In vitro and in vivo studies of ocular topically administered NLC for the treatment of uveal melanoma.

Uveal melanoma is one of the most common and aggressive intraocular malignancies, and, due to its great capability of metastasize, it constitutes the most incident intraocular tumor in adults. However, to date there is no effective treatment since achieving the inner ocular tissues still constitutes one of the greatest challenges in actual medicine, because of the complex structure and barriers. Uncoated and PEGylated nanostructured lipid carriers were developed to achieve physico-chemical properties (mean particle size, homogeneity, zeta potential, pH and osmolality) compatible for the ophthalmic administration of (S)-(-)-MRJF22, a new custom-synthetized prodrug for the potential treatment of uveal melanoma. The colloidal physical stability was investigated at different temperatures by Turbiscan® Ageing Station. Morphology analysis and mucoadhesive studies highlighted the presence of small particles suitable to be topically administered on the ocular surface. In vitro release studies performed using Franz diffusion cells demonstrated that the systems were able to provide a slow and prolonged prodrug release. In vitro cytotoxicity test on Human Corneal Epithelium and Human Uveal Melanoma cell lines and Hen's egg-chorioallantoic membrane test showed a dose-dependent cytotoxic effect of the free prodrug on corneal cells, whose cytocompatibility improved when encapsulated into nanoparticles, as also confirmed by in vivo studies on New Zealand albino rabbits. Antiangiogenic capability and preventive anti-inflammatory properties were also investigated on embryonated eggs and rabbits, respectively. Furthermore, preliminary in vivo biodistribution images of fluorescent nanoparticles after topical instillation in rabbits' eyes, suggested their ability to reach the posterior segment of the eye, as a promising strategy for the treatment of choroidal uveal melanoma.

A transcriptomic based deconvolution framework for assessing differentiation stages and drug responses of AML.

The diagnostic spectrum for AML patients is increasingly based on genetic abnormalities due to their prognostic and predictive value. However, information on the AML blast phenotype regarding their maturational arrest has started to regain importance due to its predictive power for drug responses. Here, we deconvolute 1350 bulk RNA-seq samples from five independent AML cohorts on a single-cell healthy BM reference and demonstrate that the morphological differentiation stages (FAB) could be faithfully reconstituted using estimated cell compositions (ECCs). Moreover, we show that the ECCs reliably predict ex-vivo drug resistances as demonstrated for Venetoclax, a BCL-2 inhibitor, resistance specifically in AML with CD14+ monocyte phenotype. We validate these predictions using LUMC proteomics data by showing that BCL-2 protein abundance is split into two distinct clusters for NPM1-mutated AML at the extremes of CD14+ monocyte percentages, which could be crucial for the Venetoclax dosing patients. Our results suggest that Venetoclax resistance predictions can also be extended to AML without recurrent genetic abnormalities and possibly to MDS-related and secondary AML. Lastly, we show that CD14+ monocytic dominated Ven/Aza treated patients have significantly lower overall survival. Collectively, we propose a framework for allowing a joint mutation and maturation stage modeling that could be used as a blueprint for testing sensitivity for new agents across the various subtypes of AML.

A cell-free nutrient-supplemented perfusate allows four-day ex vivo metabolic preservation of human kidneys.

The growing disparity between the demand for transplants and the available donor supply, coupled with an aging donor population and increasing prevalence of chronic diseases, highlights the urgent need for the development of platforms enabling reconditioning, repair, and regeneration of deceased donor organs. This necessitates the ability to preserve metabolically active kidneys ex vivo for days. However, current kidney normothermic machine perfusion (NMP) approaches allow metabolic preservation only for hours. Here we show that human kidneys discarded for transplantation can be preserved in a metabolically active state up to 4 days when perfused with a cell-free perfusate supplemented with TCA cycle intermediates at subnormothermia (25 °C). Using spatially resolved isotope tracing we demonstrate preserved metabolic fluxes in the kidney microenvironment up to Day 4 of perfusion. Beyond Day 4, significant changes were observed in renal cell populations through spatial lipidomics, and increases in injury markers such as LDH, NGAL and oxidized lipids. Finally, we demonstrate that perfused kidneys maintain functional parameters up to Day 4. Collectively, these findings provide evidence that this approach enables metabolic and functional preservation of human kidneys over multiple days, establishing a solid foundation for future clinical investigations.

