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OBJECTIVE: To compare the perioperative outcomes of robotic liver surgery (RLS) and laparoscopic liver surgery (LLS) in various settings. BACKGROUND: Clear advantages of RLS over LLS have rarely been demonstrated, and the associated costs of robotic surgery are generally higher than those of laparoscopic surgery. Therefore, the exact role of the robotic approach in minimally invasive liver surgery remains to be defined. METHODS: In this international retrospective cohort study, the outcomes of patients who underwent RLS and LLS for all indications between 2009 and 2021 in 34 hepatobiliary referral centers were compared. Subgroup analyses were performed to compare both approaches across several types of procedures: (1) minor resections in the anterolateral (2, 3, 4b, 5, and 6) or (2) posterosuperior segments (1, 4a, 7, 8), and (3) major resections (≥3 contiguous segments). Propensity score matching was used to mitigate the influence of selection bias. The primary outcome was textbook outcome in liver surgery (TOLS), previously defined as the absence of intraoperative incidents ≥grade 2, postoperative bile leak ≥grade B, severe morbidity, readmission, and 90-day or in-hospital mortality with the presence of an R0 resection margin in case of malignancy. The absence of a prolonged length of stay was added to define TOLS+. RESULTS: Among the 10.075 included patients, 1.507 underwent RLS and 8.568 LLS. After propensity score matching, both groups constituted 1.505 patients. RLS was associated with higher rates of TOLS (78.3% vs 71.8%, P < 0.001) and TOLS+ (55% vs 50.4%, P = 0.026), less Pringle usage (39.1% vs 47.1%, P < 0.001), blood loss (100 vs 200 milliliters, P < 0.001), transfusions (4.9% vs 7.9%, P = 0.003), conversions (2.7% vs 8.8%, P < 0.001), overall morbidity (19.3% vs 25.7%, P < 0.001), and microscopically irradical resection margins (10.1% vs. 13.8%, P = 0.015), and shorter operative times (190 vs 210 minutes, P = 0.015). In the subgroups, RLS tended to have higher TOLS rates, compared with LLS, for minor resections in the posterosuperior segments (n = 431 per group, 75.9% vs 71.2%, P = 0.184) and major resections (n = 321 per group, 72.9% vs 67.5%, P = 0.086), although these differences did not reach statistical significance. CONCLUSIONS: While both produce excellent outcomes, RLS might facilitate slightly higher TOLS rates than LLS.
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Hepatectomía , Laparoscopía , Puntaje de Propensión , Procedimientos Quirúrgicos Robotizados , Humanos , Hepatectomía/métodos , Femenino , Masculino , Laparoscopía/métodos , Estudios Retrospectivos , Persona de Mediana Edad , Anciano , Complicaciones Posoperatorias/epidemiología , Resultado del Tratamiento , Hepatopatías/cirugíaRESUMEN
Community structure is a fundamental topological characteristic of optimally organized brain networks. Currently, there is no clear standard or systematic approach for selecting the most appropriate community detection method. Furthermore, the impact of method choice on the accuracy and robustness of estimated communities (and network modularity), as well as method-dependent relationships between network communities and cognitive and other individual measures, are not well understood. This study analyzed large datasets of real brain networks (estimated from resting-state fMRI from n $$ n $$ = 5251 pre/early adolescents in the adolescent brain cognitive development [ABCD] study), and n $$ n $$ = 5338 synthetic networks with heterogeneous, data-inspired topologies, with the goal to investigate and compare three classes of community detection methods: (i) modularity maximization-based (Newman and Louvain), (ii) probabilistic (Bayesian inference within the framework of stochastic block modeling (SBM)), and (iii) geometric (based on graph Ricci flow). Extensive comparisons between methods and their individual accuracy (relative to the ground truth in synthetic networks), and reliability (when applied to multiple fMRI runs from the same brains) suggest that the underlying brain network topology plays a critical role in the accuracy, reliability and agreement of community detection methods. Consistent method (dis)similarities, and their correlations with topological properties, were estimated across fMRI runs. Based on synthetic graphs, most methods performed similarly and had comparable high accuracy only in some topological regimes, specifically those corresponding to developed connectomes with at least quasi-optimal community organization. In contrast, in densely and/or weakly connected networks with difficult to detect communities, the methods yielded highly dissimilar results, with Bayesian inference within SBM having significantly higher accuracy compared to all others. Associations between method-specific modularity and demographic, anthropometric, physiological and cognitive parameters showed mostly method invariance but some method dependence as well. Although method sensitivity to different levels of community structure may in part explain method-dependent associations between modularity estimates and parameters of interest, method dependence also highlights potential issues of reliability and reproducibility. These findings suggest that a probabilistic approach, such as Bayesian inference in the framework of SBM, may provide consistently reliable estimates of community structure across network topologies. In addition, to maximize robustness of biological inferences, identified network communities and their cognitive, behavioral and other correlates should be confirmed with multiple reliable detection methods.
