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PURPOSE: Although growth in cosmetic surgery remains constant in the private setting, academic cosmetic surgery practices are often underdeveloped. Our study aims to determine which patient populations access academic cosmetic surgery services. METHODS: The 2018 Health Care Utilization Project Nationwide Ambulatory Surgery Sample database was used for data analysis. Encounters for the following American Society of Plastic Surgery top 5 procedures for 2020 were selected: blepharoplasty, breast augmentation, liposuction, rhinoplasty, and rhytidectomy. Patient encounter data were collected because it relates to median income, geographic location, and primary payer status. RESULTS: The 2018 Nationwide Ambulatory Surgery Sample data set contained 44,078 encounters at academic surgical centers for the procedures listed previously. Low-income patients account for 13.7% of academic cosmetic surgery encounters compared with 37.9% for high-income patients. Breast augmentation rates are higher among low-income patients (20.5% vs 17.2%, P < 0.001), and high-income patients undergo rhytidectomy more frequently (5.7% vs 3.0%, P < 0.001). In the academic setting, patients from large metropolitan areas encompass the majority of cosmetic encounters (71.0%), and these patients are more likely to proceed with rhinoplasty, rhytidectomy, and liposuction procedures (P < 0.001). Patients from smaller metropolitan areas undergo blepharoplasty more frequently compared with those from larger metropolitan areas (56.4% vs 41.8%, P < 0.001). Self-pay and privately insured patients comprise the majority of academic cosmetic surgery encounters (40.8% and 29.9%, respectively). Eighty-eight percent of Medicare patients within this cohort underwent blepharoplasty, whereas self-pay patients accessed breast augmentation, liposuction, and rhytidectomy more often than other insured patients. CONCLUSIONS: Income status, patient location, and primary payer status play an important role in academic cosmetic surgery access rates and procedure preferences. Academic cosmetic practices can use these insights to tailor their services to the populations they serve.
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Blefaroplastia , Mamoplastia , Rinoplastia , Cirurgia Plástica , Idoso , Humanos , Medicare , Estados UnidosRESUMO
BACKGROUND: The purposes of this study were to compare applicant statistics to resident physician demographics among several surgical subspecialties (SSSs), to identify trends of gender and underrepresented minorities in medicine (UIM), and to evaluate current diversity among these specialties. METHODS: Graduate medical education reports from 2009 to 2019 were queried to determine trends among programs. Further identification of gender and UIM statistics was obtained in 4 several SSSs: integrated plastic surgery, orthopedic surgery (OS), otolaryngology surgery (ENT), and neurosurgery (NS). These were compared with Association of American Medical Colleges data of residency applicants for the respective years. RESULTS: Significant differences were seen among gender and UIM(s) of the applicant pool when compared with resident data. All specialties had significantly fewer American Indian and African American residents compared with applicants. Significant differences between applicants and residents were also found among Hispanic, Native Hawaiian, and female demographics. All SSSs had a significant positive trend for the percentage of female residents. Significant differences between specialties were identified among African American, Hispanic, and female residents. Orthopedic surgery and NS had significantly higher percentage of African American residents compared with ENT and integrated plastic surgery. Neurosurgery had significantly higher percentage of Hispanic residents compared with OS and ENT. Integrated plastic surgery and ENT had significantly higher percentage of female residents compared with OS and NS. CONCLUSIONS: There has been significant increase in number of residency programs and resident positions since 2009. However, increase in female residents and UIM(s) among SSSs has not matched the pace of growth.