Optical Coherence Tomography in Inherited Macular Dystrophies: A Review.

Macular dystrophies (MDs) constitute a collection of hereditary retina disorders leading to notable visual impairment, primarily due to progressive macular atrophy. These conditions are distinguished by bilateral and relatively symmetrical abnormalities in the macula that significantly impair central visual function. Recent strides in fundus imaging, especially optical coherence tomography (OCT), have enhanced our comprehension and diagnostic capabilities for MD. OCT enables the identification of neurosensory retinal disorganization patterns and the extent of damage to retinal pigment epithelium (RPE) and photoreceptor cells in the dystrophies before visible macular pathology appears on fundus examinations. It not only helps us in diagnostic retinal and choroidal pathologies but also guides us in monitoring the progression of, staging of, and response to treatment. In this review, we summarize the key findings on OCT in some of the most common MD.

A novel replication initiation region encoded in a widespread Acinetobacter plasmid lineage carrying a blaNDM-1 gene.

The blaNDM-1 gene and its variants encode metallo-beta-lactamases that confer resistance to almost all beta-lactam antibiotics. Genes encoding blaNDM-1 and its variants can be found in several Acinetobacter species, and they are usually linked to two different plasmid clades. The plasmids in one of these clades contain a gene encoding a Rep protein of the Rep_3 superfamily. The other clade consists of medium-sized plasmids in which the gene (s) involved in plasmid replication initiation (rep)have not yet been identified. In the present study, we identified the minimal replication region of a blaNDM-1-carrying plasmid of Acinetobacter haemolyticus AN54 (pAhaeAN54e), a member of this second clade. This region of 834 paired bases encodes three small peptides, all of which have roles in plasmid maintenance. The plasmids containing this minimal replication region are closely related; almost all contain blaNDM genes, and they are found in multiple Acinetobacter species, including A. baumannii. None of these plasmids contain an annotated Rep gene, suggesting that their replication relies on the minimal replication region that they share with the plasmid pAhaeAN54e. These observations suggest that this plasmid lineage plays a crucial role in the dissemination of the blaNDM-1 gene and its variants.

Acinetobacter junii: an emerging One Health pathogen.

Acinetobacter junii is an opportunistic human and animal pathogen severely understudied. Here, we conducted the largest genomic epidemiological study on this pathogen to date. Our data show that this bacterium has spread globally. Also, we found that some human and non-human isolates are not well differentiated from one another, implying transmission between clinical and non-clinical, non-human settings. Remarkably, human but also some non-human isolates have clinically important antibiotic resistance genes, and some of these genes are located in plasmids. Given these results, we put forward that A. junii should be considered an emerging One Health problem. In this regard, future molecular epidemiological studies about this species will go beyond human isolates and will consider animal-, plant-, and water-associated environments. IMPORTANCE: Acinetobacter baumannii is the most well-known species from the genus Acinetobacter. However, other much less studied Acinetobacter species could be important opportunistic pathogens of animals, plants and humans. Here, we conducted the largest genomic epidemiological study of A. junii, which has been described as a source not only of human but also of animal infections. Our analyses show that this bacterium has spread globally and that, in some instances, human and non-human isolates are not well differentiated. Remarkably, some non-human isolates have important antibiotic resistance genes against important antibiotics used in human medicine. Based on our results, we propose that this pathogen must be considered an issue not only for humans but also for veterinary medicine.

Development of clobetasol-loaded biodegradable nanoparticles as an endodontic intracanal medicament.