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Conectoma , Adolescente , Humanos , Conectoma/métodos , Reproducibilidad de los Resultados , Teorema de Bayes , Encéfalo/diagnóstico por imagen , Encéfalo/fisiología , Imagen por Resonancia Magnética/métodosRESUMEN
BACKGROUND: Laparoscopic liver surgery is increasingly used for more challenging procedures. The aim of this study was to assess the feasibility and oncological safety of laparoscopic right hepatectomy for colorectal liver metastases after portal vein embolization. METHODS: This was an international retrospective multicentre study of patients with colorectal liver metastases who underwent open or laparoscopic right and extended right hepatectomy after portal vein embolization between 2004 and 2020. The perioperative and oncological outcomes for patients who underwent laparoscopic and open approaches were compared using propensity score matching. RESULTS: Of 338 patients, 84 patients underwent a laparoscopic procedure and 254 patients underwent an open procedure. Patients in the laparoscopic group less often underwent extended right hepatectomy (18% versus 34.6% (P = 0.004)), procedures in the setting of a two-stage hepatectomy (42% versus 65% (P < 0.001)), and major concurrent procedures (4% versus 16.1% (P = 0.003)). After propensity score matching, 78 patients remained in each group. The laparoscopic approach was associated with longer operating and Pringle times (330 versus 258.5 min (P < 0.001) and 65 versus 30 min (P = 0.001) respectively) and a shorter length of stay (7 versus 8 days (P = 0.011)). The R0 resection rate was not different (71% for the laparoscopic approach versus 60% for the open approach (P = 0.230)). The median disease-free survival was 12 (95% c.i. 10 to 20) months for the laparoscopic approach versus 20 (95% c.i. 13 to 31) months for the open approach (P = 0.145). The median overall survival was 28 (95% c.i. 22 to 48) months for the laparoscopic approach versus 42 (95% c.i. 35 to 52) months for the open approach (P = 0.614). CONCLUSION: The advantages of a laparoscopic over an open approach for (extended) right hepatectomy for colorectal liver metastases after portal vein embolization are limited.
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Neoplasias Colorrectales , Embolización Terapéutica , Hepatectomía , Laparoscopía , Neoplasias Hepáticas , Vena Porta , Humanos , Hepatectomía/métodos , Neoplasias Hepáticas/secundario , Neoplasias Hepáticas/cirugía , Neoplasias Colorrectales/patología , Laparoscopía/métodos , Masculino , Femenino , Vena Porta/cirugía , Embolización Terapéutica/métodos , Estudios Retrospectivos , Persona de Mediana Edad , Anciano , Puntaje de Propensión , Resultado del Tratamiento , Estudios de Factibilidad , Tiempo de InternaciónRESUMEN
Melanoma's rare capacity to undergo heterologous differentiation can create significant diagnostic challenges. The molecular mechanisms underlying this phenomenon are not well understood. We present an unusual case of subungual melanoma exhibiting extensive cartilaginous differentiation and provide insights into its molecular and cytogenomic features. Histopathologically, the tumor was predominantly composed of nodules of malignant cartilage in association with a smaller population of nested epithelioid to rhabdoid cells. Immunohistochemically, the tumor cells in both components were positive for S100, SOX10, and PRAME, and were negative for Melan-A and HMB-45. Molecular analysis by whole exome DNA sequence did not detect any pathogenic variants in genes commonly implicated in melanoma. Additional analysis by SNP chromosomal microarray revealed a complex genome characterized by numerous chromosomal losses and gains, including a homozygous deletion of the CDKN2A locus and a heterozygous deletion of the locus containing EXT2, a tumor suppressor implicated in hereditary multiple osteochondromas and secondary chondrosarcomas. This case underscores the importance of recognizing cartilaginous differentiation as a rare manifestation of melanoma, particularly at subungual sites, and suggests that at least some of these melanomas may be driven by non-canonical molecular pathways.