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Internato e Residência , Médicos , Demografia , Educação de Pós-Graduação em Medicina , Feminino , Humanos , Grupos Minoritários , Estados UnidosRESUMO
INTRODUCTION: Hand surgery fellowships accept applicants from 3 different residencies: general surgery, orthopedic surgery, and plastic surgery. Although all of these specialties culminate into a board-certified hand surgeon, each specialty receives drastically different training in residency, which can have effects on which procedures these surgeons feel comfortable performing in their own practices. This study aims to compare practice patterns and complication rates among hand surgeons by residency training. METHODS: The National Surgical Quality Improvement Program database was queried between the years of 2014 and 2018 for all Current Procedural Terminology codes pertaining to upper-extremity surgical procedures performed below the elbow. Procedures not performed by a general, orthopedic, or plastic surgeon were excluded, as well as polytraumas. Procedures were then stratified by anatomic region, tissue type, and primary specialty of the attending surgeon. Data collected included the number of each procedure, patient complexity, and complications. Statistical analysis consisted of a t test for continuous variables, χ2 analysis for categorical variables, and linear regression analysis to compare complications rates between specialties. RESULTS: A total of 76,980 unique cases were included in our analysis: 4979 (6.4%) at the elbow, 43,680 (56.7%) at the forearm/wrist, 23,284 (30.2%) at the hand, 1421 (1.8%) flaps/grafts, 285 (0.4%) vascular, and 3331 (4.3%) neurological. Orthopedics performed most (79.5%) of the procedures, whereas plastic surgeons and general surgeons performed 17.3% and 3.1%, respectively. There were also significant differences by anatomic location/type of procedure, with orthopedic surgeons performing 99.2% of procedures at the elbow but only 67.7% of procedures at the hand. Linear regression analysis showed general surgeons had the lowest complication rates. CONCLUSIONS: Our data show significant differences in the number of upper-extremity surgeries performed by surgeons from each specialty at different anatomic locations.This could be due to differences in training during residency or proportionately more orthopedic surgeons being "full-time" hand surgeons. These data could affect hiring patterns in hospitals seeking hand surgeons depending on the variety of pathology encountered at that particular institution.
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Internato e Residência , Cirurgiões , Cirurgia Plástica , Mãos/cirurgia , Humanos , Melhoria de Qualidade , Cirurgia Plástica/educaçãoRESUMO
BACKGROUND: Dupuytren contracture (DC) is a common disorder characterized by progressive fibrosis of palmar fascia. This study analyzed cost trends of 3 common treatments for DC: fasciotomy, fasciectomy, and collagenase injection (CI)/cord manipulation. METHODS: The Vizient Clinical Data/Resource Manager electronic database was reviewed for all procedures for the treatment of DC at participating hospitals in the United States (US) from October 1, 2015, to September 1, 2019. Cases were placed into 1 of 3 categories: (1) CI, (2) needle fasciotomy (NF), and (3) open fasciectomy (OF). Total and direct costs were averaged for each procedure and compared nationally and regionally. Temporal trends and specific market share were analyzed. One-tailed t test and Pearson correlation analysis was performed (P < 0.05 and r > 0.9 or r < -0.9 was considered significant). RESULTS: A total of 22,974 total cases were identified. A total of 16,966 OF, 3962 NF, and 2046 CI were performed. There was a nearly a 4-fold increase in number of procedures to treat DC from 2015 to 2018. Market share percentage of each procedure stayed relatively similar over time. However, market share percentage differed between procedures. Needle fasciotomy had the lowest market share percentage approximately 7%. Collagenase injection had the highest average cost at US $4453.66 and was significantly higher than OF at US $3394.90 and NF at US $2010.75. Cost and distribution of procedures were further analyzed by geographic regions. In 2018, 32% of procedures performed were in the Northeastern US, 29% in the Midwestern US, 23% in the Southern US, and 16% in the Western US. Total number of Dupuytren procedures increased more than 300% in all regions across the US from 2015 to 2018. In every region, NF was the lowest cost intervention. Cost of OF and CI varied between regions and was often the most expensive intervention. CONCLUSIONS: Treatment of DCs with NF seems to be the least costly treatment option. Needle fasciotomy seems to be the least commonly performed procedure. Regional data show variations in the cost of OF and CI. However, OF has the majority market share nationally and regionally. Although the cost of these procedures seems to vary regionally, the type of procedures being performed seem to be similar across regions.
