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Background: New graduate nurses are the nursing cohort at greatest risk for turnover and attrition in every context internationally. This has possibly been heightened during the COVID-19 pandemic. Workplace conditions significantly impact nursing turnover; however, interventions under the positive psychology umbrella may have a mediating impact on the intention to leave. New graduate nurses are generally challenged most in their first three years of clinical practice, and the need for support to transition is widely accepted. Gratitude practice has been reported to improve individual control and resilient response to setbacks and, therefore, is of interest in testing if this intervention can impact turnover intention in the workforce. Objective: To report on a scoping review undertaken to identify whether 'gratitude practice' as an intervention had the potential to improve new graduate nurses' wellbeing and resilience. Methods: Arksey and O'Malley's scoping review approach. Primary research papers of any methodology, published in English between January 2010 and July 2022 were included. Literature was sourced from seven databases, including CINAHL PLUS, ERIC, MEDLINE, Professional Development Collection, APA PsychInfo, APA PsychArticles, and Psychological and Behavioural Sciences Collection. Results: We identified 130 records, of which we selected 35 for inclusion. A large range of interventions were identified; most had some form of writing, journaling, or diarising. The next most common intervention was teaching gratitude strategies via workshops, and many interventions had some form of list or activity trigger for participants to complete. Five studies had complex combined interventions, while the rest were simple, easily reproducible interventions. Interventions were delivered both face-to-face or asynchronously, with some being online only and others sent out as a 'kit' for participants to work through. Conclusion: Our review of existing literature shows a significant gap in research on gratitude practice and its impact on nursing populations. To ensure robust future studies, we suggest defining concepts clearly and selecting outcome measures and tools that are not closely related. Intervention design may not be as important as the choice of measures and tools to measure outcomes.
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Older adults are at increased risk of pressure injuries (PIs) due to age-related changes. Traditionally, PI knowledge and education have been delivered in hospitals and residential aged care facilities, however, there remains a critical gap in understanding how PI knowledge on prevention and management is shared with older adults and their carers living in the community. We aimed to describe the nature and characteristics of structured and unstructured PI education programs available to community-dwelling older adults and their carers. As coping review was undertaken. We searched five databases: CINAHL, Medline, Scopus, Cochrane Library and ProQuest from 2009 to August 2023. The review was guided by Arksey and O'Malley's six-step framework and adhered to the PRISMA-ScR guidelines. It included primary peer-reviewed papers published in English, which focus on PI education for older adults and/or their carers living in community settings. Data extraction was organised in a table, and findings presented as a narrative summary. One-hundred and thirty-six papers were screened and four included in the review. Results indicate that consideration was placed on literacy levels and cognitive status of older adults and their carers when designing PI education materials. Educational materials such as leaflets/brochures, in-person training sessions or a combination of both were used. However, duration of these interventions varied, lasting for 1-4 weeks while others were completed over 12 months. Some improvements in PI knowledge such as how to treat PI, dietary requirements and importance of mobility were noted. However, information retention and its translation into effective long-term behaviour change remained unclear. In conclusion, adopting a multifaceted educational approach increases the effectiveness of PI knowledge translation. Continuous education, support and reinforcement on PIs over time are necessary when interacting with older adults and caregivers to ensure long-term management and prevention success. Conversations on PIs should start at the primary care levels when older adults and carers are visiting their GP clinics and accessing support services for other healthcare needs. Understanding older adults' and carers' literacy levels, cognitive status and cultural background can assist clinicians in designing and delivering fit-for-purpose PI educational interventions that are accessible, relatable and effective in promoting knowledge transfer and behaviour change. Carers are vital conduits in the care continuum. These factors will lead to a more informed, collaborative and person-centred approaches to PI management and prevention.