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Melanoma , Enfermedades de la Uña , Neoplasias Cutáneas , Humanos , Melanoma/patología , Melanoma/genética , Melanoma/diagnóstico , Melanoma/metabolismo , Neoplasias Cutáneas/patología , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/metabolismo , Enfermedades de la Uña/patología , Enfermedades de la Uña/genética , Enfermedades de la Uña/metabolismo , Diferenciación Celular , Masculino , Cartílago/patología , Cartílago/metabolismo , Femenino , Factores de Transcripción SOXE/genética , Factores de Transcripción SOXE/metabolismo , Proteínas S100/metabolismo , Inhibidor p16 de la Quinasa Dependiente de Ciclina/genética , Inhibidor p16 de la Quinasa Dependiente de Ciclina/metabolismo , Antígenos de NeoplasiasRESUMEN
Underlying sociopolitical factors have emerged as important determinants of wildlife population trends and the effectiveness of conservation action. Despite mounting research into the impacts of climate change on nature, there has been little consideration of the human context in which these impacts occur, particularly at the global scale. We investigate this in two ways. First, by modeling the climatic niches of terrestrial mammals and birds globally, we show that projected species loss under climate change is greatest in countries with weaker governance and lower Gross Domestic Product, with loss of mammal species projected to be greater in countries with lower CO2 emissions. Therefore, climate change impacts on species may be disproportionately significant in countries with lower capacity for effective conservation and lower greenhouse gas emissions, raising important questions of international justice. Second, we consider the redistribution of species in the context of political boundaries since the global importance of transboundary conservation under climate change is poorly understood. Under a high-emissions scenario, we find that 35% of mammals and 29% of birds are projected to have over half of their 2070 climatic niche in countries in which they are not currently found. We map these transboundary range shifts globally, identifying borders across which international coordination might most benefit conservation and where physical border barriers, such as walls and fences, may be an overlooked obstacle to climate adaptation. Our work highlights the importance of sociopolitical context and the utility of a supranational perspective for 21st century nature conservation.
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Cambio Climático , Especies en Peligro de Extinción/estadística & datos numéricos , Sistemas Políticos , Animales , Aves , Efecto Invernadero , MamíferosRESUMEN
The conservation of long-distance migratory birds requires coordination between the multiple countries connected by the movements of these species. The recent expansion of tracking studies is shedding new light on these movements, but much of this information is fragmented and inaccessible to conservation practitioners and policy makers. We synthesized current knowledge on the connectivity established between countries by landbirds and raptors migrating along the African-Eurasian flyway. We reviewed tracking studies to compile migration records for 1229 individual birds, from which we derived 544 migratory links, each link corresponding to a species' connection between a breeding country in Europe and a nonbreeding country in sub-Saharan Africa. We used these migratory links to analyze trends in knowledge over time and spatial patterns of connectivity per country (across species), per species (across countries), and at the flyway scale (across all countries and all species). The number of tracking studies available increased steadily since 2010 (particularly for landbirds), but the coverage of existing tracking data was highly incomplete. An average of 7.5% of migratory landbird species and 14.6% of raptor species were tracked per country. More data existed from central and western European countries, and it was biased toward larger bodied species. We provide species- and country-level syntheses of the migratory links we identified from the reviewed studies, involving 123 populations of 43 species, migrating between 28 European and 43 African countries. Several countries (e.g., Spain, Poland, Ethiopia, Democratic Republic of Congo) are strategic priorities for future tracking studies to complement existing data, particularly on landbirds. Despite the limitations in existing tracking data, our data and results can inform discussions under 2 key policy instruments at the flyway scale: the African-Eurasian Migratory Landbirds Action Plan and the Memorandum of Understanding on the Conservation of Migratory Birds of Prey in Africa and Eurasia.
Conectividad entre países establecida por aves terrestres y rapaces que migran a través del corredor aéreo africano-euroasiático Resumen La conservación de las aves que migran grandes distancias requiere de una coordinación entre los varios países conectados por los movimientos de estas especies. La expansión reciente de los estudios de rastreo está descubriendo novedades en estos movimientos, aunque gran parte de esta información está fragmentada y es inaccesible para quienes practican y elaboran las políticas de conservación. Sintetizamos el conocimiento actual sobre la conectividad establecida entre países por las aves terrestres y rapaces que migran a través del corredor aéreo africano-euroasiático. Revisamos los estudios de rastreo para compilar los registros migratorios de 1229 aves, de los cuales derivamos 544 conexiones migratorias, con cada conexión correspondiendo a la conexión que tiene una especie entre un país europeo en donde se reproduce con un país de la África subsahariana en donde no se reproduce. Usamos estas conexiones migratorias para analizar las tendencias informativas en patrones espaciales y temporales de conectividad por país (en todas las especies), por especie (en todos los países) y a escala del corredor aéreo (en todas las especies y en todos los países). El número de estudios de rastreo disponibles incrementó gradualmente a partir de 2010 (particularmente para las aves terrestres), pero la cobertura de los datos de rastreo existentes estaba incompleta. Se rastreó en promedio 7.5% de especies de aves terrestres migratorias y 14.6% de aves rapaces por país. Existían más datos de los países del centro y oeste de Europa, los cuales estaban sesgados hacia las especies de mayor tamaño. Proporcionamos varias síntesis a nivel de especie y país de las conexiones migratorias que identificamos a partir de la revisión de estudios, las cuales involucran a 123 poblaciones de 43 especies que migran entre 28 países europeos y 43 países africanos. Varios países, como España, Polonia, Etiopía y la República Democrática del Congo son prioridades estratégicas para complementar los datos existentes en los siguientes estudios de rastreo, en especial para las aves terrestres. A pesar de las limitaciones que tienen los datos de rastreo existentes, nuestros datos y resultados pueden orientar las discusiones con dos instrumentos claves para las políticas: el Plan de Acción de las Aves Terrestres Migratorias Africanas-Euroasiáticas y el Memorando de Entendimiento sobre la Conservación de las Aves Rapaces Migratorias de África y Eurasia.
