GAP43 located on corticostriatal terminals restrains novelty-induced hyperactivity in mice.

Growth-associated protein of 43 kDa (GAP43) is a key cytoskeleton-associated component of the presynaptic terminal that facilitates neuroplasticity. Downregulation of GAP43 expression has been associated to various psychiatric conditions in humans and evokes hippocampus-dependent memory impairments in mice. Despite the extensive studies conducted on hippocampal GAP43 in past decades, however, very little is known about its roles in modulating the excitatory vs. inhibitory balance in other brain regions. We recently generated conditional knockout mice in which the Gap43 gene was selectively inactivated in either telencephalic glutamatergic neurons (Gap43fl/fl ;Nex1Cre mice, hereafter Glu-GAP43-/- mice) or forebrain GABAergic neurons (Gap43fl/fl ;Dlx5/6Cre mice, hereafter GABA-GAP43-/- mice). Here, we show that Glu-GAP43-/- but not GABA-GAP43-/- mice of either sex show a striking hyperactive phenotype when exposed to a novel environment. This behavioral alteration of Glu-GAP43-/- mice was linked to a selective activation of dorsal-striatum neurons, as well as to an enhanced corticostriatal glutamatergic transmission and an abrogation of corticostriatal endocannabinoid-mediated long-term depression. In line with these observations, GAP43 was abundantly expressed in corticostriatal glutamatergic terminals of wild-type mice. The novelty-induced hyperactive phenotype of Glu-GAP43-/- mice was abrogated by chemogenetically inhibiting corticostriatal afferences with a Gi-coupled "designer receptor exclusively activated by designer drugs" (DREADD), thus further supporting that novelty-induced activity is controlled by GAP43 at corticostriatal excitatory projections. Taken together, these findings show an unprecedented regulatory role of GAP43 in the corticostriatal circuitry and provide a new mouse model with a delimited neuronal-circuit alteration for studying novelty-induced hyperactivity, a phenotypic shortfall that occurs in diverse psychiatric diseases.Significance statement Psychiatric alterations such as attention deficit/hyperactivity disorder, schizophrenia and bipolar disorder pose a significant health and socioeconomic burden to our society. Animal models that recapitulate precise phenotypical traits of those diseases are therefore warranted for developing new therapeutic interventions. Here, we found that mice lacking the protein GAP43 selectively in telencephalic glutamatergic neurons show a robust novelty-induced hyperactive phenotype, a behavioral deficit often associated to psychiatric diseases. These mice exhibit profound alterations in corticostriatal excitatory plasticity and a selective overactivation of dorsal-striatum neurons in response to a novel environment. Our findings thus unveil an important role of GAP43 in corticostriatal function and provide a new animal model with a delimited neuronal-circuit alteration for studying novelty-induced hyperactivity in psychiatric disorders.

Upper-Body Muscular Endurance and Its Association with Aerobic Capacity in University Students of Physical Culture, Sport, and Recreation / Fuerza resistencia de miembros superiores y su asociación con la capacidad aeróbica en universitarios de cultura física, deporte y recreación / Resistência Muscular do Corpo Superior e sua Associação com Capacidade Aeróbica em Estudantes Universitários de Cultura Física, Esporte e Recreação

Abstract Introduction: Upper-body muscular endurance (UBME) and aerobic capacity (AC) are essential components of physical fitness. Low levels of these components are related to cardiovascular disease. Purpose: To assess the association between UBME and AC levels in college students of physical culture. Methodology: Analytical cross-sectional study carried out in 192 students (169 men, 23 women; median age 20 years). Every participant of the study signed written consent. UMBE was the dependent variable assessed by the push-up test, and AC was the main independent variable assessed using the 20 m shuttle run test. To analyze differences by sex, and academic semester, Fischer exact, Student's T, and U Mann-Whitney tests were applied. Descriptive, as well as bivariate and multivariate analysis, were realized using logistic regression models. Results: 82.29 % of participants had healthy levels of UBME. Respecting the academic semester, students had a higher probability of having healthy levels of UBME as semesters increased (OR: 1.23, 95 % CI: 1.06 to 1.44, p = 0.007). Concerning AC, 58.33 % of participants registered healthy levels. After adjusting by sex, age, socioeconomic level, and academic semester, maximum oxygen consumption (VO2max), was associated with healthy levels of UBME (OR: 1.157, CI 95 %: 1.O71 - 1.249, p=<0.001). Conclusions: Students had a higher probability of presenting healthy levels of UBME as semesters of study increased, and those with a higheVO2max were more likely to have healthy levels of UBME.