AIM: The aim of current study is the development and optimization of biodegradable polymeric nanoparticles (NPs) to be used in the field of Endodontics as intracanal medication in cases of avulsed teeth with extended extra-oral time, utilizing PLGA polymers loaded with the anti-inflammatory drug clobetasol propionate (CP). METHODOLOGY: CP-loaded nanoparticles (CP-NPs) were prepared using the solvent displacement method. CP release profile from CP-NPs was assessed for 48 h against free CP. Using extracted human teeth, the degree of infiltration inside the dentinal tubules was studied for both CP-NPs and CP. The anti-inflammatory capacity of CP-NPs was evaluated in vitro measuring their response and reaction against inflammatory cells, in particular against macrophages. The enzyme-linked immunosorbent assay (ELISA) was used to examine the cytokine release of IL-1ß and TNF-α. RESULTS: Optimized CP-NPs displayed an average size below 200 nm and a monomodal population. Additionally, spherical morphology and non-aggregation of CP-NPs were confirmed by transmission electron microscopy. Interaction studies showed that CP was encapsulated inside the NPs and no covalent bonds were formed. Moreover, CP-NPs exhibited a prolonged and steady release with only 21% of the encapsulated CP released after 48 h. Using confocal laser scanning microscopy, it was observed that CP-NPs were able to display enhanced penetration into the dentinal tubules. Neither the release of TNF-α nor IL-1ß increased in CP-NPs compared to the LPS control, displaying results similar and even less than the TCP after 48 h. Moreover, IL-1ß release in LPS-stimulated cells, decreased when macrophages were treated with CP-NPs. CONCLUSIONS: In the present work, CP-NPs were prepared, optimized and characterized displaying significant increase in the degree of infiltration inside the dentinal tubules against CP and were able to significantly reduce TNF-α release. Therefore, CP-NPs constitute a promising therapy for the treatment of avulsed teeth with extended extra-oral time.

Impact of 1-Year Supplementation with High-Rich Docosahexaenoic Acid (DHA) on Clinical Variables and Inflammatory Biomarkers in Pediatric Cystic Fibrosis: A Randomized Double-Blind Controlled Trial.

A randomized, double-blind, and placebo-controlled study was conducted to assess the effect of dietary supplementation with high-rich docosahexaenoic acid (DHA) (Tridocosahexanoin-AOX® 70%) at 50 mg/kg/day in pediatric patients with cystic fibrosis (CF) as compared with placebo. The duration of supplementation was 12 months. A total of 22 patients were included, with 11 in the DHA group and 11 in the placebo group. The mean age was 11.7 years. The outcome variables were pulmonary function, exacerbations, sputum cellularity, inflammatory biomarkers in sputum and peripheral blood, and anthropometric variables. In the DHA group, there was a significant increase in FVC (p = 0.004) and FVE1 expressed in liters (p = 0.044) as compared with placebo, and a lower median number of exacerbations (1 vs. 2). Differences in sputum cellularity (predominantly neutrophilic), neutrophilic elastase, and sputum and serum concentrations of resolvin D1 (RvD1), interleukin (IL)-8 (IL-8), and tumor necrosis factor alpha (TNF-α) between the study groups were not found. Significant increases in weight and height were also observed among DHA-supplemented patients. The administration of the study product was safe and well tolerated. In summary, the use of a highly concentrated DHA supplement for 1 year as compared with placebo improved pulmonary function and reduced exacerbations in pediatric CF.

Bacteria from the skin of amphibians promote growth of Arabidopsis thaliana and Solanum lycopersicum by modifying hormone-related transcriptome response.

Plants and microorganisms establish beneficial associations that can improve their development and growth. Recently, it has been demonstrated that bacteria isolated from the skin of amphibians can contribute to plant growth and defense. However, the molecular mechanisms involved in the beneficial effect for the host are still unclear. In this work, we explored whether bacteria isolated from three tropical frogs species can contribute to plant growth. After a wide screening, we identified three bacterial strains with high biostimulant potential, capable of modifying the root structure of Arabidopsis thaliana plants. In addition, applying individual bacterial cultures to Solanum lycopersicum plants induced an increase in their growth. To understand the effect that these microorganisms have over the host plant, we analysed the transcriptomic profile of A. thaliana during the interaction with the C32I bacterium, demonstrating that the presence of the bacteria elicits a transcriptional response associated to plant hormone biosynthesis. Our results show that amphibian skin bacteria can function as biostimulants to improve agricultural crops growth and development by modifying the plant transcriptomic responses.

