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BACKGROUND: The best approaches to supplemental oxygen administration during surgery remain unclear, which may contribute to variation in practice. This study aimed to assess determinants of oxygen administration and its variability during surgery. METHODS: Using multivariable linear mixed-effects regression, the study measured the associations between intraoperative fraction of inspired oxygen and patient, procedure, medical center, anesthesiologist, and in-room anesthesia provider factors in surgical cases of 120 min or longer in adult patients who received general anesthesia with tracheal intubation and were admitted to the hospital after surgery between January 2016 and January 2019 at 42 medical centers across the United States participating in the Multicenter Perioperative Outcomes Group data registry. RESULTS: The sample included 367,841 cases (median [25th, 75th] age, 59 [47, 69] yr; 51.1% women; 26.1% treated with nitrous oxide) managed by 3,836 anesthesiologists and 15,381 in-room anesthesia providers. Median (25th, 75th) fraction of inspired oxygen was 0.55 (0.48, 0.61), with 6.9% of cases less than 0.40 and 8.7% greater than 0.90. Numerous patient and procedure factors were statistically associated with increased inspired oxygen, notably advanced American Society of Anesthesiologists classification, heart disease, emergency surgery, and cardiac surgery, but most factors had little clinical significance (less than 1% inspired oxygen change). Overall, patient factors only explained 3.5% (95% CI, 3.5 to 3.5%) of the variability in oxygen administration, and procedure factors 4.4% (95% CI, 4.2 to 4.6%). Anesthesiologist explained 7.7% (95% CI, 7.2 to 8.2%) of the variability in oxygen administration, in-room anesthesia provider 8.1% (95% CI, 7.8 to 8.4%), medical center 23.3% (95% CI, 22.4 to 24.2%), and 53.0% (95% CI, 52.4 to 53.6%) was unexplained. CONCLUSIONS: Among adults undergoing surgery with anesthesia and tracheal intubation, supplemental oxygen administration was variable and appeared arbitrary. Most patient and procedure factors had statistical but minor clinical associations with oxygen administration. Medical center and anesthesia provider explained significantly more variability in oxygen administration than patient or procedure factors.
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Oxigenoterapia , Humanos , Feminino , Masculino , Pessoa de Meia-Idade , Estados Unidos , Estudos Retrospectivos , Idoso , Oxigenoterapia/métodos , Oxigenoterapia/estatística & dados numéricos , Estudos de Coortes , Oxigênio/administração & dosagem , Padrões de Prática Médica/estatística & dados numéricos , Adulto , Intubação Intratraqueal/métodos , Anestesiologistas/estatística & dados numéricos , Anestesia Geral/métodos , Procedimentos Cirúrgicos Operatórios/estatística & dados numéricosRESUMO
Allografts derived from live-birth tissue obtained with donor consent have emerged as an important treatment option for wound and soft tissue repairs. Placental membrane derived from the amniotic sac consists of the amnion and chorion, the latter of which contains the trophoblast layer. For ease of cleaning and processing, these layers are often separated with or without re-lamination and the trophoblast layer is typically discarded, both of which can negatively affect the abundance of native biological factors and make the grafts difficult to handle. Thus, a full-thickness placental membrane that includes a fully-intact decellularized trophoblast layer was developed for homologous clinical use as a protective barrier and scaffold in soft tissue repairs. Here, we demonstrate that this full-thickness placental membrane is effectively decellularized while retaining native extracellular matrix (ECM) scaffold and biological factors, including the full trophoblast layer. Following processing, it is porous, biocompatible, supports cell proliferation in vitro, and retains its biomechanical strength and the ability to pass through a cannula without visible evidence of movement or damage. Finally, it was accepted as a natural scaffold in vivo with evidence of host-cell infiltration, angiogenesis, tissue remodelling, and structural layer retention for up to 10 weeks in a murine subcutaneous implant model.