Resumen Introducción: La fuerza resistencia de miembros superiores (FRMS) y la capacidad aeróbica (CA) son componentes esenciales de la condición física. Bajos niveles de estos componentes están relacionados con la enfermedad cardiovascular. Propósito: El objetivo de este estudio fue evaluar la asociación entre los niveles de FRMS y la CA en estudiantes universitarios de cultura física. Metodología: Estudio transversal analítico realizado en 192 estudiantes (169 hombres, 23 mujeres; mediana de edad, 20 años). Cada participante firmó el consentimiento informado. FRMS fue la variable dependiente y se valoró con la prueba de flexiones de brazo, y la CA fue la variable independiente y se evaluó usando la prueba de ida y vuelta de 20 m. Para analizar las diferencias por sexo y semestre académico, fueron utilizadas las pruebas exacta de Fischer, T de Student y U de Mann-Whitney. Se realizaron análisis descriptivos, bivariados y múltiples, usando modelos de regresión logística. Resultados: El 82.29 % de los participantes registraron niveles saludables de FRMS. Respecto al semestre académico, se evidenció una probabilidad más alta de tener niveles saludables de FRMS al incrementarse los semestres de estudio (OR: 1.23, 95 % CI: 1.06 to 1.44, p = 0.007). En lo concerniente a la CA, el 58.33 % de los participantes registro niveles saludables. Después de realizar ajustes por sexo, edad, nivel socioeconómico y semestre académico, el consumo máximo de oxígeno (VO2máx), estuvo asociado con niveles saludables de FRMS (OR: 1.157, CI 95 % 1.O71 - 1.249, p=<0.001). Conclusiones: Los participantes presentaron una mayor probabilidad de tener niveles saludables de FRMS, a medida que incrementaron los semestres de estudio, y aquellos con niveles de VO2máx más alto, fueron más proclives a tener niveles saludables de FRMS.

Resumo Introdução: A resistência muscular do corpo superior (UBME) e a capacidade aeróbica (AC) são componentes essenciais da aptidão física. Baixos níveis desses componentes estão relacionados a doenças cardiovasculares. Propósito: Avaliar a associação entre os níveis de UBME e AC em estudantes universitários de cultura física. Metodologia: Estudo transversal analítico realizado com 192 estudantes (169 homens, 23 mulheres; idade média 20 anos). Todos os participantes do estudo assinaram consentimento por escrito. UBME foi a variável dependente avaliada pelo teste de flexão de braço, e AC foi a principal variável independente avaliada pelo teste de corrida de vaivém de 20 m. Para analisar diferenças por sexo e semestre acadêmico, foram aplicados testes exatos de Fischer, t de Student e U de MannWhitney. Análises descritivas, bivariadas e multivariadas foram realizadas usando modelos de regressão logística. Resultados: 82,29 % dos participantes apresentaram níveis saudáveis de UBME. Respeitando o semestre acadêmico, os estudantes tiveram uma probabilidade maior de ter níveis saudáveis de UBME conforme os semestres aumentavam (OR: 1,23, IC 95 %: 1,06 a 1,44, p = 0,007). Em relação à AC, 58,33 % dos participantes registraram níveis saudáveis. Após ajuste por sexo, idade, nível socioeconômico e semestre acadêmico, o consumo máximo de oxigênio (VO2max) foi associado a níveis saudáveis de UBME (OR: 1,157, IC 95 %: 1,071 - 1,249, p <0,001). Conclusões: Os estudantes tiveram uma probabilidade maior de apresentar níveis saudáveis de UBME conforme os semestres de estudo aumentaram, e aqueles com um VO2max mais alto tiveram maior probabilidade de ter níveis saudáveis de UBME.

Impact on mental health and well-being of the dialogic literary gathering among women in a primary healthcare centre.