Accuracy of Three-dimensional Scan Technology and Its Possible Function in the Field of Hand Surgery.

Background: Three-dimensional (3D) technology has become a standard manufacturing element in many industries and has gained significant interest in plastic surgery. The 3D scans are widely used for patient communication, virtual surgery planning, and intraoperative tool manufacturing, providing a more comprehensive view of procedures and their outcomes compared with 2D visualization. Methods: We evaluated the performance of six commercially available 3D scanners by acquiring 3D models of a human hand and a 3D-printed replica of a human hand. We performed objective comparisons between the 3D models of the replica using color mapping techniques. Moreover, we compared the results of the human hand 3D scans. Results: We achieved the highest precision with the Artec Space Spider 3D scanner (Artec 3D) when scanning the 3D-printed replica. The SD was ±0.05 mm, and the scan did not have major defects that needed manual correction. On the human hand scan, we achieved the best results using the Artec Eva (Artec 3D), the resulting scan was an accurate digital representation of the scanned human hand. Conclusions: In our study, the Artec Space Spider 3D scanner demonstrated superior precision when scanning a 3D-printed replica, deviating only slightly from the original data, making it an optimal choice for nonmoving objects such as casts or medical instruments. For scanning human hands, the Artec Eva 3D scanner exhibited the highest performance, offering accuracy comparable to the Artec Space Spider, but with the added benefit of being able to scan larger objects.

Implantation of a double allogeneic human engineered tissue graft on damaged heart: insights from the PERISCOPE phase I clinical trial.

BACKGROUND: In preclinical studies, the use of double allogeneic grafts has shown promising results in promoting tissue revascularization, reducing infarct size, preventing adverse remodelling and fibrosis, and ultimately enhancing cardiac function. Building upon these findings, the safety of PeriCord, an engineered tissue graft consisting of a decellularised pericardial matrix and umbilical cord Wharton's jelly mesenchymal stromal cells, was evaluated in the PERISCOPE Phase I clinical trial (NCT03798353), marking its first application in human subjects. METHODS: This was a double-blind, single-centre trial that enrolled patients with non-acute myocardial infarction eligible for surgical revascularization. Seven patients were implanted with PeriCord while five served as controls. FINDINGS: Patients who received PeriCord showed no adverse effects during post-operative phase and one-year follow-up. No significant changes in secondary outcomes, such as quality of life or cardiac function, were found in patients who received PeriCord. However, PeriCord did modulate the kinetics of circulating monocytes involved in post-infarction myocardial repair towards non-classical inflammation-resolving macrophages, as well as levels of monocyte chemoattractants and the prognostic marker Meteorin-like in plasma following treatment. INTERPRETATION: In summary, the PeriCord graft has exhibited a safe profile and notable immunomodulatory properties. Nevertheless, further research is required to fully unlock its potential as a platform for managing inflammatory-related pathologies. FUNDING: This work was supported in part by grants from MICINN (SAF2017-84324-C2-1-R); Instituto de Salud Carlos III (ICI19/00039 and Red RICORS-TERAV RD21/0017/0022, and CIBER Cardiovascular CB16/11/00403) as a part of the Plan Nacional de I + D + I, and co-funded by ISCIII-Subdirección General de Evaluación y el Fondo Europeo de Desarrollo Regional (FEDER) and AGAUR (2021-SGR-01437).

Surgical impact of bilateral transient occlusion of uterine and utero-ovarian arteries during laparoscopic myomectomy.