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Cuidadores , Vida Independiente , Úlcera por Presión , Humanos , Cuidadores/educación , Cuidadores/psicología , Anciano , Úlcera por Presión/prevención & control , Anciano de 80 o más Años , Masculino , Educación del Paciente como Asunto/métodos , Femenino , Persona de Mediana EdadRESUMEN
Delta-like ligand 3 (DLL3) is expressed in more than 70% of small cell lung cancers (SCLCs) and other neuroendocrine-derived tumor types. SCLC is highly aggressive and limited therapeutic options lead to poor prognosis for patients. HPN328 is a tri-specific T cell activating construct (TriTAC) consisting of three binding domains: a CD3 binder for T cell engagement, an albumin binder for half-life extension, and a DLL3 binder for tumor cell engagement. In vitro assays, rodent models and non-human primates were used to assess the activity of HPN328. HPN328 induces potent dose-dependent killing of DLL3-expressing SCLC cell lines in vitro concomitant with T cell activation and cytokine release. In an NCI-H82 xenograft model with established tumors, HPN328 treatment led to T cell recruitment and anti-tumor activity. In an immunocompetent mouse model expressing a human CD3ε epitope, mice previously treated with HPN328 withstood tumor rechallenge, demonstrating long-term anti-tumor immunity. When repeat doses were administered to cynomolgus monkeys, HPN328 was well tolerated up to 10 mg/kg. Pharmacodynamic changes, such as transient cytokine elevation, were observed, consistent with the expected mechanism of action of T cell engagers. HPN328 exhibited linear pharmacokinetic in the given dose range with a serum half-life of 78 to 187 hours, supporting weekly or less frequent administration of HPN328 in humans. Preclinical and nonclinical characterization suggests that HPN328 is a highly efficacious, safe, and novel therapeutic candidate. A phase 1/2 clinical trial is currently underway testing safety and efficacy in patients with DLL3 expressing malignancies.
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Purpose: To evaluate different bone-patellar tendon-bone (BPTB) plug suture configurations for pull through strength, stiffness, and elongation at failure in a biomechanical model of suspensory fixation. Methods: Forty nonpaired, fresh-frozen human cadaveric BPTB allografts with an average age of 65.6 years were tested. Tensile testing was performed with the use of a custom-designed fixture mounted in a dynamic tensile testing machine. A preload of 90 N was applied to the graft and held for 5 minutes. Following this, a tensile load-to-failure test was performed. The ultimate failure load, elongation at failure, and mode of failure were recorded, and the resulting load-elongation curve was documented. Results: The drill tunnel through the cortical surface (anterior to posterior) was found to be significantly stronger than the drill tunnel through the cancellous surface (medial to lateral). There were no significant differences found when comparing the strength of the suture augmentation through the tendon and the drill tunnel alone (P = .13 among cancellous groups, P = .09 among cortical groups). The cortical drill tunnel with suture augmentation through the tendon showed significantly greater elongation values (13.7 ± 3.2) at failure when compared with either the cancellous or cortical drill tunnel only test groups (P = .0003 compared with cancellous alone, P = .009 when compared with cortical alone). Conclusions: The BPTB suture configuration with an anterior to posterior-directed suture tunnel without a suture through tendon augmentation provides the optimal strength and stiffness while minimizing graft elongation after fixation in a biomechanical model. This configuration is best for preventing suture pull through and failure when passing sutures through the BPTB plug. Clinical Relevance: This study biomechanically evaluates the optimal suture configuration in the proximal bone plug for suspensory fixation in the setting of BPTB grafts.
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INTRODUCTION: Atrial fibrillation (AF) ablation is performed worldwide. To attract patients, hospitals frequently have webpages that tout the success of the procedure. The information disseminated to the public via these webpages has not been systematically reviewed. Our objective was to assess accuracy of information delivered to the public on hospital websites in regard to atrial AF ablation. METHODS: From July 2019 to January 2020, we performed a Google search for all US hospitals registered with Medicare to see if they had a webpage describing AF ablation. Resulting hospital webpages were abstracted for data on AF ablation success rates and risks. Success rates over 86%, the highest success rate in the medical literature, were deemed exaggerated. RESULTS: Among 4805 hospitals, 487 had webpages describing AF ablation and 33 discussed success rates of AF ablation. Twelve percentage reported exaggerated success rates, 3% referred to ablation as a cure, and 2.8% referred to ablation as a tool to eliminate AF. Less than 10% of webpages describing AF ablation noted the potential need for a second ablation to achieve the stated success rate and merely 16% mentioned risks of the procedure. One percentage of webpages directly suggested AF ablation could reduce risk of stroke while others indirectly suggested it by discussing cessation of anticoagulation. Two webpages mentioned reduced mortality. CONCLUSION: US hospital webpages rarely discuss AF ablation. When discussed, there were concerning unsubstantiated claims regarding mortality, stroke prevention, and need for medical therapy. This could lead to some patients undergoing AF ablation based on faulty understanding.
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Fibrilación Atrial , Ablación por Catéter , Accidente Cerebrovascular , Anciano , Fibrilación Atrial/diagnóstico , Fibrilación Atrial/cirugía , Ablación por Catéter/métodos , Comunicación , Hospitales , Humanos , Medicare , Accidente Cerebrovascular/diagnóstico , Accidente Cerebrovascular/etiología , Accidente Cerebrovascular/prevención & control , Resultado del Tratamiento , Estados UnidosRESUMEN
Although hip arthroscopy has been around for decades, recent developments in the understanding of hip pathology and surgical technique have led to the evolution of how labral pathology is addressed. Femoroacetabular impingement (FAI) is the primary condition that hip arthroscopy can treat and is described as the mechanical conflict between the femoral neck and acetabulum due to bony morphology. As a result, the labrum endures increased stress and is subject to disruption of its biomechanical properties, which leads to tearing, destabilization of the chondral-labral junction, and loss of the suction seal effect of the hip joint. This review provides an overview of current practices in the diagnosis and treatment of labral pathology. The 4 "R"s of labrum management are described: resect, repair, reconstruct, and replace.