There is strong scientific evidence on the academic, cognitive, social, and emotional benefits of Dialogic Literary Gatherings (DLG) for diverse people in a wide range of settings. However, the transference of DLG to a primary healthcare centre has not yet been studied. To address this gap a case study was conducted on the impact of a DLG in a primary healthcare centre on participants' mental health and wellbeing from the perception of participants and professionals involved in it. To that end, four daily life stories and a focus group with women participating in the DLG, most of them over 75 years old with no higher education, were conducted, as well as two in-depth interviews, one with the DLG facilitator and one with the director of the health centre. Results show that participants perceived their mental health and wellbeing improved thanks to the functioning and type of dialogue in the DLG, promoting friendships, support and solidarity. Participants also reported that, by being aware of their capabilities in the DLG, they became agents of transformation within their families and environments, turning relationships between healthcare professionals and patients more egalitarian. These findings hold implications for public health and healthcare centres.

Childhood-Onset Non-Infectious Uveitis in the "Biologic Era". Results From Spanish Multicenter Multidisciplinary Real-World Clinical Settings.

OBJECTIVE: To characterize and describe clinical experience with childhood-onset non-infectious uveitis. STUDY DESIGN: A multicenter retrospective multidisciplinary national web-based registry of 507 patients from 21 hospitals was analyzed. Cases were grouped as immune disease-associated (IMDu), idiopathic (IDIu) or ophthalmologically distinct. Characteristics of juvenile idiopathic arthritis-associated (non-HLA-B27-related) uveitis (JIAu), IDIu, and pars planitis (PP) were compared. RESULTS: IMDu (62.3%) and JIAu (51.9%) predominated in young females; and IDIu (22.7%) and PP (13.6%) in older children, without sex imbalance. Ocular complications occurred in 45.3% of cases (posterior synechiae [28%], cataracts [16%], band keratopathy [14%], ocular hypertension [11%] and cystoid macular edema [10%]) and were associated with synthetic (86%) and biologic (65%) disease-modifying antirheumatic drug (DMARD) use. Subgroups were significantly associated (p < 0.05) with different characteristics. JIAu was typically anterior (98%), insidious (75%), in ANA-positive (69%), young females (82%) with fewer complications (31%), better visual outcomes, and later use of uveitis-effective biologics. In contrast, IDIu was characteristically anterior (87%) or panuveitic (12.1%), with acute onset (60%) and more complications at onset (59%: synechiae [31%] and cataracts [9.6%]) and less DMARD use, while PP is intermediate, and was mostly bilateral (72.5%), persistent (86.5%) and chronic (86.8%), with more complications (70%; mainly posterior segment and cataracts at last visit), impaired visual acuity at onset, and greater systemic (81.2%), subtenon (29.1%) and intravitreal (10.1%) steroid use. CONCLUSION: Prognosis of childhood uveitis has improved in the "biologic era," particularly in JIAu. Early referral and DMARD therapy may reduce steroid use and improve outcomes, especially in PP and IDIu.

Asociación entre obesidad abdominal, consumo de alcohol y actividad física en universitarios panameños / Association between abdominal obesity, alcohol consumption and physical activity in Panamanian college students

Introducción. La obesidad abdominal es considerada un factor de riesgo de enfermedad cardiovascular y diabetes. El consumo excesivo episódico de alcohol y la inactividad física también son factores de riesgo comportamentales asociados a enfermedades no transmisibles. Objetivo: Analizar la asociación entre la obesidad abdominal, el consumo de alcohol y la inactividad física en universitarios panameños. Materiales y métodos: Estudio transversal analítico realizado en 374 estudiantes universitarios panameños en el periodo abril ­ diciembre de 2021. Se implementó el cuestionario para la vigilancia de factores de riesgo de enfermedades no transmisibles de la Organización Mundial de la Salud y se evaluó la circunferencia de cintura. La obesidad abdominal se estableció con una circunferencia de cintura ≥80 cm en mujeres y ≥90 cm en hombres. Se realizaron análisis descriptivos, bivariados y múltiples usando modelos de regresión logística para determinar la asociación entre las variables del estudio. Las pruebas U Mann-Whitney y Chi cuadrado fueron utilizadas para analizar diferencias por sexo. Resultados: Una tercera parte de los universitarios participantes presentaron obesidad abdominal. Las mujeres reportaron mayores niveles de inactividad física (<0,0001) y conducta sedentaria (p=0,0010) que los hombres. Después de ajustar por sexo, edad y nivel socioeconómico, la obesidad abdominal estuvo asociada con la inactividad física (OR: 1,762, IC 95%: 1,040 ­ 2,985, p=0,035) y el consumo excesivo episódico de alcohol (OR 1,114, IC: 1,015 ­ 1,223, p=0,023). Conclusiones: Los universitarios panameños que reportaron bajos niveles de actividad física y consumo excesivo episódico de alcohol tuvieron una mayor probabilidad de registrar obesidad abdominal(AU)