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Placenta , Humanos , Feminino , Gravidez , Animais , Camundongos , Alicerces Teciduais , Liofilização/métodos , Matriz Extracelular Descelularizada , Cicatrização/fisiologiaRESUMO
INTRODUCTION: Crises like the COVID-19 pandemic create blood product shortages. Patients requiring transfusions are placed at risk and institutions may need to judiciously administer blood during massive blood transfusions protocols (MTP). The purpose of this study is to provide data-driven guidance for the modification of MTP when the blood supply is severely limited. METHODS: This is a retrospective cohort study of 47 Level I and II trauma centers (TC) within a single healthcare system whose patients received MTP from 2017 to 2019. All TC used a unifying MTP protocol for balanced blood product transfusions. The primary outcome was mortality as a function of volume of blood transfused and age. Hemoglobin thresholds and measures of futility were also estimated. Risk-adjusted analyses were performed using multivariable and hierarchical regression to account for confounders and hospital variation. RESULTS: Proposed MTP maximum volume thresholds for three age groupings are as follows: 60 units for ages 16-30 y, 48 units for ages 31-55 y, and 24 units for >55 y. The range of mortality under the transfusion threshold was 30%-36% but doubled to 67-77% when the threshold was exceeded. Hemoglobin concentration differences relative to survival were clinically nonsignificant. Prehospital measures of futility were prehospital cardiac arrest and nonreactive pupils. In hospital risk factors of futility were mid-line shift on brain CT and cardiopulmonary arrest. CONCLUSIONS: Establishing MTP threshold practices under blood shortage conditions, such as the COVID pandemic, could sustain blood availability by following relative thresholds for MTP use according to age groups and key risk factors.
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COVID-19 , Ferimentos e Lesões , Humanos , Estudos Retrospectivos , Pandemias , COVID-19/terapia , Transfusão de Sangue/métodos , Protocolos Clínicos , Centros de TraumatologiaRESUMO
BACKGROUND: There is a lack of literature regarding the most effective timing to initiate physical therapy (PT) among traumatically injured patients. We aim to evaluate the association between early PT/mobilization versus delayed or late PT/mobilization and clinical outcomes of trauma patients. METHODS: A retrospective cohort analysis of an urban level-I trauma center from 2014 to 2019 was performed. Univariate analyses and multivariable logistic regression were performed with significance defined as P < 0.05. RESULTS: A total of 11,937 patients were analyzed. Among patients without a traumatic brain injury (TBI), late PT initiation times were associated with 60% lower odds of being discharged home without services (P < 0.05), significantly increased hospital and ICU length of stay (H-LOS, ICU-LOS) (P < 0.05), and significantly higher odds of complications (VTE, pneumonia, pressure ulcers, ARDS) (P < 0.001). Among patients with a TBI, late PT initiation time had 76% lower odds of being discharged home without services (P < 0.05) and significantly longer H-LOS and ICU-LOS (P < 0.05) however did not experience significantly higher odds of complications (P > 0.05). CONCLUSIONS: Among traumatically injured patients, early PT is associated with decreased odds of complications, shorter H-LOS and ICU-LOS, and a favorable discharge disposition to home without services. Adoption of early PT initiation/mobilization protocols and establishment of prophylactic measures against complications associated with delayed PT is critical to maximize quality of care and trauma patient outcomes. Multi-center prospective studies are needed to ascertain the impact of PT initiation times in greater detail and to minimize trauma patient morbidity.
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Lesões Encefálicas Traumáticas , Centros de Traumatologia , Lesões Encefálicas Traumáticas/complicações , Lesões Encefálicas Traumáticas/terapia , Humanos , Tempo de Internação , Modalidades de Fisioterapia , Estudos RetrospectivosRESUMO
INTRODUCTION: We aim to assess the trends in trauma patient volume, injury characteristics, and facility resource utilization that occurred during four surges in COVID-19 cases. METHODS: A retrospective cohort study of 92 American College of Surgeons (ACS)-verified trauma centers (TCs) in a national hospital system during 4 COVID-19 case surges was performed. Patients who were directly transported to the TC and were an activation or consultation from the emergency department (ED) were included. Trends in injury characteristics, patient demographics & outcomes, and hospital resource utilization were assessed during four COVID-19 case surges and compared to the same dates in 2019. RESULTS: The majority of TCs were within a metropolitan or micropolitan division. During the pandemic, trauma admissions decreased overall, but displayed variable trends during Surges 1-4 and across U.S. regions and TC levels. Patients requiring surgery or blood transfusion increased significantly during Surges 1-3, whereas the proportion of patients requiring plasma and/or platelets increased significantly during Surges 1-2. Patients admitted to the hospital had significantly higher Injury Severity Score (ISS) and mortality as compared to pre-pandemic during Surge 1 and 2. Patients with Medicaid or uninsured increased significantly during the pandemic. Hospital length of stay (LOS) decreased significantly during the pandemic and more trauma patients were discharged home. CONCLUSIONS: Trauma admissions decreased during Surge 1, but increased during Surge 2, 3 and 4. Penetrating injuries and firearm-related injuries increased significantly during the pandemic, patients requiring surgery or packed red blood cells (PRBCs) transfusion increased significantly during Surges 1-3. The number of patients discharged home increased during the pandemic and was accompanied by a decreased hospital length of stay (LOS).