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Rapaces , Animales , Migración Animal , Conservación de los Recursos Naturales/métodos , Aves , Etiopía , Estaciones del AñoRESUMEN
OBJECTIVE: Community-based residential rehabilitation for people experiencing severe and persistent mental illness (SPMI) is increasingly available as an alternative to psychiatric inpatient care. Understanding who accesses these services and their outcomes will inform the optimal allocation of limited public mental health resources. METHOD: This retrospective cohort study explored the outcomes of the first 100 consumers supported by a new Australian Community Care Unit (CCU). The primary outcome focus was acute mental health service use (emergency department presentations, acute mental health inpatient admission days), and secondary outcome foci were accommodation independence and substance use. RESULTS: When the 365 days before and after CCU support were compared, significant reductions in acute mental health bed days were observed (22 days, W = 3.373, p = .001); greater reductions were noted for those staying >182 days (31 days, W = 3.373, p = .001). Additionally, significant improvements in accommodation independence were found, (W = 3.373, p = .001). CONCLUSION: CCU consumers experienced reductions in acute mental health inpatient service use and improved accommodation independence. These observations are consistent with the intended functioning of the residential rehabilitation service.
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Servicios Comunitarios de Salud Mental , Trastornos Mentales , Humanos , Estudios Retrospectivos , Australia , Hospitalización , Trastornos Mentales/psicología , Enfermedad CrónicaRESUMEN
Despite their importance for biodiversity and ecosystem services, wetlands are among the most threatened ecosystems globally. The conservation of many migratory waterbirds depends on the conservation of a network of key sites along their flyways. However, the suitability of these sites is changing under climate change, and it is important that management of individual sites in the network adapts to these changes. Using bioclimatic models that also account for changes in inundation, we found that projected climate change will reduce habitat suitability for waterbirds at 57.5% of existing Critical Sites within Africa-Eurasia, varying from 20.1% in Eastern Europe to 87.0% in Africa. African and Middle East sites are particularly threatened, comprising 71 of the 100 most vulnerable sites. By highlighting priority sites for conservation and classifying Critical Sites into Climate Change Adaptation Strategy (CCAS) classes, our results can be used to support the climate change adaptation of both individual sites and the entire site network.
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Cambio Climático , Ecosistema , Animales , Biodiversidad , Aves , Conservación de los Recursos NaturalesRESUMEN
BACKGROUND: Solitary fibrous tumour (SFT) is a unique mesenchymal neoplasm with classic features on histology and is characterised by the NAB2-STAT6 gene fusion. There are rare reports of SFTs with pancreatic involvement and only two cases in the literature reporting its features by preoperative fine needle aspiration (FNA). Herein, we characterise the cytomorphological features of four SFTs involving the pancreas by FNA to establish a preoperative diagnostic approach. METHODS: The anatomic pathology archives of two academic medical centres were searched to identify patients with a pancreatic FNA cytology specimen and a confirmed diagnosis of SFT by surgical resection. The clinical history, pathological diagnosis, cytomorphological findings, and results of immunohistochemistry (IHC) were reviewed. RESULTS: Four SFTs were identified from four patients with a median age of 59 years. The morphological features were variable but most frequently showed a bland spindled-to-epithelioid proliferation in fragments and single cells with small, oval, elongated, and hypochromatic nuclei in a haphazard arrangement with or without dense collagen. One tumour presented with a concurrent metastasis and showed a pure epithelioid component with necrosis and enlarged, hyperchromatic nuclei with conspicuous nucleoli and scattered mitoses. IHC was necessary for all diagnoses which were confirmed by surgical resection. CONCLUSIONS: SFTs with pancreatic involvement are rare, and non-specific features and tumour heterogeneity can pose a diagnostic challenge on FNA; however, IHC can be used to make a definitive diagnosis. As a result, FNA is a simple, safe, cost-effective, and accurate approach that can be used to diagnose SFT in the pancreas.