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Artroscopía , Pinzamiento Femoroacetabular , Acetábulo/diagnóstico por imagen , Acetábulo/cirugía , Artroscopía/efectos adversos , Pinzamiento Femoroacetabular/diagnóstico por imagen , Pinzamiento Femoroacetabular/cirugía , Articulación de la Cadera/diagnóstico por imagen , Articulación de la Cadera/cirugía , Humanos , RoturaRESUMEN
BACKGROUND: Influenza vaccination is uncommon in low-resource settings. We evaluated aspects of operational feasibility of influenza vaccination programs targeting risk groups in the World Health Organization (WHO) African (AFR) and South-East Asian (SEAR) Regions. METHODS: We estimated routine immunization and influenza vaccination campaign doses, doses per vaccinator, and cold storage requirements for 1 simulated country in each region using evidence-based population distribution, vaccination schedule, and vaccine volumes. Influenza vaccination targeted persons <5 years, pregnant women, persons with chronic diseases, persons ≥65 years, and healthcare workers (HCW). For the AFR country, we compared vaccine volumes to actual storage capacities. RESULTS: Targeting HCW had a small operational impact, and subsequent findings exclude this group. During 3-month influenza vaccination campaigns, monthly doses delivered in the AFR country increased from 15.0% for ≥65 years to 93.1% for <5 years and in the SEAR country from 19.6% for pregnant women to 145.0% for persons with chronic diseases. National-level cold storage capacity requirements increased in the AFR country from 4.1% for ≥65 years to 20.3% for <5 years and in the SEAR country from 3.9% for pregnant women to 28.8% for persons with chronic diseases. Subnational-level cold storage capacity requirements increased in the AFR country from 5.9% for ≥65 years to 36.8% for <5 years and the SEAR country from 17.6% for pregnant women to 56.0% for persons with chronic diseases. CONCLUSIONS: Influenza vaccination of most risk groups will require substantial increases in doses, doses per vaccinator, and cold storage capacity in countries where infrastructure and resources are limited.
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Vacunas contra la Influenza , Gripe Humana , Estudios de Factibilidad , Femenino , Humanos , Programas de Inmunización , Gripe Humana/epidemiología , Gripe Humana/prevención & control , Embarazo , Estaciones del Año , Vacunación , Organización Mundial de la SaludRESUMEN
BACKGROUND: Lymphocytic hypophysitis (LH) is a rare condition that mostly affects women of the reproductive age. Because it is infrequently encountered, it is not often considered as a differential diagnosis of sellar masses. The diagnosis is made clinically with the aid of magnetic resonance imaging (MRI) and should be considered if the patient has endocrine derangements in addition to a sellar mass. CASE DESCRIPTION: A 37-year-old female presents with a complaint of headaches and CT imaging showed a sellar mass. She was also being investigated simultaneously by the endocrine department and was diagnosed with panhypopituitarism. She proceeded to surgery for a presumed pituitary adenoma but histopathology returned as LH. CONCLUSION: It is important to have a wide differential diagnosis when managing pituitary masses. Clinical correlation with atypical MRI findings is useful to determine the diagnosis of LH.
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BACKGROUND: SARS-CoV-2 vaccines will be deployed to countries with limited immunization systems. METHODS: We assessed the effect of deploying SARS-Cov-2 vaccines on cold storage capacity and immunization workload in a simulated WHO African Region country using region-specific data on immunization, population, healthcare workers (HCWs), cold storage capacity (quartile values for national and subnational levels), and characteristics of an approved SARS-CoV-2 vaccine. We calculated monthly increases in vaccine doses, doses per vaccinator, and cold storage volumes for four-month SARS-CoV-2 vaccination campaigns targeting risk groups compared to routine immunization baselines. RESULTS: Administering SARS-CoV-2 vaccines to risk groups would increase total monthly doses by 27.0% for ≥ 65 years, 91.7% for chronic diseases patients, and 1.1% for HCWs. Assuming median nurse density estimates adjusted for absenteeism and proportion providing immunization services, SARS-CoV-2 vaccination campaigns would increase total monthly doses per vaccinator by 29.3% for ≥ 65 years, 99.6% for chronic diseases patients, and 1.2% for HCWs. When we applied quartiles of actual African Region country vaccine storage capacity, routine immunization vaccine volumes exceeded national-level storage capacity for at least 75% of countries, but subnational levels had sufficient storage capacity for SARS-CoV-2 vaccines for at least 75% of countries. CONCLUSIONS: In the WHO African Region, SARS-CoV-2 vaccination campaigns would substantially increase doses per vaccinator and cold storage capacity requirements over routine immunization baselines. Pandemic vaccination campaigns would increase storage requirements of national-level stores already at their limits, but sufficient capacity exists at subnational levels. Immediate attention to strengthening immunization systems is essential to support pandemic responses.