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COVID-19 , Centros de Traumatologia , COVID-19/epidemiologia , Humanos , Escala de Gravidade do Ferimento , Tempo de Internação , Prevalência , Estudos Retrospectivos , Estados Unidos/epidemiologiaRESUMO
INTRODUCTION: Delirium occurs frequently after lung transplantation and is associated with poor clinical outcomes. Significantly prolonged jugular venous congestion (JVC) occurs during off-pump lung transplantation and is thought to impair cerebral perfusion. Our study aimed to test the hypothesis that increased intraoperative JVC is associated with an increased risk of postoperative delirium among lung transplantation recipients. METHODS: This is a retrospective observational cohort study. Adult patients who received off-pump lung transplantation at the Vanderbilt University Medical Center between 2006 and 2016 are included. The magnitude of JVC was calculated by the area under the curve (AUC) of the central venous pressure (CVP) above the threshold of 12 mmHg. Postoperative delirium was assessed by Confusion Assessment Method for the Intensive Care Unit (CAM-ICU) criteria during their ICU stay. Multivariate regression analysis was used to determine the association of intraoperative JVC with postoperative delirium, adjusting for baseline demographics, surgical, and intraoperative characteristics. RESULTS: Thirty-two (23.5%) out of 136 patients developed delirium in the ICU. There was no statistical difference in terms of intraoperative JVC between patients with delirium and those without (4058 ± 6650 vs. 3495 ± 10 151 mmHg min; p = .772). Furthermore, during multivariate regression analysis, JVC was not associated with an increased risk of delirium (odds ratio: 1.03 per 100 mmHg min increase in venous congestion; 95% confidence interval: .31, 3.39; p = .96). CONCLUSIONS: Delirium occurred frequently after off-pump lung transplantation. Although physiologically plausible, the present study did not find an association between increased JVC during off-pump lung transplantation and an increased risk of postoperative delirium.
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Delírio , Delírio do Despertar , Hiperemia , Transplante de Pulmão , Adulto , Humanos , Delírio/etiologia , Delírio do Despertar/complicações , Estudos de Coortes , Hiperemia/complicações , Transplante de Pulmão/efeitos adversos , Unidades de Terapia Intensiva , Fatores de RiscoRESUMO
The activation of 41BB costimulatory signals by agonistic Abs enhances the expansion and function of tumor-infiltrating lymphocytes (TILs) for treating cancer patients with adoptive cell therapy. However, the impact of 41BB agonism is not limited to enhancing the activity of T cells, and the mechanism by which additional activation of this costimulatory axis in tumor-associated myeloid cells is poorly understood. In this study, we describe that the intratumoral administration of 41BB agonistic Abs led to increases in CD8 T cell infiltration followed by tumor regression in murine models. We found that granulocytes and monocytes rapidly replaced macrophages and dendritic cells in tumors following administration of anti-41BB Abs. Overall, myeloid cells from anti-41BB-treated tumors had an improved capacity to stimulate T cells in comparison with control-treated tumors. In human coculture systems, we demonstrated that the agonism of the 41BB-41BBL axis enhanced costimulatory signals and effector functions among APC and autologous TILs. Overall, these findings suggest that the effect of 41BB agonistic Abs are supported by additional costimulatory signals from tumor-associated myeloid cells,v leading to enhanced TIL expansion and function.