Introduction. Abdominal obesity is considered a risk factor for cardiovascular disease and diabetes. Episodic excessive consumption of alcohol and physical inactivity are behavioral risk factors associated with non-communicable diseases. Objective: To analyze the association between abdominal obesity, alcohol consumption and physical inactivity in Panamanian university students. Materials and methods: Analytical cross-sectional study conducted on 374 Panamanian university students in the period April ­ December 2021. The questionnaire for the surveillance of risk factors for non-communicable diseases of the World Health Organization was implemented and waist circumference was evaluated. Abdominal obesity was established with a waist circumference ≥80 cm in women and ≥90 cm in men. Descriptive, bivariate, and multiple analyzes were performed using logistic regression models to determine the association between the study variables. The Mann-Whitney U and Chi square tests were used to analyze differences by sex. Results: A third of the participating university students had abdominal obesity. Women reported higher levels of physical inactivity (<0,0001) and sedentary behavior (p=0,0010) than men. After adjusting for sex, age and socioeconomic status, abdominal obesity was associated with physical inactivity (OR: 1,762, 95% CI: 1,040 ­ 2,985, p=0,035) and episodic heavy alcohol consumption (OR 1,114, CI: 1,015 ­ 1,223, p=0,023). Conclusions: Students who reported low levels of physical inactivity and binge drinking were more likely to have abdominal obesity(AU)

The CB1 receptor interacts with cereblon and drives cereblon deficiency-associated memory shortfalls.

Cereblon/CRBN is a substrate-recognition component of the Cullin4A-DDB1-Roc1 E3 ubiquitin ligase complex. Destabilizing mutations in the human CRBN gene cause a form of autosomal recessive non-syndromic intellectual disability (ARNSID) that is modelled by knocking-out the mouse Crbn gene. A reduction in excitatory neurotransmission has been proposed as an underlying mechanism of the disease. However, the precise factors eliciting this impairment remain mostly unknown. Here we report that CRBN molecules selectively located on glutamatergic neurons are necessary for proper memory function. Combining various in vivo approaches, we show that the cannabinoid CB1 receptor (CB1R), a key suppressor of synaptic transmission, is overactivated in CRBN deficiency-linked ARNSID mouse models, and that the memory deficits observed in these animals can be rescued by acute CB1R-selective pharmacological antagonism. Molecular studies demonstrated that CRBN interacts physically with CB1R and impairs the CB1R-Gi/o-cAMP-PKA pathway in a ubiquitin ligase-independent manner. Taken together, these findings unveil that CB1R overactivation is a driving mechanism of CRBN deficiency-linked ARNSID and anticipate that the antagonism of CB1R could constitute a new therapy for this orphan disease.

Microevolution, reinfection and highly complex genomic diversity in patients with sequential isolates of Mycobacterium abscessus.

Mycobacterium abscessus is an opportunistic, extensively drug-resistant non-tuberculous mycobacterium. Few genomic studies consider its diversity in persistent infections. Our aim was to characterize microevolution/reinfection events in persistent infections. Fifty-three sequential isolates from 14 patients were sequenced to determine SNV-based distances, assign resistance mutations and characterize plasmids. Genomic analysis revealed 12 persistent cases (0-13 differential SNVs), one reinfection (15,956 SNVs) and one very complex case (23 sequential isolates over 192 months), in which a first period of persistence (58 months) involving the same genotype 1 was followed by identification of a genotype 2 (76 SNVs) in 6 additional alternating isolates; additionally, ten transient genotypes (88-243 SNVs) were found. A macrolide resistance mutation was identified from the second isolate. Despite high diversity, the genotypes shared a common phylogenetic ancestor and some coexisted in the same specimens. Genomic analysis is required to access the true intra-patient complexity behind persistent infections involving M. abscessus.