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Vacunas contra la COVID-19/administración & dosificación , COVID-19/prevención & control , Programas de Inmunización/organización & administración , Refrigeración , Carga de Trabajo , Adolescente , Adulto , África , Anciano , Niño , Preescolar , Humanos , Persona de Mediana Edad , Vacunación , Organización Mundial de la Salud , Adulto JovenRESUMEN
PURPOSE: To identify clinical and radiographic factors associated with failure of revision hip arthroscopy (RHA). METHODS: A database was used to identify patients who underwent primary hip arthroscopy and revision hip arthroscopy (RHA) from January 2007 to December 2017 for the indication of femoroacetabular impingement and failure of the index procedure, respectively. The primary outcome was defined as the change, or difference, in the preoperative to postoperative alpha angle between patients with successful RHA and those with failed RHA. Failure was defined as reoperation on the operative hip for any indication or a modified Harris Hip Score (mHHS) of less than 70 at the 1-year postoperative time point. All patients had a minimum of 2 years' follow-up from the date of revision hip surgery. Patients with a history of revision were divided into those with failed revisions and those with successful revisions. The inclusion criteria for failed revision included a history of subsequent revision surgery (or arthroplasty) or an mHHS of less than 70 at final follow-up. RESULTS: The study included 26 patients, comprising 8 (31%) with failed RHA and 18 (69%) with successful revision. The failure group showed a significantly smaller decrease in the alpha angle with surgery, measured on the Dunn view, compared with the success group. When the preoperative alpha angle was held constant, each 1° increase in the difference between the preoperative and postoperative alpha angles achieved during surgery was associated with a 17% decrease in the odds of failure. Patients included in the success group had both a higher preoperative mHHS (44.2 ± 8.6 vs 34.7 ± 9.6) and a higher postoperative mHHS (83.2 ± 8.3 vs 62.3 ± 14.2) than patients with failed RHA. There was a statistically significant difference in the frequency of patients who achieved the patient acceptable symptomatic state of +74.0 between the failure (25%) and success (83%) groups; 88% of patients in the failure group met the minimal clinically important difference, whereas 100% of patients in the success group (n = 18) met it. CONCLUSIONS: Complete resection of cam lesions as determined by changes in the alpha angle, anterior offset, and head-neck ratio when measured on the Dunn 45° view correlates with positive clinical outcomes after RHA. LEVEL OF EVIDENCE: III, Retrospective Comparative Study.
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T cells have a unique capability to eliminate cancer cells and fight malignancies. Cancer cells have adopted multiple immune evasion mechanisms aimed at inhibiting T cells. Dramatically improved patient outcomes have been achieved with therapies genetically reprogramming T cells, blocking T-cell inhibition by cancer cells, or transiently connecting T cells with cancer cells for redirected lysis. This last modality is based on antibody constructs that bind a surface antigen on cancer cells and an invariant component of the T-cell receptor. Although high response rates were observed with T-cell engagers specific for CD19, CD20, or BCMA in patients with hematologic cancers, the treatment of solid tumors has been less successful. Here, we developed and characterized a novel T-cell engager format, called TriTAC (for Trispecific T-cell Activating Construct). TriTACs are engineered with features to improve patient safety and solid tumor activity, including high stability, small size, flexible linkers, long serum half-life, and highly specific and potent redirected lysis. The present study establishes the structure/activity relationship of TriTACs and describes the development of HPN424, a PSMA- (FOLH1-) targeting TriTAC in clinical development for patients with metastatic castration-resistant prostate cancer.