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Ligante 4-1BB/agonistas , Antineoplásicos Imunológicos/administração & dosagem , Linfócitos T CD8-Positivos/efeitos dos fármacos , Imunoterapia Adotiva/métodos , Membro 9 da Superfamília de Receptores de Fatores de Necrose Tumoral/agonistas , Ligante 4-1BB/metabolismo , Animais , Linfócitos T CD8-Positivos/imunologia , Proliferação de Células/efeitos dos fármacos , Técnicas de Cocultura , Modelos Animais de Doenças , Feminino , Granulócitos/efeitos dos fármacos , Granulócitos/imunologia , Humanos , Injeções Intralesionais , Ativação Linfocitária/efeitos dos fármacos , Linfócitos do Interstício Tumoral/efeitos dos fármacos , Linfócitos do Interstício Tumoral/imunologia , Camundongos , Monócitos/efeitos dos fármacos , Monócitos/imunologia , Neoplasias/imunologia , Neoplasias/patologia , Cultura Primária de Células , Células Tumorais Cultivadas , Membro 9 da Superfamília de Receptores de Fatores de Necrose Tumoral/metabolismoRESUMO
OBJECTIVES: To determine the incidence and predictive factors of acute kidney injury (AKI) after off-pump lung transplantation. DESIGN: A retrospective cohort study. SETTING: The operating room and intensive care unit. PARTICIPANTS: Adult patients who underwent lung transplant without cardiopulmonary bypass or extracorporeal membrane oxygenator between 2006 and 2016 at the Vanderbilt University Medical Center. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The presence of postoperative AKI was assessed by the Kidney Disease: Improving Global Outcomes criteria in the first seven postoperative days. Multivariate logistic regression analysis was used to determine the independent predictive factors of AKI. One hundred forty-eight patients were included in the final analysis, of whom 63 (42.6%) subsequently developed AKI: 43 (29.0%) stage 1, ten (6.8%) stage 2, and ten (6.8%) stage 3. Patients who had AKI had a longer hospital length of stay (12 days [interquartile range (IQR): 10-17] vs ten days [IQR: 8-12], p < 0.001). For every one-year increase in age, the odds of AKI decreased by 8% (odds ratio [OR] 0.92, 95% confidence interval [CI]: 0.87-0.98, p = 0.008). The odds of having AKI in patients with bilateral lung transplant was lower than patients with unilateral transplant (OR 0.09, 95% CI: 0.01-0.63, p = 0.015). Additionally, a diagnosis of chronic obstructive pulmonary disease increased the odds of AKI by four-fold compared with a diagnosis of idiopathic pulmonary fibrosis (OR 4.73, 95% CI: 1.44-15.56, p = 0.011). CONCLUSIONS: AKI is a common complication after off-pump lung transplantation and is associated with increased hospital length of stay. Younger age, unilateral lung transplant, and diagnosis of chronic obstructive pulmonary disease are independently associated with AKI.
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Injúria Renal Aguda , Transplante de Pulmão , Injúria Renal Aguda/diagnóstico , Injúria Renal Aguda/epidemiologia , Injúria Renal Aguda/etiologia , Humanos , Incidência , Transplante de Pulmão/efeitos adversos , Complicações Pós-Operatórias/diagnóstico , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/etiologia , Estudos Retrospectivos , Fatores de RiscoRESUMO
IMPORTANCE: Fatigue is a chronic and distressing sequela of traumatic brain injury (TBI). Little evidence exists for the efficacy of interventions that address post-TBI fatigue. OBJECTIVE: To evaluate the preliminary efficacy of a self-management intervention (Maximizing Energy; MAX) for reducing the impact (primary outcome) and severity of fatigue on daily life, improving fatigue experience, and increasing participation compared with a health education (HE) intervention. DESIGN: Pilot randomized controlled trial (RCT). SETTING: Community. PARTICIPANTS: Forty-one participants randomly assigned to the MAX (n = 20) or HE (n = 21) intervention. INTERVENTIONS: The MAX intervention included problem-solving therapy with energy conservation education to teach participants fatigue management. The HE intervention included diet, exercise, and energy conservation education. Both interventions (30 min/day, 2 days/wk for 8 wk) were delivered online by occupational therapists. OUTCOME AND MEASURES: The primary outcome was the modified Fatigue Impact Scale (mFIS). Outcome measures were collected at baseline, postintervention, and 4- and 8-wk postintervention. RESULTS: At 8 wk postintervention, participants in the MAX group reported significantly lower levels of fatigue impact (mFIS) than those in the HE group, F(1, 107) = 29.54, p = .01; Cohen's d = 0.87; 95% confidence interval [0.18, 1.55]. CONCLUSIONS AND RELEVANCE: These findings provide preliminary evidence that the MAX intervention may decrease the impact of fatigue on daily life among people with post-TBI fatigue. What This Article Adds: An internet-based, self-management intervention combining occupational therapy- delivered energy conservation education with cognitive-behavioral therapy seems to reduce fatigue impact and severity among people with post-TBI fatigue. Future appropriately powered RCTs could positively contribute to the evidence available to occupational therapy practitioners for this chronic, debilitating, and often overlooked symptom.