Predicting progression of cognitive decline to dementia using dyadic patterns of subjective reporting: evidence from the CompAS longitudinal study.

Objective: To analyze the validity of self and informant reports, depressive symptomatology, and some sociodemographic variables to predict the risk of cognitive decline at different follow-up times. Methods: A total of 337 participants over 50 years of age included in the CompAS and classified as Cognitively Unimpaired (CU), Subjective Cognitive Decline (SCD) and Mild Cognitive Impairment (MCI) groups were assessed at baseline and three follow-ups. A short version of the QAM was administered to assess the severity of subjective cognitive complaints (SCCs), and the GDS-15 was used to evaluate the depressive symptoms. At each follow-up assessment, participants were reclassified according to the stability, regression or progression of their conditions. Logistic regression analysis was used to predict which CU, SCD and MCI participants would remain stable, regress or progress at a 3rd follow-up by using self- and informant-reported complaints, depressive symptomatology, age and education at baseline and 2nd follow-ups as the predictive variables. Results: Overall, self-reported complaints predicted progression between the asymptomatic and presymptomatic stages. As the objective deterioration increased, i.e., when SCD progressed to MCI or dementia, the SCCs reported by informants proved the best predictors of progression. Depressive symptomatology was also a predictor of progression from CU to SCD and from SCD to MCI. Conclusion: A late increase in self-reported complaints make valid estimates to predict subjective decline at asymptomatic stages. However, an early increase in complaints reported by informants was more accurate in predicting objective decline from asymptomatic stages. Both, early and late decrease in self-reported complaints successfully predict dementia from prodromic stage. Only late decrease in self-reported complaints predict reversion from prodromic and pre-symptomatic stages.

Effects of a Primary Care Antimicrobial Stewardship Program on Meticillin-Resistant Staphylococcus aureus Strains across a Region of Catalunya (Spain) over 5 Years.

Primary care antimicrobial stewardship program (ASP) interventions can reduce the over-prescription of unnecessary antibiotics, but the impact on the reduction in bacterial resistance is less known, and there is a lack of available data. We implemented a prolonged educational counseling ASP in a large regional outpatient setting to assess its feasibility and effectiveness. Over a 5-year post-implementation period, which was compared to a pre-intervention period, a significant reduction in antibiotic prescriptions occurred, particularly those associated with greater harmful effects and resistance selection. There was also a decrease in methicillin-resistant Staphylococcus aureus (MRSA) strains and in their co-resistance to other antibiotics, particularly those with an ecological impact.

Effect of aging on the human myometrium at single-cell resolution.

Age-associated myometrial dysfunction can prompt complications during pregnancy and labor, which is one of the factors contributing to the 7.8-fold increase in maternal mortality in women over 40. Using single-cell/single-nucleus RNA sequencing and spatial transcriptomics, we have constructed a cellular atlas of the aging myometrium from 186,120 cells across twenty perimenopausal and postmenopausal women. We identify 23 myometrial cell subpopulations, including contractile and venous capillary cells as well as immune-modulated fibroblasts. Myometrial aging leads to fewer contractile capillary cells, a reduced level of ion channel expression in smooth muscle cells, and impaired gene expression in endothelial, smooth muscle, fibroblast, perivascular, and immune cells. We observe altered myometrial cell-to-cell communication as an aging hallmark, which associated with the loss of 25 signaling pathways, including those related to angiogenesis, tissue repair, contractility, immunity, and nervous system regulation. These insights may contribute to a better understanding of the complications faced by older individuals during pregnancy and labor.

Nodule-specific Cu+ -chaperone NCC1 is required for symbiotic nitrogen fixation in Medicago truncatula root nodules.