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Tumores Fibrosos Solitarios , Biopsia con Aguja Fina/métodos , Humanos , Inmunohistoquímica , Persona de Mediana Edad , Páncreas/patología , Tumores Fibrosos Solitarios/diagnóstico , Tumores Fibrosos Solitarios/patologíaRESUMEN
BACKGROUND: "Meds-to-beds" programs are a quality improvement intervention that is gaining wider implementation throughout the United States. The University of Oklahoma hospital system did not have this program and sought to implement one. There are sufficient data on the benefits of meds-to-beds programs, but there is a lack of literature on describing the development and implementation process. OBJECTIVES: The objective of this article is to describe the planning process, implementation, and barriers encountered during the organization of a pharmacy-led meds-to-beds program operating within 2 large teaching hospitals. PRACTICE DESCRIPTION: The University of Oklahoma Health Sciences Center campus has 7 colleges, multiple primary care and specialty clinics, and 2 hospitals. In addition, there are 3 on-campus outpatient pharmacies operated by the University of Oklahoma College of Pharmacy (OUCOP). PRACTICE INNOVATION: The college implemented a meds-to-beds program primarily serving 2 on-campus hospitals, The Oklahoma Children's Hospital and University of Oklahoma College of Pharmacy Medical Center. The program operated out of The Children's Pharmacy, an outpatient pharmacy located within the Children's Hospital. EVALUATION METHODS: A Plan-Do-Study-Act model was used, which allowed for adaptation in response to barriers encountered throughout the process. Frequent meetings among stakeholders were held to continuously evaluate progress (e.g., awareness and utilization of the program and prescription counts) and make necessary changes. RESULTS: Implementation of the program required changes in workflow both within the pharmacy and within the registration and discharge processes of medical teams. In addition, after the initiation of the meds-to-beds program, the daily prescription count more than doubled. The program averages 40 deliveries per day and 3 prescriptions per delivery and continues to grow, providing evidence of a successful meds-to-beds implementation. CONCLUSION: The Plan-Do-Study-Act model allowed for many adjustments to be made throughout the process, including the conversion from an opt-in to an opt-out model to increase program utilization.
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Servicios Farmacéuticos , Farmacias , Farmacia , Niño , Hospitales de Enseñanza , Humanos , Alta del Paciente , Estados UnidosRESUMEN
Biofilm growth is thought to be a significant obstacle to the successful treatment of Mycobacterium abscessus infections. A search for agents capable of inhibiting M. abscessus biofilms led to our interest in 2-aminoimidazoles and related scaffolds, which have proven to display antibiofilm properties against a number of Gram-negative and Gram-positive bacteria, including Mycobacterium tuberculosis and Mycobacterium smegmatis. The screening of a library of 30 compounds led to the identification of a compound, AB-2-29, which inhibits the formation of M. abscessus biofilms with an IC50 (the concentration required to inhibit 50% of biofilm formation) in the range of 12.5 to 25 µM. Interestingly, AB-2-29 appears to chelate zinc, and its antibiofilm activity is potentiated by the addition of zinc to the culture medium. Preliminary mechanistic studies indicate that AB-2-29 acts through a distinct mechanism from those reported to date for 2-aminoimidazole compounds.
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Infecciones por Mycobacterium no Tuberculosas , Mycobacterium abscessus , Antibacterianos/farmacología , Biopelículas , Humanos , Imidazoles/farmacología , Pruebas de Sensibilidad Microbiana , Zinc/farmacologíaRESUMEN
In the textbook view, N-methyl-d-aspartate (NMDA) receptors are postsynaptically located detectors of coincident activity in Hebbian learning. However, controversial presynaptically located NMDA receptors (preNMDARs) have for decades been repeatedly reported in the literature. These preNMDARs have typically been implicated in the regulation of short-term and long-term plasticity, but precisely how they signal and what their functional roles are have been poorly understood. The functional roles of preNMDARs across several brain regions and different forms of plasticity can differ vastly, with recent discoveries showing key involvement of unusual subunit composition. Increasing evidence shows preNMDAR can signal through both ionotropic action by fluxing calcium and in metabotropic mode even in the presence of magnesium blockade. We argue that these unusual properties may explain why controversy has surrounded this receptor type. In addition, the expression of preNMDARs at some synapse types but not others can underlie synapse-type-specific plasticity. Last but not least, preNMDARs are emerging therapeutic targets in disease states such as neuropathic pain. We conclude that axonally located preNMDARs are required for specific purposes and do not end up there by accident.
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Receptores de N-Metil-D-Aspartato , Sinapsis , AxonesRESUMEN
OBJECTIVES: Assertive community treatment (ACT) teams are increasingly being adapted to suit the needs of consumers who have never experienced long-term institutional care yet struggle to retain community tenure and quality of life due to residual functional disabilities associated with severe mental illness. Support needs can be provided by the growing disability support sector but recovery-orientated rehabilitation services delivered by specialist rehabilitation clinicians are also required. The Mobile Intensive Rehabilitation Team (MIRT) within the Metro South Addiction and Mental Health Service has adapted the ACT model to deliver assertive outreach that aims to work collaboratively with the person and their chosen supports to improve their function and their sense of self-efficacy in illness self-management. We described the characteristics of the consumers referred to MIRT over a 20-month time period, and reported on on their discharge location. CONCLUSION: After two years with MIRT, half the participants were discharged out of case-management. Being on clozapine was a barrier to discharge from case-management despite functional improvement. Psychiatric hospitalisations predicted longer duration working with MIRT.
