to medical practice, based on an adequate selection and scientific foundation. Since its development as part of the professional improvement process in specialties such as Orthopedics and Traumatology, it achieves quality medical care, adjusts itself to the current sociohistorical conditions and the development of new action styles, improves interpersonal relationships, as well as promotes ethical and moral values in close relationship with the community. Objective: To present the foundations that support the design and application of a professional improvement strategy with Orthopedics and Traumatology specialists for the application of natural and traditional medicine. Methods: A pedagogical and prospective study was carried out, using theoretical and empirical methods. Modeling was used for the elaboration of the professional improvement strategy, which made possible the concretion-abstraction process with its interrelations and links in view of the application of natural and traditional medicine. The criteria used by Yerina Figueredo, Ph.D., were assumed. The population was 43 Orthopedics and Traumatology specialists from Hospital Juan Bruno Zayas Alfonso, of Santiago de Cuba, between July and December 2021. Results: A high level of satisfaction with the application of the strategy was demonstrated and the consultation with experts evidenced an improvement in the performance of these professionals. Conclusions: The updating in the modalities of natural and traditional medicine for the training of Orthopedics and Traumatology specialists contributed a group of regularities to permanent and continuous training, which enriches the sciences of medical education.

Eficacia del tratamiento acupuntural en pacientes con sacrolumbalgia de causa no neurológica / Effectiveness of the acupuncture treatment in patients with non neurological low back pain

Se realizó un ensayo clinicoterapéutico de fase II de 120 pacientes con sacrolumbalgia no neurológica, atendidos en el cuerpo de guardia y en la consulta ambulatoria del Instituto Superior de Medicina Militar "Dr. Luis Díaz Soto" y del Hospital Militar Central "Dr. Carlos J. Finlay", desde enero de 2009 hasta junio de 2010, con vistas a evaluar la eficacia del tratamiento acupuntural. Se conformaron 2 grupos de 60 integrantes cada uno, los cuales fueron comparados con un grupo control con la misma cantidad de pacientes, pero con tratamiento farmacológico. Se obtuvo que los tratados con acupuntura mejoraron en menor tiempo, en particular los del grupo 2, de donde se infiere que esta técnica resultó eficaz para aliviar el dolor lumbar en quienes se aplicó, a la vez que permitió a los enfermos reducir el período de tratamiento, ahorrar medicamentos y lograr una rápida reincorporación a la vida laboral y social.

A phase II clinical and therapeutical trial was conducted in 120 patients with non neurological low back pain, attended at the emergency ward and the outpatient department of "Dr. Luis Díaz Soto" Higher Institute of Military Medicine and "Dr. Carlos J Finlay" Central Military Hospital, from January 2009 to June 2010, with the purpose of evaluating the effectiveness of acupuncture treatment. Two groups of 60 patients each were divided, which were compared with a control group with the same number of patients, but with drug treatment. It was found that patients treated with acupuncture improved in less time, particularly those in group 2, so that this technique was effective in relieving back pain in those patients it was applied, while allowing to reduce the time of treatment, save medications and achieve rapid return to work and social life.

El Consejo de Farmacia y Química de la Asociación Médica Americana

Traducido por la OPS, del Jour. Am. Med. Assn., pp. 433-439, feb. 12, 1944