Cu+ -chaperones are a diverse group of proteins that allocate Cu+ ions to specific copper proteins, creating different copper pools targeted to specific physiological processes. Symbiotic nitrogen fixation carried out in legume root nodules indirectly requires relatively large amounts of copper, for example for energy delivery via respiration, for which targeted copper deliver systems would be required. MtNCC1 is a nodule-specific Cu+ -chaperone encoded in the Medicago truncatula genome, with a N-terminus Atx1-like domain that can bind Cu+ with picomolar affinities. MtNCC1 is able to interact with nodule-specific Cu+ -importer MtCOPT1. MtNCC1 is expressed primarily from the late infection zone to the early fixation zone and is located in the cytosol, associated with plasma and symbiosome membranes, and within nuclei. Consistent with its key role in nitrogen fixation, ncc1 mutants have a severe reduction in nitrogenase activity and a 50% reduction in copper-dependent cytochrome c oxidase activity. A subset of the copper proteome is also affected in the ncc1 mutant nodules. Many of these proteins can be pulled down when using a Cu+ -loaded N-terminal MtNCC1 moiety as a bait, indicating a role in nodule copper homeostasis and in copper-dependent physiological processes. Overall, these data suggest a pleiotropic role of MtNCC1 in copper delivery for symbiotic nitrogen fixation.

Visual Performance and Higher Order Aberrations Obtained With Omafilcon A Dual-Focus and Single-Vision Contact Lens Designs.

OBJECTIVE: The purpose of this study was to assess the visual performance and monochromatic higher-order aberrations (HOAs) obtained while wearing a MiSight dual-focus (DF) contact lenses (CL) in comparison with a single-vision contact lens (SVCL). METHODS: A randomized, double-masked, cross-over study was performed. Participants were fitted with a DFCL and a SVCL composed of the same material (omafilcon A) and parameters. Logarithm of the Minimum Angle of Resolution high-contrast (100%) and low-contrast (10%) visual acuity (VA) and contrast sensitivity (CS) for 3, 6, 12, and 18 cycles per degree were measured. Higher-order aberrations were also evaluated using a Hartmann-Shack aberrometer with the CLs on. RESULTS: Twenty-four subjects (21 females and 3 males) with a mean age of 21.9±1.9 years (range: 18-27) were included. Low-contrast VA was significantly lower with the DFCL regarding the SVCL design (0.39±0.23 vs 0.25±0.18, P=0.002). However, there were no differences in high-contrast VA between both CLs (-0.03±0.10 vs -0.09±0.14, P=0.187). Contrast sensitivity was lower with the DFCL under all spatial frequencies (P≤0.048). Second-, third-, fourth-, and fifth-order aberrations were significantly (P<0.001) higher for the DFCL. There were also significant differences between DFCL and SVCL in defocus (0.87±0.28 vs 0.16±0.35, P<0.001), oblique trefoil (-0.16±0.27 vs -0.01±0.08, P=0.005), vertical coma (0.13±0.17 vs 0.00±0.08, P=0.002), and spherical aberration (0.09±0.11 vs -0.02±0.05, P=0.002). CONCLUSION: Visual performance for detecting low-contrast targets is reduced when wearing MiSight DFCL compared with a SVCL with the same material. The main reason might be the induction of second-order and HOAs by the DFCL design.

Synthetic peptides of IL-1Ra and HSP70 have anti-inflammatory activity on human primary monocytes and macrophages: Potential treatments for inflammatory diseases.

Chronic inflammatory diseases are increasing in developed societies, thus new anti-inflammatory approaches are needed in the clinic. Synthetic peptides complexes can be designed to mimic the activity of anti-inflammatory mediators, in order to alleviate inflammation. Here, we evaluated the anti-inflammatory efficacy of tethered peptides mimicking the interleukin-1 receptor antagonist (IL-1Ra) and the heat-shock protein 70 (HSP70). We tested their biocompatibility and anti-inflammatory activity in vitro in primary human monocytes and differentiated macrophages activated with two different stimuli: the TLR agonists (LPS + IFN-γ) or Pam3CSK4. Our results demonstrate that IL-1Ra and HSP70 synthetic peptides present a satisfactory biocompatible profile and significantly inhibit the secretion of several pro-inflammatory cytokines (IL-6, IL-8, IL-1ß and TNFα). We further confirmed their anti-inflammatory activity when peptides were coated on a biocompatible material commonly employed in surgical implants. Overall, our findings support the potential use of IL-1Ra and HSP70 synthetic peptides for the treatment of inflammatory conditions.