The objective of this article is to compare the amount of intraoperative blood loss during laparoscopic myomectomy when performing bilateral transient clamping of the uterine and utero-ovarian arteries versus no intervention. It´s a randomized controlled prospective study carried out in the Department of Obstetrics and Gynecology Ramón y Cajal University Hospital and HM Montepríncipe-Sanchinarro University Hospital, Madrid, Spain, in women with fibroid uterus undergoing laparoscopic myomectomy. Eighty women diagnosed with symptomatic fibroid uterus were randomly assigned to undergo laparoscopic myomectomy without additional intervention (Group A) or temporary clamping of bilateral uterine and utero-ovarian arteries prior to laparoscopic myomectomy (Group B). Estimated blood loss, operating time, length of hospital stay, and postoperative hemoglobin values were compared in both groups. The number of fibroids removed was similar in both groups (p = 0.77). Estimated blood loss was lower in the group of patients with prior occlusion of uterine arteries (p = 0.025) without increasing operating time (p = 0.17) nor length of stay (p = 0.17). No patient had either intra or postoperative complications. Only two patients (2.5%) required blood transfusion after surgery. We conclude that temporary clamping of bilateral uterine arteries prior to laparoscopic myomectomy is a safe intervention that reduces blood loss without increasing operative time.

Protocol for stimulating specific rodent limb receptive fields while recording in vivo somatosensory-evoked activity.

Studies on sensory information processing typically focus on whisker-related tactile information, overlooking the question of how sensory inputs from other body areas are processed at cortical levels. Here, we present a protocol for stimulating specific rodent limb receptive fields while recording in vivo somatosensory-evoked activity. We describe steps for localizing cortical-hindlimb coordinates using acute peripheral stimulation, electrode placement, and the application of electrical stimulation. This protocol overcomes the challenge of inducing a reproducible and consistent stimulation of specific limbs. For complete details on the use and execution of this protocol, please refer to Miguel-Quesada et al.1.

Coactivation of the Pelvic Floor and Gluteus Medius Muscles While Walking and Running in Female Runners.

(1) Background: Pelvic-floor-muscle (PFM) activation acts synergistically with multiple muscles while performing functional actions in humans. The purpose of this study was to characterize the activity of the PFMs and gluteus medius (GM) while walking and running in physically active nulliparous females. (2) Methods: The peak and average amplitude of maximal voluntary contractions (MVCs) during 60 s of walking (5 and 7 km/h) and running (9 and 11 km/h) were measured with electromyography of the GM and PFMs in 10 healthy female runners. (3) Results: The activation of both muscles increased (p < 0.001) while walking and running. The MVC of the GM was reached when walking and tripled when running, while the PFMs were activated at half their MVC when running. The global ratio of the GM (75.3%) was predominant over that of the PFMs (24.6%) while static and walking. The ratio reached 9/1 (GM/PFM) while running. (4) Conclusion: The GM and PFMs were active while walking and running. The GM's MVC tripled at high speeds, while the PFMs reached only half of their maximum contraction.

Calcium hydroxide-loaded nanoparticles dispersed in thermosensitive gel as a novel intracanal medicament.