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Contratura de Dupuytren , Procedimentos Ortopédicos , Colagenases , Custos e Análise de Custo , Contratura de Dupuytren/cirurgia , Fasciotomia , Humanos , Colagenase Microbiana/uso terapêutico , Agulhas , Resultado do TratamentoRESUMO
BACKGROUND: Complications after microvascular surgery, such as partial flap loss, and arterial/venous compromise cannot only increase morbidity for the patient but also tax the healthcare system. Thrombocytosis, both essential and reactive, can predispose patients to thrombosis and hemorrhage and thus should intuitively have an effect on the outcome of microvascular free tissue transfers. We sought to evaluate the effect of preoperative thrombocytosis on outcomes after microvascular free flap surgery. METHODS: A retrospective review of the 2013-2016 American Collges of Surgeons, National Surgical Quality Improvement Program (ACS NSQIP) database identified 4,299 patients who had microsurgical flaps. Of these 3,744 had preoperative platelet levels recorded. Fifty-four patients had preoperative thrombocytosis, defined as a platelet count >450 K/CUMM, while 3,690 did not. The groups were compared; demographics, comorbidities, and smoking status were recorded. We then examined outcomes between groups including average operative time, length of hospital stay, need for transfusion, deep vein thrombosis (DVT) postoperatively, and need for reoperation. RESULTS: When comparing the two cohorts, there was no statistical difference in comorbidities. We found a significant difference between the thrombocytosis and control cohort in need for transfusion (29.6 vs. 12.8%, p = .0002), average days till discharge (8.36 vs. 5.75, p = .009), and need for reoperation (27.8 vs. 13.8%, p = .003). There was no difference in DVT occurrence (0 vs. 0.1%, p = .46) or average operation time (535 m vs. 482 min, p = .088). CONCLUSION: Patients with thrombocytosis undergoing microvascular free flaps are at increased risk for complications, including the need for a blood transfusion, prolonged hospital stays, and reoperation.
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Microcirurgia , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/etiologia , Trombocitose/complicações , Procedimentos Cirúrgicos Vasculares/métodos , Adulto , Análise de Dados , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias/prevenção & controle , Melhoria de Qualidade , Estudos Retrospectivos , Resultado do Tratamento , Estados UnidosRESUMO
PURPOSE: Orbital trauma, particularly with open globe injury, can have a wide range of visual outcomes, which can be difficult to predict at presentation. Clinical features on presentation may provide insight into visual prognosis. We hypothesized that patients with open globe injuries and concomitant orbital fractures have poorer visual outcomes than patients without orbital fractures. METHODS: We reviewed the charts of 77 patients with isolated open globe injuries (OG) and 76 patients with open globe injuries and concomitant orbital fractures (OGOF). Multivariate regression analysis was performed to assess the relative influence of individual presenting historical and clinical features on visual outcome. RESULTS: OGOF patients were more likely to have sustained blunt trauma than a sharp, penetrating injury compared to OG patients. Ocular wound locations were more posterior and likely to involve multiple zones in OGOF compared to OG patients. Among OGOF patients, orbital floor fractures were the most common and roof fractures were the least common, but the latter was associated with presenting NLP vision and multiple zone involvement. The presence of an orbital fracture independently increased the odds of subsequent evisceration/enucleation (OR: 4.6, 95% CI 1.3-20.1, p = .0246) and NLP vision (OR: 6.81, 95% CI 2.42-21.85, p = .0005) when controlling for zone, mechanism of injury, uveal prolapse and demographic variables. CONCLUSIONS: The presence of an orbital fracture independently confers a worse visual and ocular prognosis in patients with open globe injuries. Patients with open globe injuries in this category should be appropriately counseled.