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Servicios Comunitarios de Salud Mental , Trastornos Mentales , Servicios de Salud Mental , Manejo de Caso , Humanos , Trastornos Mentales/terapia , Calidad de VidaRESUMEN
Similar to other prokaryotes, mycobacteria decorate their major cell envelope glycans with minor covalent substituents whose biological significance remains largely unknown. We report on the discovery of a mycobacterial enzyme, named here SucT, that adds succinyl groups to the arabinan domains of both arabinogalactan (AG) and lipoarabinomannan (LAM). Disruption of the SucT-encoding gene in Mycobacterium smegmatis abolished AG and LAM succinylation and altered the hydrophobicity and rigidity of the cell envelope of the bacilli without significantly altering AG and LAM biosynthesis. The changes in the cell surface properties of the mutant were consistent with earlier reports of transposon mutants of the closely related species Mycobacterium marinum and Mycobacterium avium harboring insertions in the orthologous gene whose ability to microaggregate and form biofilms were altered. Our findings point to an important role of SucT-mediated AG and LAM succinylation in modulating the cell surface properties of mycobacteria.
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Aciltransferasas/metabolismo , Proteínas Bacterianas/metabolismo , Pared Celular/química , Galactanos/química , Lipopolisacáridos/química , Mycobacterium smegmatis/enzimología , Succinatos/química , Aciltransferasas/antagonistas & inhibidores , Aciltransferasas/genética , Proteínas Bacterianas/antagonistas & inhibidores , Proteínas Bacterianas/genética , MutaciónRESUMEN
BACKGROUND: Deficits in social cognition are common in people with schizophrenia and are associated with impaired functioning. Finding effective interventions to address these deficits is a priority. Social Cognition Interaction Training (SCIT) is a psychosocial intervention that has demonstrated acceptability and feasibility in various health care settings. Larger, well-designed randomized controlled trials are needed to examine the effectiveness of this intervention. DESIGN: A randomized controlled trial. METHODS: One hundred and twenty adults diagnosed with schizophrenia spectrum disorder were randomized to receive SCIT (n = 61) or Befriending Therapy (BT) (n = 59). Both intervention groups were delivered weekly for 2 hr over 12 weeks. Neurocognitive assessment was completed at baseline. Participants completed assessments of social cognition, social functioning, and meta-cognition at baseline, post-intervention, and 3-month follow-up. RESULTS: There were no clinically significant differences between group outcomes on any measure of social cognition or social functioning. There was a trend for both groups to improve over time but not at a level of statistical significance. CONCLUSIONS: SCIT did not show any additional benefits on measures of social cognition compared to Befriending Therapy for people with schizophrenia spectrum disorder. The findings are discussed in terms of potential improvements to the programme. PRACTITIONER POINTS: Effective interventions for the social cognitive deficits of schizophrenia spectrum disorders are still being refined. Social Cognition Interaction Training is a promising therapy but requires further modifications to improve its effectiveness.
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Terapia Cognitivo-Conductual/métodos , Esquizofrenia/terapia , Cognición Social , Adulto , Femenino , Humanos , MasculinoRESUMEN
Mycobacterium tuberculosis' success as a pathogen comes from its ability to evade degradation by macrophages. Normally macrophages clear microorganisms that activate pathogen-recognition receptors (PRRs) through a lysosomal-trafficking pathway called "LC3-associated phagocytosis" (LAP). Although Mtuberculosis activates numerous PRRs, for reasons that are poorly understood LAP does not substantially contribute to Mtuberculosis control. LAP depends upon reactive oxygen species (ROS) generated by NADPH oxidase, but Mtuberculosis fails to generate a robust oxidative response. Here, we show that CpsA, a LytR-CpsA-Psr (LCP) domain-containing protein, is required for Mtuberculosis to evade killing by NADPH oxidase and LAP. Unlike phagosomes containing wild-type bacilli, phagosomes containing the ΔcpsA mutant recruited NADPH oxidase, produced ROS, associated with LC3, and matured into antibacterial lysosomes. Moreover, CpsA was sufficient to impair NADPH oxidase recruitment to fungal particles that are normally cleared by LAP. Intracellular survival of the ΔcpsA mutant was largely restored in macrophages missing LAP components (Nox2, Rubicon, Beclin, Atg5, Atg7, or Atg16L1) but not in macrophages defective in a related, canonical autophagy pathway (Atg14, Ulk1, or cGAS). The ΔcpsA mutant was highly impaired in vivo, and its growth was partially restored in mice deficient in NADPH oxidase, Atg5, or Atg7, demonstrating that CpsA makes a significant contribution to the resistance of Mtuberculosis to NADPH oxidase and LC3 trafficking in vivo. Overall, our findings reveal an essential role of CpsA in innate immune evasion and suggest that LCP proteins have functions beyond their previously known role in cell-wall metabolism.