AIM: Design, produce and assess the viability of a novel nanotechnological antibacterial thermo-sensible intracanal medicament This involves encapsulating calcium hydroxide (Ca(OH)2) within polylactic-co-glycolic acid (PLGA) nanoparticles (NPs) and dispersing them in a thermosensitive gel (Ca(OH)2-NPs-gel). In addition, perform in vitro and ex vivo assessments to evaluate tissue irritation and penetration capacity into dentinal tubules in comparison to free Ca(OH)2. METHODOLOGY: Reproducibility of Ca(OH)2-NPs was confirmed by obtaining the average size of the NPs, their polydispersity index, zeta potential and entrapment efficiency. Moreover, rheological studies of Ca(OH)2-NPs-gel were carried out with a rheometer, studying the oscillatory stress sweep, the mean viscosity value, frequency and temperature sweeps. Tolerance was assessed using the membrane of an embryonated chicken egg. In vitro Ca(OH)2 release was studied by direct dialysis in an aqueous media monitoring the amount of Ca(OH)2 released. Six extracted human teeth were used to study the depth of penetration of fluorescently labelled Ca(OH)2-NPs-gel into the dentinal tubules and significant differences against free Ca(OH)2 were calculated using one-way anova. RESULTS: Ca(OH)2-NPs-gel demonstrated to be highly reproducible with an average size below 200 nm, a homogeneous NPs population, negative surface charge and high entrapment efficiency. The analysis of the thermosensitive gel allowed us to determine its rheological characteristics, showing that at 10°C gels owned a fluid-like behaviour meanwhile at 37°C they owned an elastic-like behaviour. Ca(OH)2-NPs-gel showed a prolonged drug release and the depth of penetration inside the dentinal tubules increased in the most apical areas. In addition, it was found that this drug did not produce irritation when applied to tissues such as eggs' chorialantoidonic membrane. CONCLUSION: Calcium hydroxide-loaded PLGA NPs dispersed in a thermosensitive gel may constitute a suitable alternative as an intracanal antibacterial medicament.

Comparison of Mechanical Insufflation-Exsufflation and Hypertonic Saline and Hyaluronic Acid With Conventional Open Catheter Suctioning in Intubated Patients.

BACKGROUND: Open respiratory secretion suctioning with a catheter causes pain and tracheobronchial mucosal injury in intubated patients. The goal of mechanical insufflation-exsufflation (MI-E) is to move secretions proximally and noninvasively by generating a high peak expiratory air flow. Nebulized hypertonic saline with hyaluronic acid (HS-HA) may facilitate suctioning by hydration. We assessed the safety and tolerance of a single session of airway clearance with MI-E and HS-HA in critically ill intubated patients. METHODS: Adults with a cuffed artificial airway were randomized to (1) open suctioning, (2) open suctioning after HS-HA, (3) MI-E, or (4) MI-E with HS-HA. Adverse events, pain and sedation/agitation scores, and respiratory and hemodynamic variables were collected before, during, and 5-min and 60-min post intervention. RESULTS: One-hundred twenty subjects were enrolled and completed the study. Median (interquartile range [IQR]) Acute Physiology and Chronic Health Evaluation II (APACHE II) score was 22 (16-28); median (IQR) age was 69.0 (57.0-75.7) y, and 90 (75%) were male. Baseline respiratory and hemodynamic variables were comparable. Adverse events occurred in 30 subjects (25%), with no between-group differences. Behavioral pain equivalents and Richmond Agitation-Sedation Scale were higher during suctioning in groups 1 (P < .001) and 2 (P < .001). Independent predictive variables for higher pain and agitation/sedation scores were study groups 1 and 2 and simultaneous analgosedation, respectively. Noradrenaline infusion rates were lower at 60 min in groups 2 and 4. PaO2 /FIO2 had decreased at 5 min after open suctioning in group 1 and increased at 60 min in group 3. CONCLUSIONS: We observed no difference in adverse events. MI-E avoids pain and agitation.

Distinct intestinal microbial signatures linked to accelerated systemic and intestinal biological aging.

