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BACKGROUND: Tarlatamab, a bispecific T-cell engager immunotherapy targeting delta-like ligand 3 and CD3, showed promising antitumor activity in a phase 1 trial in patients with previously treated small-cell lung cancer. METHODS: In this phase 2 trial, we evaluated the antitumor activity and safety of tarlatamab, administered intravenously every 2 weeks at a dose of 10 mg or 100 mg, in patients with previously treated small-cell lung cancer. The primary end point was objective response (complete or partial response), as assessed by blinded independent central review according to the Response Evaluation Criteria in Solid Tumors, version 1.1. RESULTS: Overall, 220 patients received tarlatamab; patients had previously received a median of two lines of treatment. Among patients evaluated for antitumor activity and survival, the median follow-up was 10.6 months in the 10-mg group and 10.3 months in the 100-mg group. An objective response occurred in 40% (97.5% confidence interval [CI], 29 to 52) of the patients in the 10-mg group and in 32% (97.5% CI, 21 to 44) of those in the 100-mg group. Among patients with an objective response, the duration of response was at least 6 months in 59% (40 of 68 patients). Objective responses at the time of data cutoff were ongoing in 22 of 40 patients (55%) in the 10-mg group and in 16 of 28 patients (57%) in the 100-mg group. The median progression-free survival was 4.9 months (95% CI, 2.9 to 6.7) in the 10-mg group and 3.9 months (95% CI, 2.6 to 4.4) in the 100-mg group; the estimates of overall survival at 9 months were 68% and 66% of patients, respectively. The most common adverse events were cytokine-release syndrome (in 51% of the patients in the 10-mg group and in 61% of those in the 100-mg group), decreased appetite (in 29% and 44%, respectively), and pyrexia (in 35% and 33%). Cytokine-release syndrome occurred primarily during treatment cycle 1, and events in most of the patients were grade 1 or 2 in severity. Grade 3 cytokine-release syndrome occurred less frequently in the 10-mg group (in 1% of the patients) than in the 100-mg group (in 6%). A low percentage of patients (3%) discontinued tarlatamab because of treatment-related adverse events. CONCLUSIONS: Tarlatamab, administered as a 10-mg dose every 2 weeks, showed antitumor activity with durable objective responses and promising survival outcomes in patients with previously treated small-cell lung cancer. No new safety signals were identified. (Funded by Amgen; DeLLphi-301 ClinicalTrials.gov number, NCT05060016.).
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Antineoplásicos Imunológicos , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Carcinoma de Pequenas Células do Pulmão , Humanos , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Citocinas , Neoplasias Pulmonares/tratamento farmacológico , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico , Antineoplásicos Imunológicos/administração & dosagem , Antineoplásicos Imunológicos/efeitos adversos , Antineoplásicos Imunológicos/uso terapêutico , Administração Intravenosa , Síndrome da Liberação de Citocina/induzido quimicamente , Síndrome da Liberação de Citocina/etiologiaRESUMO
OBJECTIVE: This study aims to appraise recommendations from an expert panel of surgical educators on optimizing surgical education and training in the setting of contemporary challenges. BACKGROUND: The Blue Ribbon Committee (BRC II), a group of surgical educators, was convened to make recommendations to optimize surgical training considering the current changes in the landscape of surgical education. Surgical trainees were recruited to assess their impressions of the recommendations. METHODS: A mixed-methods study design was employed, with a survey, followed by focus group interviews. Participating residents and fellows were recruited through a purposeful sampling approach. Descriptive statistics were applied to analyze the survey data, and a thematic data analysis on interview transcripts was employed. RESULTS: The majority of trainee respondents (n=16) thought that all of the subcommittee recommendations should be included in the final BRC II recommendations and paper. According to the interviews, overall, the feedback from the trainees was positive, with particular excitement around work-life integration, education support and faculty development, and funding pitfalls. Some themes about concerns included a lack of clarity about the recommendations, concern about some recommendations being in conflict with one another, and a disconnect between the initial BRC II survey and the subsequent recommendations. CONCLUSIONS: The residents gathered for this focus group were encouraged by the thought, effort, and intention that gathered the surgical leaders across the country to make the recommendations. While there were areas the trainees wanted clarity on, the overall opinion was in agreement with the recommendations.