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Proteínas Bacterianas/metabolismo , Macrófagos/inmunología , Proteínas Asociadas a Microtúbulos/fisiología , NADPH Oxidasa 2/fisiología , Fagocitosis/fisiología , Tuberculosis/prevención & control , Animales , Autofagia , Proteínas Bacterianas/genética , Femenino , Interacciones Huésped-Patógeno , Macrófagos/microbiología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones SCID , Mycobacterium tuberculosis/patogenicidad , Óxido Nítrico Sintasa de Tipo II/fisiología , Fagosomas , Especies Reactivas de Oxígeno/metabolismo , Tuberculosis/inmunología , Tuberculosis/microbiologíaRESUMEN
AIMS: Lumbosacral lipomas (LSL) are congenital disorders of the terminal spinal cord region that have the potential to cause significant spinal cord dysfunction in children. They are of unknown embryogenesis with variable clinical presentation and natural history. It is unclear whether the spinal cord dysfunction reflects a primary developmental dysplasia or whether it occurs secondarily to mechanical traction (spinal cord tethering) with growth. While different anatomical subtypes are recognised and classified according to radiological criteria, these subtypes correlate poorly with clinical prognosis. We have undertaken an analysis of surgical specimens in order to describe the spectrum of histological changes that occur and have correlated the histology with the anatomical type of LSL to determine if there are distinct histological subtypes. METHODS AND RESULTS: The histopathology was reviewed of 64 patients who had undergone surgical resection of LSL. The presence of additional tissues and cell types were recorded. LSLs were classified from pre-operative magnetic resonance imaging (MRI) scans according to Chapman classification. Ninety-five per cent of the specimens consisted predominantly of mature adipocytes with all containing thickened bands of connective tissue and peripheral nerve fibres, 91% of samples contained ectatic blood vessels with thickened walls, while 22% contained central nervous system (CNS) glial tissue. Additional tissue was identified of both mesodermal and neuroectodermal origin. CONCLUSIONS: Our analysis highlights the heterogeneity of tissue types within all samples, not reflected in the nomenclature. The diversity of tissue types, consistent across all subtypes, challenges currently held notions regarding the embryogenesis of LSLs and the assumption that clinical deterioration is due simply to tethering.
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Adipocitos/patología , Lipoma/patología , Neoplasias de la Médula Espinal/patología , Deterioro Clínico , Humanos , Lipoma/diagnóstico por imagen , Lipoma/cirugía , Región Lumbosacra/diagnóstico por imagen , Región Lumbosacra/patología , Región Lumbosacra/cirugía , Imagen por Resonancia Magnética , Neoplasias de la Médula Espinal/diagnóstico por imagen , Neoplasias de la Médula Espinal/cirugíaRESUMEN
BACKGROUND: Chronic ethanol (EtOH) exposure has been found to inhibit adult hippocampal neurogenesis in multiple models of alcohol addiction. However, acute EtOH inhibition of adult neurogenesis is not well studied. Although many abused drugs have been found to inhibit adult neurogenesis, few have studied cannabinoids or cannabinoids with EtOH, although human use of both together is becoming more common. We used an acute binge alcohol drinking model in combination with select cannabinoid receptor agonists and antagonists to investigate the actions of each alone and together on hippocampal neurogenesis. METHODS: Adult male Wistar rats were treated with an acute binge dose of EtOH (5 g/kg, i.g.), cannabinoid 1 receptor (CB1R) or cannabinoid 2 receptor (CB2R) agonists, as well as selective cannabinoid (CB) antagonists, alone or combined. Hippocampal doublecortin (DCX), Ki67, and activated cleaved caspase-3 (CC3) immunohistochemistry were used to assess neurogenesis, neuroprogenitor proliferation, and cell death, respectively. RESULTS: We found that treatment with EtOH or the CB1R agonist, arachidonoyl-2'-chloroethylamide (ACEA), and the combination significantly reduced DCX-positive neurons (DCX + IR) in dentate gyrus (DG) and increased CC3. Further, using an inhibitor of endocannabinoid metabolism, for example, JZL195, we also found reduced DCX + IR neurogenesis. Treatment with 2 different CB1R antagonists (AM251 or SR141716) reversed both CB1R agonist and EtOH inhibition of adult neurogenesis. CB2R agonist HU-308 treatment did not produce any significant change in DCX + IR. Interestingly, neither EtOH nor CB1R agonist produced any alteration in cell proliferation in DG as measured by Ki67 + cell population, but CC3-positive cell numbers increased following EtOH or ACEA treatment suggesting an increase in cell death. CONCLUSIONS: Together, these findings suggest that acute CB1R cannabinoid receptor activation and binge EtOH treatment reduce neurogenesis through mechanisms involving CB1R.