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Antineoplásicos/uso terapéutico , Neoplasias/tratamiento farmacológico , Linfocitos T/metabolismo , Albúminas/farmacología , Animales , Antineoplásicos/sangre , Antineoplásicos/farmacocinética , Antineoplásicos/farmacología , Complejo CD3/metabolismo , Muerte Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Semivida , Humanos , Activación de Linfocitos/efectos de los fármacos , Activación de Linfocitos/inmunología , Macaca fascicularis , Ratones Endogámicos NOD , Ratones SCID , Neoplasias/patología , Antígeno Prostático Específico/metabolismo , Linfocitos T/efectos de los fármacosRESUMEN
BACKGROUND: When available, SARS-CoV-2 vaccines will be deployed to countries with limited immunization systems. METHODS: We conducted an immunization capacity assessment of a simulated WHO African Region country using region-specific data on immunization, population, healthcare workers (HCWs), vaccine cold storage capacity (quartile values for national and subnational levels), and characteristics of influenza vaccines to represent future SARS-CoV-2 vaccines. We calculated monthly increases in vaccine doses, doses per vaccinator, and cold storage volumes for four-month SARS-CoV-2 vaccination campaigns targeting risk groups compared to routine immunization baselines. FINDINGS: Administering SARS-CoV-2 vaccines to risk groups would increase total monthly doses by 27.0% for ≥65 years, 91.7% for chronic diseases patients, and 1.1% for HCWs. Assuming median nurse density estimates adjusted for absenteeism and proportion providing immunization services, SARS-CoV-2 vaccination campaigns would increase total monthly doses per vaccinator by 29.3% for ≥65 years, 99.6% for chronic diseases patients, and 1.2% for HCWs. When we applied quartiles of actual African Region country vaccine storage capacity, routine immunization vaccine volumes exceeded national-level storage capacity for at least 75% of countries, but subnational levels had sufficient storage capacity for SARS-CoV-2 vaccines for at least 75% of countries. INTERPRETATION: In the WHO African Region, SARS-CoV-2 vaccination campaigns would substantially increase doses per vaccinator and cold chain capacity requirements over routine immunization baselines. Pandemic vaccination campaigns would add volume to national-level stores already at their limits, but sufficient capacity exists at subnational levels. Immediate attention to strengthening immunization systems is essential to support pandemic responses. FUNDING: None.
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Diffuse large B-cell lymphoma (DLBCL) patients are typically treated with immunochemotherapy containing rituximab (rituximab, cyclophosphamide, hydroxydaunorubicin-vincristine (Oncovin), and prednisone [R-CHOP]); however, prognosis is extremely poor if R-CHOP fails. To identify genetic mechanisms contributing to primary or acquired R-CHOP resistance, we performed target-panel sequencing of 135 relapsed/refractory DLBCLs (rrDLBCLs), primarily comprising circulating tumor DNA from patients on clinical trials. Comparison with a metacohort of 1670 diagnostic DLBCLs identified 6 genes significantly enriched for mutations upon relapse. TP53 and KMT2D were mutated in the majority of rrDLBCLs, and these mutations remained clonally persistent throughout treatment in paired diagnostic-relapse samples, suggesting a role in primary treatment resistance. Nonsense and missense mutations affecting MS4A1, which encodes CD20, are exceedingly rare in diagnostic samples but show recurrent patterns of clonal expansion following rituximab-based therapy. MS4A1 missense mutations within the transmembrane domains lead to loss of CD20 in vitro, and patient tumors harboring these mutations lacked CD20 protein expression. In a time series from a patient treated with multiple rounds of therapy, tumor heterogeneity and minor MS4A1-harboring subclones contributed to rapid disease recurrence, with MS4A1 mutations as founding events for these subclones. TP53 and KMT2D mutation status, in combination with other prognostic factors, may be used to identify high-risk patients prior to R-CHOP for posttreatment monitoring. Using liquid biopsies, we show the potential to identify tumors with loss of CD20 surface expression stemming from MS4A1 mutations. Implementation of noninvasive assays to detect such features of acquired treatment resistance may allow timely transition to more effective treatment regimens.