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Ferimentos Oculares Penetrantes/fisiopatologia , Fraturas Orbitárias/fisiopatologia , Transtornos da Visão/fisiopatologia , Acuidade Visual/fisiologia , Adulto , Idoso , Enucleação Ocular , Evisceração do Olho , Ferimentos Oculares Penetrantes/diagnóstico por imagem , Ferimentos Oculares Penetrantes/cirurgia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fraturas Orbitárias/diagnóstico por imagem , Fraturas Orbitárias/cirurgia , Prognóstico , Estudos Retrospectivos , Tomografia Computadorizada por Raios X , Ultrassonografia , Adulto JovemRESUMO
BACKGROUND: The purpose of our study was to determine the incidence and average cost of nerve injuries in patients presenting with upper extremity trauma. METHODS: The Nationwide Emergency Department Sample database was queried using International Classification of Diseases, Ninth Revision codes specific to peripheral nerve injuries of the upper extremity. Data on the incidence, patient demographics, average number of associated diagnoses, Injury Severity Scale (ISS) score, mechanism of injury, and average cost of care were collected and analyzed. RESULTS: Of 1.58 million upper extremity traumatic injuries, there were 5244 nerve injuries, resulting in an annual incidence of 16.9 per 100,000 persons with an average age of 38.42 years. Ulnar nerve injuries were the most common (3.86 per 100,000) followed by digital nerve (2.96 per 100,000), radial nerve (2.90 per 100,000), and median nerve (2.01 per 100,000). Injuries to the brachial plexus had the highest average ISS score (9.79 ± 0.71) and number of presenting diagnoses (8.85 ± 0.61) while having a lower than average emergency department (ED) cost. Patients with digital nerve injuries had the highest average ED cost ($8931.01 ± $847.03), whereas their ISS score (2.82 ± 0.19) and number of presenting diagnoses (4.92 ± 0.22) were the lowest. The most commonly reported mechanism of injury in this study population was from a laceration (29.2%) followed by blunt injury, fall (14.8%), and being struck (7.20%). Males were 2.14 (2.01-2.28) times more likely to have an injury to an upper extremity nerve and 3.25 (2.79-3.79) times more likely to injure a digital nerve. CONCLUSIONS: While there was a low incidence of upper extremity nerve injuries associated with upper extremity trauma, the ulnar nerve was most frequently injured. Males were twice as likely to sustain a traumatic upper extremity nerve injury, with laceration being the most common mechanism of injury. The average ED cost associated with upper extremity nerve injuries in the United States was determined to be approximately $5779.
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Traumatismos do Braço/epidemiologia , Traumatismos dos Nervos Periféricos/epidemiologia , Extremidade Superior/lesões , Adolescente , Adulto , Fatores Etários , Plexo Braquial/lesões , Bases de Dados Factuais , Serviço Hospitalar de Emergência , Feminino , Custos Hospitalares , Humanos , Incidência , Escala de Gravidade do Ferimento , Masculino , Pessoa de Meia-Idade , Traumatismos dos Nervos Periféricos/diagnóstico , Traumatismos dos Nervos Periféricos/economia , Estudos Retrospectivos , Medição de Risco , Fatores Sexuais , Nervo Ulnar/lesões , Estados Unidos , Extremidade Superior/inervaçãoRESUMO
BACKGROUND AND PURPOSE: Elevation of intracellular calcium was traditionally thought to be detrimental in stroke pathology. However, clinical trials testing treatments that block calcium signaling have failed to improve outcomes in ischemic stroke. Emerging data suggest that calcium may also trigger endogenous protective pathways after stroke. Calcium/calmodulin-dependent protein kinase kinase (CaMKK) is a major kinase activated by rising intracellular calcium. Compelling evidence has suggested that CaMKK and its downstream kinase CaMK IV are critical in neuronal survival when cells are under ischemic stress. We examined the functional role of CaMKK/CaMK IV signaling in stroke. METHODS: We used a middle cerebral artery occlusion model in mice. RESULTS: Our data demonstrated that pharmacological and genetic inhibition of CaMKK aggravated stroke injury. Additionally, deletion of CaMKK ß, one of the 2 CaMKK isoforms, reduced CaMK IV activation, and CaMK IV deletion in mice worsened stroke outcome. Finally, CaMKK ß or CaMK IV knockout mice had exacerbated blood-brain barrier disruption evidenced by increased hemorrhagic transformation and activation of matrix metalloproteinase. We observed transcriptional inactivation including reduced levels of histone deacetylase 4 phosphorylation in mice with CaMKK ß or CaMK IV deletion after stroke. CONCLUSIONS: Our data have established that the CaMKK/CaMK IV pathway is a key endogenous protective mechanism in ischemia. Our results suggest that this pathway serves as an important regulator of blood-brain barrier integrity and transcriptional activation of neuroprotective molecules in stroke.