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Lesões Encefálicas Traumáticas , Fadiga , Intervenção Baseada em Internet , Autogestão , Lesões Encefálicas Traumáticas/complicações , Fadiga/etiologia , Fadiga/prevenção & controle , Humanos , Projetos PilotoRESUMO
BACKGROUND: Only a fraction of pediatric trauma patients are treated in pediatric-specific facilities, leaving the remaining to be seen in centers that must decide to admit the patient to a pediatric or adult unit. Thus, there may be inconsistencies in pediatric trauma admission practices among trauma centers. OBJECTIVE: Describe current practices in admission decision making for pediatric patients. METHODS: An email survey was distributed to members of three professional organizations: The American Association for the Surgery of Trauma, Society of Trauma Nurses, and Pediatric Trauma Society. The survey contained questions regarding pediatric age cutoffs, institutional placement decisions, and scenario-based assessments to determine mitigating placement factors. RESULTS: There were 313 survey responses representing freestanding children's hospitals (114, 36.4%); children's hospitals within general hospitals (107, 34.2%), and adult centers (not a children's hospital; 90, 28.8%). The mean age cutoff for pediatric admission was 16.6 years. The most reported cutoff ages were 18 years (77, 25.6%) and 15 years (76, 25.2%). The most common rationales for the age cutoffs were "institutional experience/tradition" (139, 44.4%) and "physician preference" (89, 28.4%). CONCLUSION: There was no single widely accepted age cutoff that distinguished pediatric from adult trauma patients for admission placement. There was significant variability between and within the types of facilities, with noted ambiguity in the definition of a "pediatric" patient. Thresholds appear to be based primarily on subjective criteria such as traditions or preferences rather than scientific data. Institutions should strive for objective, evidence-based policies for determining the appropriate placement of pediatric patients.
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Hospitais Pediátricos , Centros de Traumatologia , Adolescente , Adulto , Criança , Tomada de Decisões , Hospitais Gerais , Humanos , Inquéritos e Questionários , Estados UnidosRESUMO
Every single human being who has ever been conceived has come into existence precisely because God wants him or her to exist. The present article offers psychological and spiritual considerations to assist people who, in a variety of settings, are evaluating medical-assisted technologies that require the removal of gametes from the body, especially those procedures that involve the buying and selling of gametes. Gamete "donation" is a misnomer when the transactions involve cash payment. Gamete "donation" is contrasted with the "self-donation" that a married couple makes to each other, and by extension to their children, in the marital embrace. The article draws out some of the implications of this contrast, particularly to the child's sense of identity. Particular attention is drawn to the mistakes and mix-ups that can occur when the gametes are removed from the body, which would be literally impossible under the circumstances of natural procreation. I conclude that the perennial teaching of the Catholic Church makes a uniquely humane and personalist contribution to the important public conversation about the use of assisted reproduction.
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BACKGROUND: Chemotherapy regimens that include the utilization of gemcitabine are the standard of care in pancreatic cancer patients. However, most patients with advanced pancreatic cancer die within the first 2 years after diagnosis, even when treated with standard of care chemotherapy. This study aims to explore combination therapies that could boost the efficacy of standard of care regimens in pancreatic cancer patients. METHODS: In this study, we used PV-10, a 10% solution of rose bengal, to induce the death of human pancreatic tumor cells in vitro. Murine in vivo studies were carried out to examine the effectiveness of the direct injection of PV-10 into syngeneic pancreatic tumors in causing lesion-specific ablation. Intralesional PV-10 treatment was combined with systemic gemcitabine treatment in tumor-bearing mice to investigate the control of growth among treated tumors and distal uninjected tumors. The involvement of the immune-mediated clearance of tumors was examined in immunogenic tumor models that express ovalbumin (OVA). RESULTS: In this study, we demonstrate that the injection of PV-10 into mouse pancreatic tumors caused lesion-specific ablation. We show that the combination of intralesional PV-10 with the systemic administration of gemcitabine caused lesion-specific ablation and delayed the growth of distal uninjected tumors. We observed that this treatment strategy was markedly more successful in immunogenic tumors that express the neoantigen OVA, suggesting that the combination therapy enhanced the immune clearance of tumors. Moreover, the regression of tumors in mice that received PV-10 in combination with gemcitabine was associated with the depletion of splenic CD11b+Gr-1+ cells and increases in damage associated molecular patterns HMGB1, S100A8, and IL-1α. CONCLUSIONS: These results demonstrate that intralesional therapy with PV-10 in combination with gemcitabine can enhance anti-tumor activity against pancreatic tumors and raises the potential for this strategy to be used for the treatment of patients with pancreatic cancer.