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Protocolos de Quimioterapia Combinada Antineoplásica , Linfoma de Células B Grandes Difuso , Anticuerpos Monoclonales de Origen Murino , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Humanos , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Linfoma de Células B Grandes Difuso/genética , Recurrencia Local de Neoplasia/tratamiento farmacológico , Recurrencia Local de Neoplasia/genética , Rituximab/uso terapéuticoRESUMEN
Treatment of hormone sensitive breast cancer tumors with endocrine therapy such as antiestrogens or aromatase inhibitors has improved the outcome significantly. Studies including our own have shown that downregulation of ERα with pure antiestrogen fulvestrant in combination with aromatase inhibitors may prolong responsiveness of the tumors to endocrine therapy. Fulvestrant has been studied as second line or first line treatment for post-menopausal hormone receptor positive breast cancers as a single agent or in combination with AIs. Studies have also suggested that further escalation of dose may improve benefit. However, dose escalation of fulvestrant, which is administered via intramuscular injection, is difficult due to its poor solubility. To overcome this shortcoming of an injectable drug, a novel orally active antiestrogen, AZD9496 was developed. In addition to being orally active, AZD9496 is designed as a selective ERα downregulator (SERD). In the current study, we compared the effect of AZD9496 and fulvestrant on the growth of MCF-7Ca (human estrogen receptor positive MCF-7 cells stably transfected with human placental aromatase gene) xenografts grown in ovariectomized athymic nude mice. AZD9496 was also compared to fulvestrant in vitro as a single agent or in combination with anastrozole. Our current study shows that AZD9496 is equally effective as fulvestrant at controlling the growth of hormone sensitive human breast cancer tumors. Similar to fulvestrant, AZD9496 inhibits cellular aromatase activity through ERα mediated signaling. However, unlike fulvestrant, combination of AZD9496 with anastrozole did not produce increased tumor inhibition. Our results show that AZD9496 was significantly better at inhibiting cellular aromatase which contributed to its anticancer activity. Next, we measured the effect of AZD9496 on the mouse uterus. Uterine weight of mice treated with AZD9496 was significantly lower than that for mice treated with androstenedione. This reduction in uterine weight was due to AZD9496 mediated inhibition of aromatase activity and not a direct effect on uterine ERα expression. We also observed that anti-cancer efficacy of AZD9496 depended on its ability to inhibit cellular aromatase. These results suggest that AZD9496 may be a better alternative to fulvestrant due to its selectivity for mammary ER and ability to inhibit aromatase in addition of downregulating ERα that can be obtained upon oral administration. As such, AZD9496 may prove to be a better option than fulvestrant for the treatment of hormone sensitive human breast cancer.
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Inhibidores de la Aromatasa/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Cinamatos/uso terapéutico , Indoles/uso terapéutico , Neoplasias Mamarias Experimentales/tratamiento farmacológico , Moduladores Selectivos de los Receptores de Estrógeno/uso terapéutico , Anastrozol/farmacología , Anastrozol/uso terapéutico , Animales , Antineoplásicos Hormonales/farmacología , Antineoplásicos Hormonales/uso terapéutico , Aromatasa/metabolismo , Inhibidores de la Aromatasa/farmacología , Neoplasias de la Mama/metabolismo , Línea Celular Tumoral , Cinamatos/farmacología , Antagonistas del Receptor de Estrógeno/farmacología , Antagonistas del Receptor de Estrógeno/uso terapéutico , Receptor alfa de Estrógeno , Femenino , Fulvestrant/farmacología , Fulvestrant/uso terapéutico , Humanos , Indoles/farmacología , Neoplasias Mamarias Experimentales/metabolismo , Ratones Desnudos , Posmenopausia , Moduladores Selectivos de los Receptores de Estrógeno/farmacologíaRESUMEN
Dysregulation of CDK8 (Cyclin-Dependent Kinase 8) and its regulatory partner CycC (Cyclin C), two subunits of the conserved Mediator (MED) complex, have been linked to diverse human diseases such as cancer. Thus, it is essential to understand the regulatory network modulating the CDK8-CycC complex in both normal development and tumorigenesis. To identify upstream regulators or downstream effectors of CDK8, we performed a dominant modifier genetic screen in Drosophila based on the defects in vein patterning caused by specific depletion or overexpression of CDK8 or CycC in developing wing imaginal discs. We identified 26 genomic loci whose haploinsufficiency can modify these CDK8- or CycC-specific phenotypes. Further analysis of two overlapping deficiency lines and mutant alleles led us to identify genetic interactions between the CDK8-CycC pair and the components of the Decapentaplegic (Dpp, the Drosophila homolog of TGFß, or Transforming Growth Factor-ß) signaling pathway. We observed that CDK8-CycC positively regulates transcription activated by Mad (Mothers against dpp), the primary transcription factor downstream of the Dpp/TGFß signaling pathway. CDK8 can directly interact with Mad in vitro through the linker region between the DNA-binding MH1 (Mad homology 1) domain and the carboxy terminal MH2 (Mad homology 2) transactivation domain. Besides CDK8 and CycC, further analyses of other subunits of the MED complex have revealed six additional subunits that are required for Mad-dependent transcription in the wing discs: Med12, Med13, Med15, Med23, Med24, and Med31. Furthermore, our analyses confirmed the positive roles of CDK9 and Yorkie in regulating Mad-dependent gene expression in vivo. These results suggest that CDK8 and CycC, together with a few other subunits of the MED complex, may coordinate with other transcription cofactors in regulating Mad-dependent transcription during wing development in Drosophila.