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Barreira Hematoencefálica/metabolismo , Isquemia Encefálica/metabolismo , Sinalização do Cálcio/fisiologia , Quinase da Proteína Quinase Dependente de Cálcio-Calmodulina/antagonistas & inibidores , Proteína Quinase Tipo 4 Dependente de Cálcio-Calmodulina/antagonistas & inibidores , Cálcio/fisiologia , Animais , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/enzimologia , Isquemia Encefálica/enzimologia , Isquemia Encefálica/etiologia , Quinase da Proteína Quinase Dependente de Cálcio-Calmodulina/metabolismo , Proteína Quinase Tipo 4 Dependente de Cálcio-Calmodulina/metabolismo , Modelos Animais de Doenças , Infarto da Artéria Cerebral Média/enzimologia , Infarto da Artéria Cerebral Média/etiologia , Infarto da Artéria Cerebral Média/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Vias Neurais/enzimologia , Vias Neurais/metabolismo , Vias Neurais/patologiaRESUMO
Social isolation (SI) is increasingly recognized as a risk factor for stroke. Individuals with lack of social support systems have an increased incidence of stroke, poorer recovery, and greater functional decline after injury compared to individuals with social support. Attesting to the importance of social factors in stroke outcome is that these same effects can be reproducibly demonstrated in animals; social interaction improves behavioral deficits and reduces damage after experimental stroke, whereas SI enhances injury. The mechanism by which SI exacerbates injury is unclear. We investigated the role of nuclear factor-kappaB (NF-κB) signaling in male mice that were pair housed (PH) with an ovariectomized female prior to random assignment into continued PH or SI for 7 days prior to middle cerebral artery occlusion. The effects of SI on infarct volume and functional recovery were assessed at 72 h post-stroke. Nuclear NF-κB levels and activity were assessed by Western blot and transcriptional assays. SI significantly exacerbated infarct size in both male and female mice compared to PH mice. SI mice had delayed functional recovery compared to PH mice. An elevation of systemic IL-6 levels, increased nuclear NF-κB transcriptional activity, and enhanced nuclear translocation of NF-κB was seen in SI stroke animals. Interference with NF-κB signaling using either a pharmacological inhibitor or genetically engineered NF-κB p50 knockout mice abolished the detrimental effects of SI on both infarct size and functional recovery. This suggests that NF-κB mediates the detrimental effects of SI.
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Comportamento Animal/fisiologia , Isquemia Encefálica/metabolismo , Encéfalo/metabolismo , NF-kappa B/metabolismo , Isolamento Social , Acidente Vascular Cerebral/metabolismo , Animais , Comportamento Animal/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Encéfalo/fisiopatologia , Isquemia Encefálica/patologia , Isquemia Encefálica/fisiopatologia , Feminino , Interleucina-6/sangue , Masculino , Camundongos , Camundongos Knockout , Atividade Motora/efeitos dos fármacos , Atividade Motora/fisiologia , NF-kappa B/antagonistas & inibidores , NF-kappa B/genética , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/patologia , Pirrolidinas/farmacologia , Recuperação de Função Fisiológica/efeitos dos fármacos , Recuperação de Função Fisiológica/fisiologia , Transdução de Sinais/efeitos dos fármacos , Acidente Vascular Cerebral/patologia , Acidente Vascular Cerebral/fisiopatologia , Tiocarbamatos/farmacologiaRESUMO
INTRODUCTION: Cosmetic surgery and other elective noninvasive aesthetic procedures have become significantly more popular throughout the 21st century. As these procedures have grown in popularity, more and more Americans have begun to research potential procedures via social media. However, it is unclear whether plastic surgery practices have done an adequate job advertising these services via social media to men. MATERIALS AND METHODS: A systematic search was conducted Google, Facebook, and Instagram in order to examine potential gender disparities in social media plastic surgery marketing in America. Each practice's Facebook and Instagram profile were analyzed in two separate fashions: the presence or absence of advertisement for male services in the last ten posts, and the proportion of specific procedures advertised.. Two Pearson chi-squared analyses comparing the statistical significance of differences in the Facebook and Instagram data were then performed. RESULTS: A total of 242 Facebook and 231 Instagram profiles were selected and subsequently analyzed. The number of both Facebook and Instagram profiles that advertised to male patients varied widely from state to state. Additionally, there was substantial disparity in the procedures most heavily marketed toward men and their actual popularity amongst the male demographic. CONCLUSIONS: Plastic surgery practices have not done an effective job in capitalizing upon the increased popularity of cosmetic procedures among men with their social media advertising. Although the industry has improved its presence on Instagram, the marketing efforts of plastic surgery practices geared toward capturing the interest and demand of the male demographic remain lacking.