An in vitro model for osteoarthritis using long-cultured inflammatory human macrophages repeatedly stimulated with TLR agonists.

Osteoarthritis (OA) is characterized by an abundance of inflammatory M1-like macrophages damaging local tissues. The search for new potential drugs for OA suffers from the lack of appropriate methods of long-lasting inflammation. Here we developed and characterized an in vitro protocol of long-lasting culture of primary human monocyte-derived macrophages differentiated with a combination of M-CSF+GM-CSF that optimally supported long-cultured macrophages (LC-Mϕs) for up to 15 days, unlike their single use. Macrophages repeatedly stimulated for 15 days with the TLR2 ligand Pam3CSK4 (LCS-Mϕs), showed sustained levels over time of IL-6, CCL2, and CXCL8, inflammatory mediators that were also detected in the synovial fluids of OA patients. Furthermore, macrophages isolated from the synovia of two OA patients showed an expression profile of inflammation-related genes similar to that of LCS-Mϕs, validating our protocol as a model of chronically activated inflammatory macrophages. Next, to confirm that these LCS-Mϕs could be modulated by anti-inflammatory compounds, we employed dexamethasone and/or celecoxib, two drugs widely used in OA treatment, that significantly inhibited the production of inflammatory mediators. This easy-to-use in vitro protocol of long-lasting inflammation with primary human macrophages could be useful for the screening of new compounds to improve the therapy of inflammatory disorders.

Uterine leiomyoma with RAD51B::NUDT3 fusion: a report of 2 cases.

Three main uterine leiomyoma molecular subtypes include tumors with MED12 mutation, molecular aberrations leading to HMGA2 overexpression, and biallelic loss of FH. These aberrations are mutually exclusive and can be found in approximately 80-90% of uterine leiomyoma, in which they seem to be a driver event. Approximately 10% of uterine leiomyoma, however, does not belong to any of these categories. Uterine leiomyoma with HMGA2 overexpression is the most common subtype in cellular and second most common category of usual leiomyoma. In some of these tumors, rearrangement of HMGA2 gene is present. The most common fusion partner of HMGA2 gene is RAD51B. Limited data suggests that RAD51B fusions with other genes may be present in uterine leiomyoma. In our study, we described two cases of uterine leiomyoma with RAD51B::NUDT3 fusion, which occur in one case of usual and one case of highly cellular leiomyoma. In both cases, no other driver molecular aberrations were found. The results of our study showed that RAD51::NUDT3 fusion can occur in both usual and cellular leiomyoma. RAD51B may be a fusion partner of multiple genes other than HMGA2 and HMGA1. In these cases, RAD51B fusion seems to be mutually exclusive with other driver aberrations defining molecular leiomyoma subtypes. RAD51B::NUDT3 fusion should be added to the spectrum of fusions which may occur in uterine leiomyoma, which can be of value especially in cellular leiomyoma in the context of differential diagnosis against endometrial stromal tumors.

Human femur fracture by mechanical compression: Towards the repeatability of bone fracture acquisition.

The increase in life expectancy combined with greater bone fragility over the years is causing a rise in the bone fracture cases. Femur fractures are the most important due to their high mortality rate. This multidisciplinary work is carried out in this context and focuses on the experimental reproduction of human femur fractures by compression. We describe a sequence of steps supervised by orthopaedic surgeons for the correct arrangement of specimens on the system set up to perform the experiment. The device applies force by compression until the human bone is fractured. All tests performed have been monitored and evaluated from different knowledge perspectives. The results obtained have demonstrated the repeatability of the fracture type in a controlled environment as well as identifying the main features involved in this process. In addition, the fractured bones have been digitized to analyze the fracture zone to recreate and evaluate future simulations.

Subspecies Distribution and Antimicrobial Susceptibility Testing of Mycobacterium abscessus Clinical Isolates in Madrid, Spain: a Retrospective Multicenter Study.