Asunto(s)
Consumo Excesivo de Bebidas Alcohólicas/fisiopatología , Etanol/efectos adversos , Hipocampo/efectos de los fármacos , Hipocampo/fisiopatología , Neurogénesis/efectos de los fármacos , Receptor Cannabinoide CB1/metabolismo , Animales , Cannabinoides/farmacología , Carbamatos/farmacología , Caspasa 3/metabolismo , Muerte Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Proteínas de Dominio Doblecortina , Proteína Doblecortina , Interacciones Farmacológicas , Endocannabinoides/farmacología , Hipocampo/metabolismo , Antígeno Ki-67/metabolismo , Masculino , Proteínas Asociadas a Microtúbulos/metabolismo , Neuropéptidos/metabolismo , Piperazinas/farmacología , Piperidinas/farmacología , Pirazoles/farmacología , Ratas , Receptor Cannabinoide CB1/agonistas , Receptor Cannabinoide CB1/antagonistas & inhibidores , Receptor Cannabinoide CB2/agonistas , Receptor Cannabinoide CB2/antagonistas & inhibidores , Receptor Cannabinoide CB2/metabolismo , Rimonabant/farmacologíaRESUMEN
PURPOSE: Rotation of the lipoma-neural placode has been noted in transitional lumbosacral lipomas. The purpose of this study was to confirm this rotation; that this rotation occurs with a preference to the left, and correlates with clinical symptoms. In addition, this study tests the hypothesis that this rotation occurs through local mechanical forces rather than intrinsic congenital malformation. METHODS: Lipomas were classified as per the Chapman classification. Degree of rotation of the placode from the coronal plane was recorded along with the presence of herniation outside of the vertebral canal. Abnormalities on urodynamic testing were recorded, along with neuro-orthopaedic signs picked up on formal neuro-physiotherapy assessment. RESULTS: Placode rotation occurs more frequently in the transitional group. Regardless of lipoma classification, rotation was much more common to the left. Furthermore, when lateralisation of symptoms was present, this strongly correlated with the direct of rotation. There was no difference in rotation of the placode whether it was within (lipomyelocoele) or without the vertebral canal (lipomyelomeningocoele). CONCLUSIONS: Placode rotation is a feature of transitional lumbosacral lipomas and may account for the increase in symptoms amongst this subgroup. Herniation of the placode outside the vertebral canal does not increase the risk of rotation suggesting a congenital cause for this finding rather than a purely mechanical explanation.
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Lipoma/diagnóstico por imagen , Rotación , Neoplasias de la Médula Espinal/diagnóstico por imagen , Raíces Nerviosas Espinales/diagnóstico por imagen , Humanos , Lipoma/fisiopatología , Región Lumbosacra/diagnóstico por imagen , Región Lumbosacra/fisiopatología , Estudios Retrospectivos , Neoplasias de la Médula Espinal/fisiopatologíaRESUMEN
BACKGROUND: To evaluate the planned implementation of group based Cognitive Remediation therapy (CR) and Social Cognitive Interaction Training (SCIT) into routine psychosis care in a mental health service in Australia. METHOD: The study was conducted over 3 years in a mental health service in a metropolitan city in Australia. Participants were 22 program facilitators and 128 patients attending the programs. Implementation outcomes were assessed using administrative data, staff surveys and program audits. RESULTS: There was fidelity to the particular therapies at a program level. Programs were assessed as being feasible within the study setting with each hospital district developing a capacity to run CR and SCIT. The establishment of new programs improved the reach, but waiting lists indicate a need to expand capacity. There was a relatively high dropout and several factors impacted on completion of the programs - notably, acute exacerbation of psychosis. Once initiated the therapies were acceptable with no-one ceasing SCIT due to loss of interest and only 10% of participants ceasing CR due to loss of interest. Annual audits of programs found programs established were maintained and facilitators were retained. CONCLUSION: SCIT and CR programs were successfully implemented in three hospital districts. Several factors impeded participants receiving the recommended "dose" of the programs. The maintenance of the programs in the short term is encouraging in regards to organisational fit. Dissemination of cognitive rehabilitation programs to a service population takes planning. An implementation plan is essential for guiding development and maintenance of programs. These therapies are best suited to people in a stable phase of illness. Service user co-production is recommended to improve recruitment in future studies.