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Antimetabólitos Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Desoxicitidina/análogos & derivados , Neoplasias Pancreáticas/tratamento farmacológico , Rosa Bengala/uso terapêutico , Animais , Antimetabólitos Antineoplásicos/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Desoxicitidina/farmacologia , Desoxicitidina/uso terapêutico , Humanos , Camundongos , Neoplasias Pancreáticas/patologia , Rosa Bengala/farmacologia , Gencitabina , Neoplasias PancreáticasRESUMO
BACKGROUND: Increased intravascular volume has been associated with protection from acute kidney injury (AKI), but in patients with congestive heart failure, venous congestion is associated with increased AKI. We tested the hypothesis that intraoperative venous congestion is associated with AKI after cardiac surgery. METHODS: In patients enrolled in the Statin AKI Cardiac Surgery trial, venous congestion was quantified as the area under the curve (AUC) of central venous pressure (CVP) >12, 16, or 20 mm Hg during surgery (mm Hg min). AKI was defined using Kidney Disease Improving Global Outcomes (KDIGO) criteria and urine concentrations of tissue inhibitor of metalloproteinase-2 and insulin-like growth factor binding protein 7 ([TIMP-2]â [IGFBP7]), a marker of renal stress. We measured associations between venous congestion, AKI and [TIMP-2]â [IGFBP7], adjusted for potential confounders. Values are reported as median (25th-75th percentile). RESULTS: Based on KDIGO criteria, 104 of 425 (24.5%) patients developed AKI. The venous congestion AUCs were 273 mm Hg min (81-567) for CVP >12 mm Hg, 66 mm Hg min (12-221) for CVP >16 mm Hg, and 11 mm Hg min (1-54) for CVP >20 mm Hg. A 60 mm Hg min increase above the median venous congestion AUC above each threshold was independently associated with increased AKI (odds ratio=1.06; 95% confidence interval [CI], 1.02-1.10; P=0.008; odds ratio=1.12; 95% CI, 1.02-1.23; P=0.013; and odds ratio=1.30; 95% CI, 1.06-1.59; P=0.012 for CVP>12, >16, and >20 mm Hg, respectively). Venous congestion before cardiopulmonary bypass was also associated with increased [TIMP-2]â [IGFBP7] measured during cardiopulmonary bypass and after surgery, but neither venous congestion after cardiopulmonary bypass nor venous congestion throughout surgery was associated with postoperative [TIMP-2]â [IGFBP7]. CONCLUSION: Intraoperative venous congestion was independently associated with increased AKI after cardiac surgery.
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Injúria Renal Aguda/etiologia , Procedimentos Cirúrgicos Cardíacos/efeitos adversos , Pressão Venosa Central , Hiperemia/etiologia , Injúria Renal Aguda/epidemiologia , Idoso , Estudos de Coortes , Feminino , Humanos , Hiperemia/epidemiologia , Período Intraoperatório , Masculino , Estudos Prospectivos , Fatores de Risco , Resultado do TratamentoRESUMO
Emm55 is a bacterial gene derived from Streptococcus pyogenes (S. pyogenes) that was cloned into a plasmid DNA vaccine (pAc/emm55). In this study, we investigated the anti-tumor efficacy of pAc/emm55 in a B16 murine melanoma model. Intralesional (IL) injections of pAc/emm55 significantly delayed tumor growth compared to the pAc/Empty group. There was a significant increase in the CD8+ T cells infiltrating into the tumors after pAc/emm55 treatment compared to the control group. In addition, we observed that IL injection of pAc/emm55 increased antigen-specific T cell infiltration into tumors. Depletion of CD4+ or CD8+ T cells abrogated the anti-tumor effect of pAc/emm55. Combination treatment of IL injection of pAc/emm55 with anti-PD-1 antibody significantly delayed tumor growth compared to either monotherapy. pAc/emm55 treatment combined with PD-1 blockade enhanced anti-tumor immune response and improved systemic anti-tumor immunity. Together, these strategies may lead to improvements in the treatment of patients with melanoma.