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Ciclina C/genética , Quinasa 8 Dependiente de Ciclina/genética , Proteínas de Unión al ADN/metabolismo , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Factores de Transcripción/metabolismo , Animales , Ciclina C/metabolismo , Quinasa 8 Dependiente de Ciclina/metabolismo , Drosophila , Regulación del Desarrollo de la Expresión Génica , Haploinsuficiencia , Discos Imaginales/crecimiento & desarrollo , Discos Imaginales/metabolismo , Transducción de Señal , Transcripción GenéticaRESUMEN
BACKGROUND: Dilute povidone-iodine lavage has been shown to be safe and effective in decreasing acute periprosthetic joint infection (PJI) following total joint arthroplasty (TJA). Vancomycin powder is reported to be effective in preventing infection in spine surgery. We hypothesize that a "vanco-povidone protocol" (VIP) for TJA patients at high risk for infection is safe and will decrease the rate of PJI. METHODS: High-risk TJA patients (body mass index >40, active smokers, American Society of Anesthesiologists ≥3, immunosuppression/diabetes, methicillin-resistant Staphylococcus aureus colonization, revision surgery) utilizing VIP were compared to a high-risk historical cohort not treated with VIP, at a single institution. VIP consisted of dilute povidone-iodine lavage followed by application of vancomycin powder prior to wound closure. Primary endpoint was PJI within 3 months postoperatively. RESULTS: The historical, high-risk control cohort consisted of 3251 patients with a PJI incidence of 1.8%. A total of 1413 subjects received the VIP protocol with a PJI incidence of 1.3%. There was a 27.8% risk reduction when compared to the control group of high-risk subjects not treated with the VIP. There were no medical complications secondary to the use of VIP, no increase in vancomycin-resistant enterococcus or vancomycin-resistant Staph aureus, and no cases of acute renal impairment secondary to application of the local vancomycin. CONCLUSIONS: PJI remains a common complication of TJA, especially in high-risk populations. This study indicates that a protocol of dilute povidone-iodine lavage combined with topical vancomycin powder is safe and may reduce PJI incidence in high-risk TJA patients. Due to low, current PJI rates, a multi-institutional randomized controlled trial is necessary to assess interventions that minimize the risk of PJI. LEVEL OF EVIDENCE: Retrospective Observational Cohort.
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Staphylococcus aureus Resistente a Meticilina , Infecciones Relacionadas con Prótesis , Humanos , Povidona Yodada , Polvos , Infecciones Relacionadas con Prótesis/epidemiología , Infecciones Relacionadas con Prótesis/prevención & control , Estudios Retrospectivos , Irrigación Terapéutica , VancomicinaRESUMEN
Paralleling the activation of dorsal horn microglia after peripheral nerve injury is a significant expansion and proliferation of macrophages around injured sensory neurons in dorsal root ganglia (DRG). Here we demonstrate a critical contribution of DRG macrophages, but not those at the nerve injury site, to both the initiation and maintenance of the mechanical hypersensitivity that characterizes the neuropathic pain phenotype. In contrast to the reported sexual dimorphism in the microglial contribution to neuropathic pain, depletion of DRG macrophages reduces nerve injury-induced mechanical hypersensitivity and expansion of DRG macrophages in both male and female mice. However, fewer macrophages are induced in the female mice and deletion of colony-stimulating factor 1 from sensory neurons, which prevents nerve injury-induced microglial activation and proliferation, only reduces macrophage expansion in male mice. Finally, we demonstrate molecular cross-talk between axotomized sensory neurons and macrophages, revealing potential peripheral DRG targets for neuropathic pain management.