Mycobacterium abscessus (MABS) is the most pathogenic and drug-resistant rapidly growing mycobacteria. However, studies on MABS epidemiology, especially those focusing on subspecies level, are scarce. We aimed to determine MABS subspecies distribution and its correlation with phenotypic and genotypic antibiotic profiles. A retrospective multicenter study of 96 clinical MABS isolates in Madrid between 2016 to 2021 was conducted. Identification at the subspecies level and resistance to macrolides and aminoglycosides were performed by the GenoType NTM-DR assay. The MICs of 11 antimicrobials tested against MABS isolates were determined using the broth microdilution method (RAPMYCOI Sensititer titration plates). Clinical isolates included 50 (52.1%) MABS subsp. abscessus; 33 (34.4%) MABS subsp. massiliense; and 13 (13.5%) MABS subsp. bolletii. The lowest resistance rates corresponded to amikacin (2.1%), linezolid (6.3%), cefoxitin (7.3%), and imipenem (14.6%), and the highest to doxycycline (100.0%), ciprofloxacin (89.6%), moxifloxacin (82.3%), cotrimoxazole (82.3%), tobramycin (81.3%), and clarithromycin (50.0% at day 14 of incubation). Regarding tigecycline, although there are no susceptibility breakpoints, all strains but one showed MICs ≤ 1 µg/mL. Four isolates harbored mutations at positions 2058/9 of the rrl gene, one strain harbored a mutation at position 1408 of the rrl gene, and 18/50 harbored the T28C substitution at erm(41) gene. Agreement of the GenoType results with clarithromycin and amikacin susceptibility testing was 99.0% (95/96). The rate of MABS isolates showed an upward trend during the study period, being M. abscessus subsp. abscessus the most frequently isolated subspecies. Amikacin, cefoxitin, linezolid, and imipenem showed great in vitro activity. The GenoType NTM-DR assay provides a reliable and complementary tool to broth microdilution for drug resistance detection. IMPORTANCE Infections caused by Mycobacterium abscessus (MABS) are increasingly being reported worldwide. Identifying MABS subspecies and assessing their phenotypic resistance profiles are crucial for optimal management and better patient outcomes. M. abscessus subspecies differ in erm(41) gene functionality, which is a critical determinant of macrolide resistance. Additionally, resistance profiles of MABS and the subspecies distribution can vary geographically, highlighting the importance of understanding local epidemiology and resistance patterns. This study provides valuable insights into the epidemiology and resistance patterns of MABS and its subspecies in Madrid. Elevated resistance rates were observed for several recommended antimicrobials, emphasizing the need for cautious drug use. Furthermore, we assessed the GenoType NTM-DR assay, which examines principal mutations in macrolides and aminoglycosides resistance-related genes. We observed a high level of agreement between the GenoType NTM-DR assay and the microdilution method, indicating its usefulness as an initial tool for early initiation of appropriate therapy.

Effectiveness of Subcutaneous Administration of Antibiotics to Control Infections in Elder Palliative Patients: A Systematic Review.

Background: Infections are common in patients with advanced illnesses for whom the intravenous or oral route is not possible. The subcutaneous administration of antibiotics is a promising alternative, but there is not enough theoretical support for its use. This study aims to explore the effectiveness and safety of subcutaneous antibiotic therapy in the context of palliative care in elderly patients. Methods: A systematic review was conducted using PubMed and Embase, without time or language limits. Seven articles were selected on the effectiveness of subcutaneous antibiotic therapy in adult patients with chronic progressive diseases. The quality of the articles was assessed with the Newcastle Ottawa Scale and relevant data was extracted using a selection capture file. Results: Seven quasi-experimental studies evaluated 865 elderly patients with advanced diseases, comorbidities, and infections (ie, urinary tract, respiratory system, and bone joint) who received subcutaneous antibiotic therapy (ie, Ceftriaxone, Ertapenem, and Teicoplanin). The pooled success rate of subcutaneous antibiotics for the 7 studies was 71%, the therapy failure rate was 22%, its withdrawal mean was 8%, and the mean mortality rate was 7%. The studies were of low quality and were heterogeneous in the types of infections, types of antibiotics, time of follow-up, and outcomes assessed. Conclusions: Pilot studies have found a limited number of antibiotics that can be safely used to treat specific infections. Nevertheless, the data isn´t robust enough to recommend their use.