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Antígenos de Bactérias/imunologia , Antineoplásicos Imunológicos/administração & dosagem , Proteínas da Membrana Bacteriana Externa/imunologia , Imunoterapia/métodos , Melanoma Experimental/terapia , Animais , Antígenos de Bactérias/genética , Proteínas da Membrana Bacteriana Externa/genética , Linfócitos T CD8-Positivos/imunologia , Linhagem Celular Tumoral/transplante , Terapia Combinada/métodos , Feminino , Humanos , Injeções Intralesionais , Linfócitos do Interstício Tumoral/imunologia , Melanoma Experimental/imunologia , Camundongos , Plasmídeos/administração & dosagem , Plasmídeos/genética , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologiaRESUMO
BACKGROUND: Mechanisms of postoperative delirium remain poorly understood, limiting development of effective treatments. We tested the hypothesis that intraoperative oxidative damage is associated with delirium and neuronal injury and that disruption of the blood-brain barrier modifies these associations. METHODS: In a prespecified cohort study of 400 cardiac surgery patients enrolled in a clinical trial of atorvastatin to reduce kidney injury and delirium, we measured plasma concentrations of F2-isoprostanes and isofurans using gas chromatography-mass spectrometry to quantify oxidative damage, ubiquitin carboxyl-terminal hydrolase isozyme L1 to quantify neuronal injury, and S100 calcium-binding protein B using enzyme-linked immunosorbent assays to quantify blood-brain barrier disruption before, during, and after surgery. We performed the Confusion Assessment Method for the Intensive Care Unit twice daily to diagnose delirium. We measured the independent associations between intraoperative F2-isoprostanes and isofurans and delirium (primary outcome) and postoperative ubiquitin carboxyl-terminal hydrolase isozyme L1 (secondary outcome), and we assessed if S100 calcium-binding protein B modified these associations. RESULTS: Delirium occurred in 109 of 400 (27.3%) patients for a median (10th, 90th percentile) of 1.0 (0.5, 3.0) days. In the total cohort, plasma ubiquitin carboxyl-terminal hydrolase isozyme L1 concentration was 6.3 ng/ml (2.7, 14.9) at baseline and 12.4 ng/ml (7.9, 31.2) on postoperative day 1. F2-isoprostanes and isofurans increased throughout surgery, and the log-transformed sum of intraoperative F2-isoprostanes and isofurans was independently associated with increased odds of postoperative delirium (odds ratio, 3.70 [95% CI, 1.41 to 9.70]; P = 0.008) and with increased postoperative ubiquitin carboxyl-terminal hydrolase isozyme L1 (ratio of geometric means, 1.42 [1.11 to 1.81]; P = 0.005). The association between increased intraoperative F2-isoprostanes and isofurans and increased postoperative ubiquitin carboxyl-terminal hydrolase isozyme L1 was amplified in patients with elevated S100 calcium-binding protein B (P = 0.049). CONCLUSIONS: Intraoperative oxidative damage was associated with increased postoperative delirium and neuronal injury, and the association between oxidative damage and neuronal injury was stronger among patients with increased blood-brain barrier disruption.
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Procedimentos Cirúrgicos Cardíacos/efeitos adversos , Delírio do Despertar/patologia , Delírio do Despertar/psicologia , Estresse Oxidativo , Complicações Pós-Operatórias/patologia , Complicações Pós-Operatórias/psicologia , Idoso , Idoso de 80 Anos ou mais , Barreira Hematoencefálica , Estudos de Coortes , F2-Isoprostanos/sangue , Feminino , Furanos/sangue , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Proteínas S100/sangue , Ubiquitina Tiolesterase/sangueRESUMO
In natural grasslands, C4 plant dominance increases with growing season temperatures and reflects distinct differences in plant growth rates and water use efficiencies of C3 vs. C4 photosynthetic pathways. However, in lawns, management decisions influence interactions between planted turfgrass and weed species, leading to some uncertainty about the degree of human vs. climatic controls on lawn species distributions. We measured herbaceous plant carbon isotope ratios (δ13 C, index of C3 /C4 relative abundance) and C4 cover in residential lawns across seven U.S. cities to determine how climate, lawn plant management, or interactions between climate and plant management influenced C4 lawn cover. We also calculated theoretical C4 carbon gain predicted by a plant physiological model as an index of expected C4 cover due to growing season climatic conditions in each city. Contrary to theoretical predictions, plant δ13 C and C4 cover in urban lawns were more strongly related to mean annual temperature than to growing season temperature. Wintertime temperatures influenced the distribution of C4 lawn turf plants, contrary to natural ecosystems where growing season temperatures primarily drive C4 distributions. C4 cover in lawns was greatest in the three warmest cities, due to an interaction between climate and homeowner plant management (e.g., planting C4 turf species) in these cities. The proportion of C4 lawn species was similar to the proportion of C4 species in the regional grass flora. However, the majority of C4 species were nonnative turf grasses, and not of regional origin. While temperature was a strong control on lawn species composition across the United States, cities differed as to whether these patterns were driven by cultivated lawn grasses vs. weedy species. In some cities, biotic interactions with weedy plants appeared to dominate, while in other cities, C4 plants were predominantly imported and cultivated. Elevated CO2 and temperature in cities can influence C3 /C4 competitive outcomes; however, this study provides evidence that climate and plant management dynamics influence biogeography and ecology of C3 /C4 plants in lawns. Their differing water and nutrient use efficiency may have substantial impacts on carbon, water, energy, and nutrient budgets across cities.