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Ganglios Espinales/inmunología , Macrófagos/fisiología , Neuralgia/inmunología , Animales , Comunicación Celular , Proliferación Celular/efectos de los fármacos , Femenino , Hiperalgesia/inmunología , Inmunosupresores/farmacología , Factor Estimulante de Colonias de Macrófagos/genética , Factor Estimulante de Colonias de Macrófagos/metabolismo , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Mutantes , Microglía/metabolismo , Microglía/fisiología , Traumatismos de los Nervios Periféricos/inmunología , Embarazo , Células Receptoras Sensoriales/metabolismo , Factores Sexuales , Tacrolimus/análogos & derivados , Tacrolimus/farmacologíaRESUMEN
BACKGROUND: Perioperative pain management for patients undergoing total knee arthroplasty (TKA) improves patient outcomes and facilitates recovery. In this study, we compared the effects of preoperative oral acetaminophen vs intravenous (IV) acetaminophen administered once intraoperatively and once postoperatively. METHODS: Two standardized, multimodal analgesia protocols were compared in patients undergoing primary, unilateral TKA. The oral acetaminophen cohort (OA) received doses of oral acetaminophen preoperatively and an as-needed basis postoperatively (n = 698). The IV acetaminophen cohort (IA) received 2 doses of IV acetaminophen, one intraoperative and one 6 hours postoperatively, with no oral acetaminophen given (n = 318). No other variables were significantly changed during the study period. RESULTS: The IV acetaminophen group demonstrated less narcotic usage on postoperative day 0 (OA: 13.3 mme [morphine mg equivalents], IA: 6.2 mme, P < .001) and overall usage (OA: 66.1 mme, IA: 48.5 mme, P < .001). Pain scores were statistically and clinically significantly decreased in the immediate postoperative (the first 8 hours) for the IA group (OA: patient-reported pain scores of 4.0; IA: patient-reported pain scores of 2.0, P < .001). Both groups progressed and completed their physical therapy similarly for each postoperative day. Length of stay and percent discharge home were slightly improved in the IA group as well, however did not reach statistical difference. CONCLUSION: An iterative approach to multimodal pain management after TKA led to improvements in narcotic usage, pain scores, and several quality measures. IV acetaminophen is an integral and effective part of our opioid-sparing multimodal pain regimen in TKA.
Asunto(s)
Analgésicos no Narcóticos , Artroplastia de Reemplazo de Rodilla , Acetaminofén , Analgésicos Opioides , Artroplastia de Reemplazo de Rodilla/efectos adversos , Humanos , Manejo del Dolor , Dolor Postoperatorio/tratamiento farmacológico , Dolor Postoperatorio/prevención & controlRESUMEN
BACKGROUND: Reducing intraoperative wound contamination is a critical preventive strategy for reducing the risk of prosthetic joint infection in shoulder arthroplasty. The aim of this study was to investigate the potential microbial colonization of subscapularis tagging sutures during shoulder arthroplasty. METHODS: In this prospective study, 50 consecutive patients undergoing primary shoulder arthroplasty (anatomic or reverse) were enrolled. Patients with revision shoulder arthroplasty and proximal humeral fractures were excluded. Nonabsorbable, braided tagging sutures were placed through the subscapularis tendon prior to tenotomy. A similar nonabsorbable, braided suture (control) was placed in a sterile container on the back table, open to the operating room environment. Subscapularis tagging sutures (experimental specimens) and control sutures were collected prior to subscapularis tenotomy repair and submitted for aerobic and anaerobic cultures. Cultures were held for 21 days to account for extended growth of slow-growing bacteria. RESULTS: A total of 12 of 50 experimental and 16 of 50 control sutures had positive cultures. Staphylococcus epidermidis and Cutibacterium acnes were the 2 most commonly isolated organisms. Active tobacco use (P = .038) and procedure length (P = .03) were significantly associated with positive cultures. No significant association between positive subscapularis tagging suture cultures and positive control cultures was found (P = .551). Patient age, sex, body mass index, and significant medical comorbidities were not significantly associated with positive cultures. DISCUSSION: Subscapularis tagging sutures are a potential source of microbial contaminant in shoulder arthroplasty, and we recommend exchanging the tagging suture with a suture opened immediately prior to subscapularis repair.
Asunto(s)
Artroplastía de Reemplazo de Hombro/efectos adversos , Infecciones Relacionadas con Prótesis/prevención & control , Suturas/microbiología , Anciano , Artroplastía de Reemplazo de Hombro/instrumentación , Femenino , Humanos , Masculino , Persona de Mediana Edad , Tempo Operativo , Propionibacterium acnes/aislamiento & purificación , Estudios Prospectivos , Infecciones Relacionadas con Prótesis/microbiología , Factores de Riesgo , Manguito de los Rotadores/cirugía , Staphylococcus epidermidis/aislamiento & purificación , Suturas/efectos adversos , Tenotomía , Uso de TabacoRESUMEN
CASE: We review the case of a 44-year-old man with Camurati-Engelmann disease, who presented with chronic right hip pain that did not improve following intra-articular hip injections. He was functionally debilitated because of the worsening pain. Routine radiographs demonstrated severe right hip osteoarthritis and severe diaphyseal sclerosis of the femur. To address the narrowed medullary cavity, appropriate reaming of the diaphysis and broaching to fill the metaphysis were performed. The patient underwent an uncemented total hip arthroplasty that resulted in an excellent recovery with no complications. CONCLUSION: Uncemented total hip arthroplasty serves as a good option for patients with hip osteoarthritis secondary to Camurati-Engelmann disease. Anticipation of potential operative challenges is the key to avoiding complications and achieving an optimal, durable outcome.