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Cosméticos , Procedimentos de Cirurgia Plástica , Mídias Sociais , Cirurgia Plástica , Humanos , Masculino , Marketing , Marketing de Serviços de Saúde/métodos , Marketing Social , Cirurgia Plástica/métodos , Estados UnidosRESUMO
BACKGROUND: Work-related musculoskeletal disorders in surgeons have been well documented. Hand surgeons, however, represent a unique population of surgical subspecialists due to frequent use of operative magnification. Thus, we aim to examine the contributing factors, types, and frequencies of work-related musculoskeletal injuries experienced by hand surgeons. METHODS: A Research Electronic Data Capture survey including 12 demographic and 13 Nordic Musculoskeletal Injury Questionnaire questions was emailed twice to all active members of the American Association for Hand Surgery (AAHS). Data collection remained open for 30 days. RESULTS: Ninety-six of 1228 AAHS members (8%) responded. Respondents were predominantly attendings (88, 91.7%), male (67, 69.8%), in academic practice (48, 50%), and in the age range of 35 to 44 years (34, 35.4%). Sixty-nine respondents (71.9%) attribute discomfort to their profession. Pain (56, 82.4%) and stiffness (46, 67.6%) were the most frequent symptoms, most common in the neck and wrist/hand regions. Fifty-nine (61.5%) respondents had acute (<1 week) discomfort, with onset most frequently reported after surgery (45, 48.9%). Thirty-two (34.8%) of the respondents state they worry these symptoms will hinder their ability to perform surgery in future. Sixteen (16.7%) respondents sustained a musculoskeletal injury directly related to work. Exercise was the most popular nonmedical therapy, while over-the-counter medications were the most popular medical therapy. CONCLUSION: The unique ergonomics of hand surgery, including frequent use of loupes and microscopes, appear detrimental to the surgeons' health and career longevity. Further research will allow for the development of preventative measures, with the goal of facilitating longer, more productive careers for hand surgeons.
RESUMO
Background: Distal radius fractures (DRFs) are the most common upper extremity fractures with more than 600 000 cases per year in the United States and account for up to 18% of fractures in the geriatric population. The purpose of our study was to identify the influence of age on 30-day postoperative outcomes while adjusting for patient demographics and comorbidities. Methods: The National Surgery Quality Improvement Program database was queried for patients having undergone open reduction internal fixation (ORIF) of DRFs. Current Procedural Terminology codes 25607, 25608, and 25609 between the years 2007 and 2016 were collected and analyzed. Patients were divided into 2 groups: group 1, 18 to 64 years; and group 2, 65 years and older. Patient demographics; preoperative, perioperative, and postoperative variables; and complications were recorded and analyzed. Results: In all, 5894 patients were identified; group 1 consisted of 4056 patients aged <64 years, and group 2 consisted of 1838 patients aged 65 years and older. The total complication rate was 2.7% for all patients, 2.2% for group 1, and 3.4% for group 2. The most common complications included surgical site infection for group 1 and urinary tract infection for group 2. Univariate analysis demonstrated association between age ≥65 years and complication (hazard ratio, 1.55; 95% confidence interval, 1.12-2.14; P = .009). However, after controlling for statistically significant factors, age was not an independent predictor of complications (P = .685). Admission status, American Society of Anesthesiologists classification, operative time, renal failure, and bleeding disorders were independent predictors of 30-day complications across all patients. Conclusion: Our data suggest that patients aged 65 years and older without high-risk comorbidities should be offered ORIF of DRFs as their complication risk remains low.