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Ecossistema , Poaceae , Cidades , Humanos , Fotossíntese , Dispersão Vegetal , Estados UnidosRESUMO
OBJECTIVES: Interventions addressing burden have limited impact among long-term family caregivers. We examined whether problem-solving therapy (PST) would reduce burden levels of caregivers of individuals diagnosed with mild cognitive impairment (MCI) or early-stage dementia (AD). METHODS: Caregivers (N = 73) randomly received PST or nutritional training (NT). Burden measures were assessed over 1-year post-intervention. RESULTS: Relative to NT, caregivers receiving PST endorsed improved perceived burden levels over time, regardless of the type of caregiver. Distress over the care recipient's dementia-related behaviors remained low over time among MCI caregivers receiving PST, while these burden levels among MCI caregivers receiving NT rose over time. AD caregivers receiving PST endorsed reductions in these burden levels over time, while AD caregivers in the NT group endorsed higher burden levels over time. CONCLUSION: PST, taught early in the caregiving trajectory, improves subjective burden levels among caregivers of family members with relatively mild cognitive deficits.
Assuntos
Cuidadores/psicologia , Disfunção Cognitiva/enfermagem , Resolução de Problemas , Psicoterapia/métodos , Estresse Psicológico/prevenção & controle , Idoso , Idoso de 80 Anos ou mais , Família , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
INTRODUCTION: The Southern Community Cohort Study is a prospective study of low socioeconomic status (SES) blacks and whites from the southeastern US, where the burden of end-stage renal disease (ESRD) and its risk factors are high. We tested whether the 2.4-fold elevated risk of ESRD we previously observed in blacks compared to whites was explained by differences in baseline kidney function. METHODS: We conducted a case-cohort study of incident ESRD cases (n = 737) with stored blood and a probability sampled subcohort (n = 4238) and calculated estimated glomerular filtration rate (eGFR) from serum creatinine. 86% of participants were enrolled from community health centers in medically underserved areas and 14% from the general population in 12 states in the southeastern United States. Incident ESRD after entry into the cohort was ascertained by linkage of the cohort with the US Renal Data System (USRDS). RESULTS: Median (25th, 75th percentile) eGFR at baseline was 63.3 (36.0, 98.2) ml/min/1.73m2 for ESRD cases and 103.2 (86.0, 117.9) for subcohort. Black ESRD cases had higher median (25th, 75th) eGFR [63.3 (35.9, 95.9)] compared to whites [59.1 (39.4, 99.2)]. In multivariable Cox models accounting for sampling weights, baseline eGFR was a strong predictor of ESRD risk, and an interaction with race was detected (P = 0.029). The higher ESRD risk among blacks relative to whites persisted (hazard ratio: 2.58; 95% confidence interval: 1.65, 4.03) after adjustment for eGFR. CONCLUSION: In this predominantly lower SES cohort, the racial disparity in ESRD risk is not explained by differences in baseline kidney function.
Assuntos
População Negra , Taxa de Filtração Glomerular/fisiologia , Falência Renal Crônica/epidemiologia , Área Carente de Assistência Médica , População Branca , Adulto , Idoso , Idoso de 80 Anos ou mais , População Negra/estatística & dados numéricos , Estudos de Coortes , Creatinina/sangue , Feminino , Humanos , Incidência , Rim/fisiopatologia , Falência Renal Crônica/sangue , Falência Renal Crônica/etnologia , Falência Renal Crônica/fisiopatologia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Fatores de Risco , Sudeste dos Estados Unidos/epidemiologia , População Branca/estatística & dados numéricosRESUMO
OBJECTIVE: As a sequel to the Depression in Later Life trial of lay counselor-delivered problem-solving therapy for depression prevention among older adults in Goa, India, this qualitative study aimed to explore participant experiences to illuminate the reasons for the trial's positive findings and implications for further efforts at depression prevention in low-resource settings. METHODS: In-depth interviews were conducted with 19 participants (21% of those randomly assigned to the original intervention). Two independent raters coded the data and organized narratives according to broad themes. RESULTS: Most participants valued their relationship with the lay counselor, learned self-care strategies to cope with illnesses, and increased engagement in pleasurable social and physical activities. Some participants reported needing assistance with managing financial strain and family conflicts. CONCLUSIONS: The lay-counselor-delivered intervention was well received. The relationship with the counselor and behavioral activation toward better self-care and more-pleasurable activities may have been keys to the intervention's success.