BACKGROUND: People living with HIV (PLWH), even when viral replication is controlled through antiretroviral therapy (ART), experience persistent inflammation. This inflammation is partly attributed to intestinal microbial dysbiosis and translocation, which may lead to non-AIDS-related aging-associated comorbidities. The extent to which living with HIV - influenced by the infection itself, ART usage, sexual orientation, or other associated factors - affects the biological age of the intestines is unclear. Furthermore, the role of microbial dysbiosis and translocation in the biological aging of PLWH remains to be elucidated. To investigate these uncertainties, we used a systems biology approach, analyzing colon and ileal biopsies, blood samples, and stool specimens from PLWH on ART and people living without HIV (PLWoH) as controls. RESULTS: PLWH exhibit accelerated biological aging in the colon, ileum, and blood, as measured by various epigenetic aging clocks, compared to PLWoH. Investigating the relationship between microbial translocation and biological aging, PLWH had decreased levels of tight junction proteins in the intestines, along with increased microbial translocation. This intestinal permeability correlated with faster biological aging and increased inflammation. When investigating the relationship between microbial dysbiosis and biological aging, the intestines of PLWH had higher abundance of specific pro-inflammatory bacteria, such as Catenibacterium and Prevotella. These bacteria correlated with accelerated biological aging. Conversely, the intestines of PLWH had lower abundance of bacteria known for producing the anti-inflammatory short-chain fatty acids, such as Subdoligranulum and Erysipelotrichaceae, and these bacteria were associated with slower biological aging. Correlation networks revealed significant links between specific microbial genera in the colon and ileum (but not in feces), increased aging, a rise in pro-inflammatory microbe-related metabolites (e.g., those in the tryptophan metabolism pathway), and a decrease in anti-inflammatory metabolites like hippuric acid. CONCLUSIONS: We identified specific microbial compositions and microbiota-related metabolic pathways that are intertwined with intestinal and systemic biological aging. This microbial signature of biological aging is likely reflecting various factors including the HIV infection itself, ART usage, sexual orientation, and other aspects associated with living with HIV. A deeper understanding of the mechanisms underlying these connections could offer potential strategies to mitigate accelerated aging and its associated health complications. Video Abstract.

Mapping AML heterogeneity - multi-cohort transcriptomic analysis identifies novel clusters and divergent ex-vivo drug responses.

Subtyping of acute myeloid leukaemia (AML) is predominantly based on recurrent genetic abnormalities, but recent literature indicates that transcriptomic phenotyping holds immense potential to further refine AML classification. Here we integrated five AML transcriptomic datasets with corresponding genetic information to provide an overview (n = 1224) of the transcriptomic AML landscape. Consensus clustering identified 17 robust patient clusters which improved identification of CEBPA-mutated patients with favourable outcomes, and uncovered transcriptomic subtypes for KMT2A rearrangements (2), NPM1 mutations (5), and AML with myelodysplasia-related changes (AML-MRC) (5). Transcriptomic subtypes of KMT2A, NPM1 and AML-MRC showed distinct mutational profiles, cell type differentiation arrests and immune properties, suggesting differences in underlying disease biology. Moreover, our transcriptomic clusters show differences in ex-vivo drug responses, even when corrected for differentiation arrest and superiorly capture differences in drug response compared to genetic classification. In conclusion, our findings underscore the importance of transcriptomics in AML subtyping and offer a basis for future research and personalised treatment strategies. Our transcriptomic compendium is publicly available and we supply an R package to project clusters to new transcriptomic studies.

Is the Elite Female Athlete's Pelvic Floor Stronger?

Background: Exercise can stress the pelvic floor muscles (PFMs). This study sought to assess the strength of the PFMs according to the level of physical exercise. Methods: An analytical observational study was carried out using digital palpation and dynamometry measurements to assess PF strength. Healthy nulliparous women were stratified according to physical exercise (physically active and sedentary) and level of physical exercise (elite, amateur, and sedentary). Results: Fifty-four women were analyzed, with a mean age of 25.64 (5.33) years and a BMI of 21.41 (2.96) kg/m2. Differences in the passive force and strength were observed between both groups of women (p < 0.05), and the strength was around two times higher in physically active women (p < 0.05). The strength was similar between elite female athletes and sedentary women (p > 0.05), but statistical differences were found with amateurs (p < 0.05). The PFM strength (p = 0.019) of elite female athletes (0.34 N) was almost half that of amateurs (0.63 N) and twice as strong as that of sedentary women (0.20 N). However, these differences were not significant using digital palpation (p = 0.398). Conclusions: Women who exercise generally have greater PFM strength than women who do not exercise. Physical exercise could strengthen the PFM; however, the high intensity demanded by high-level sports does not seem to proportionally increase the strength of the PFMs.