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Fraturas do Rádio , Adulto , Idoso , Estudos de Coortes , Fixação Interna de Fraturas/efeitos adversos , Humanos , Pessoa de Meia-Idade , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/etiologia , Fraturas do Rádio/epidemiologia , Fraturas do Rádio/etiologia , Fraturas do Rádio/cirurgia , Estudos Retrospectivos , Fatores de Risco , Estados Unidos/epidemiologiaRESUMO
BACKGROUND: Ischemic stroke is a devastating disease, often resulting in death or permanent neurological deficits. EMMPRIN/CD147 is a plasma membrane protein that induces the production of matrix metalloproteinases (MMPs), which contribute to secondary damage after stroke by disrupting the blood brain barrier (BBB) and facilitating peripheral leukocyte infiltration into the brain. RESULTS: CD147 surface expression increased significantly after stroke on infiltrating leukocytes, astrocytes and endothelial cells, but not on resident microglia. Inhibition of CD147 reduced MMP levels, decreased ischemic damage, and improved functional, cognitive and histological outcomes after experimental ischemic stroke in both young and aged mice. In stroke patients, high levels of serum CD147 24 hours after stroke predicted poor functional outcome at 12 months. Brain CD147 levels were correlated with MMP-9 and secondary hemorrhage in post-mortem samples from stroke patients. CONCLUSIONS: Acute inhibition of CD147 decreases levels of MMP-9, limits tissue loss, and improves long-term cognitive outcomes following experimental stroke in aged mice. High serum CD147 correlates with poor outcomes in stroke patients. This study identifies CD147 as a novel, clinically relevant target in ischemic stroke.
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Basigina/metabolismo , AVC Isquêmico/metabolismo , Idoso , Idoso de 80 Anos ou mais , Animais , Astrócitos/metabolismo , Barreira Hematoencefálica/metabolismo , Modelos Animais de Doenças , Células Endoteliais/metabolismo , Feminino , Humanos , Masculino , Metaloproteinase 9 da Matriz/metabolismo , Camundongos , Pessoa de Meia-IdadeRESUMO
OBJECTIVE: Transforming growth factor-ß-activated kinase (TAK1) is a member of the mitogen-activated protein kinase family that plays important roles in apoptosis and inflammatory signaling, both of which are critical components of stroke pathology. TAK1 has recently been identified as a major upstream kinase that phosphorylates and activates adenosine monophosphate-activated protein kinase (AMPK), a major mediator of neuronal injury after experimental cerebral ischemia. We studied the functional role of TAK1 and its mechanistic link with AMPK after stroke. METHODS: Male mice were subjected to transient middle cerebral artery occlusion (MCAO). The TAK1 inhibitor 5Z-7-oxozeaenol was injected either intracerebroventricularly or intraperitoneally at various doses and infarct size and functional outcome after long term survival was assessed. Mice with deletion of the AMPK α2 isoform were utilized to assess the contribution of downstream AMPK signaling to stroke outcomes. Levels of pTAK1, pAMPK, and other TAK1 targets including the pro-apoptotic molecule c-Jun-N-terminal kinase (JNK)/c-Jun and the pro-inflammatory protein cyclooxygenase-2 were also examined. RESULTS: TAK1 is critical in stroke pathology. Delayed treatment with a TAK1 inhibitor reduced infarct size and improved behavioral outcome even when given several hours after stroke onset. This protective effect may be independent of AMPK activation but was associated with a reduction in JNK and c-Jun signaling. CONCLUSIONS: Enhanced TAK1 signaling, via activation of JNK, contributes to cell death in ischemic stroke. TAK1 inhibition is a novel therapeutic approach for stroke as it is neuroprotective with systemic administration, has a delayed therapeutic window, and demonstrates sustained neuroprotective effects.