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INTRODUCTION: Clinical practice guidelines have recommended an endovascular-first approach (ENDO) for the management of patients with chronic mesenteric ischemia (CMI), whereas an open mesenteric bypass (OMB) is proposed for subjects deemed to be poor ENDO candidates. However, the impact of a previous failed endovascular or open mesenteric reconstruction on a subsequent OMB is unknown. Accordingly, this study was designed to examine the results of a remedial OMB (R-OMB) after a failed ENDO or a primary OMB (P-OMB) for patients with recurrent CMI. METHODS: All patients who underwent an OMB from 2002 to 2022 at the University of Florida were reviewed. Outcomes after an R-OMB (ie, history of a failed ENDO or P-OMB) and P-OMB were compared. The primary end point was 30-day mortality, whereas secondary outcomes included complications, reintervention, and survival. The Kaplan-Meier methodology was used to estimate freedom from reintervention and all-cause mortality, whereas multivariable Cox proportional hazards modeling identified predictors of death. RESULTS: A total of 145 OMB procedures (R-OMB, n = 48 [33%]; P-OMB, n = 97 [67%]) were analyzed. A majority of R-OMB operations were performed for a failed stent (prior ENDO, n = 39 [81%]; prior OMB, n = 9 [19%]). R-OMB patients were generally younger (66 ± 9 years vs P-OMB, 69 ± 11 years; P = .09) and had lower incidence of smoking exposure (29% vs P-OMB, 48%; P = .07); however, there were no other differences in demographics or comorbidities. R-OMB was associated with less intraoperative transfusion (0.6 units vs P-OMB, 1.4 units; P = .01), but there were no differences in conduit choice or bypass configuration.The overall 30-day mortality and complication rates were 7% (n = 10/145) and 53% (n = 77/145), respectively, with no difference between the groups. Notably, R-OMB had decreased cardiac (6% vs P-OMB, 21%; P < .01) and bleeding complication rates (2% vs P-OMB, 15%; P = .01). The freedom from reintervention (1 and 5 years: R-OMB: 95% ± 4%, 83% ± 9% vs P-OMB: 97% ± 2%, 93% ± 5%, respectively; log-rank P = .21) and survival (1 and 5 years: R-OMB: 82% ± 6%, 68% ± 9% vs P-OMB: 84% ± 4%, 66% ± 7%; P = .91) were similar. Independent predictors of all-cause mortality included new postoperative hemodialysis requirement (hazard ratio [HR], 7.4, 95% confidence interval [CI], 3.1-17.3; P < .001), pulmonary (HR, 2.7, 95% CI, 1.4-5.3; P = .004) and cardiac (HR, 2.4, 95% CI, 1.1-5.1; P = .04) complications, and female sex (HR, 2.1, 95% CI, 1.03-4.8; P = .04). Notably, R-OMB was not a predictor of death. CONCLUSIONS: The perioperative and longer-term outcomes for a remedial OMB after a failed intraluminal stent or previous open bypass appear to be comparable to a P-OMB. These findings support the recently updated clinical practice guideline recommendations for an endovascular-first approach to treating recurrent CMI due to the significant perioperative complication risk of OMB. However, among the subset of patients deemed ineligible for endoluminal reconstruction after failed mesenteric revascularization, R-OMB results appear to be acceptable and highlight the utility of this strategy in selected patients.
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Procedimentos Endovasculares , Isquemia Mesentérica , Falha de Tratamento , Humanos , Masculino , Feminino , Isquemia Mesentérica/cirurgia , Isquemia Mesentérica/mortalidade , Idoso , Procedimentos Endovasculares/efeitos adversos , Procedimentos Endovasculares/mortalidade , Estudos Retrospectivos , Pessoa de Meia-Idade , Doença Crônica , Fatores de Risco , Fatores de Tempo , Medição de Risco , Reoperação , Oclusão Vascular Mesentérica/cirurgia , Oclusão Vascular Mesentérica/mortalidade , Oclusão Vascular Mesentérica/diagnóstico por imagem , Oclusão Vascular Mesentérica/fisiopatologia , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/mortalidade , Recidiva , Implante de Prótese Vascular/efeitos adversos , Implante de Prótese Vascular/mortalidade , Implante de Prótese Vascular/instrumentação , Florida , Resultado do TratamentoRESUMO
OBJECTIVE: Constitutional symptoms (fatigue, lymphadenopathy, and weight loss) are not included in the SLE disease activity index-2000 (SLEDAI-2K). In this pilot study, we assessed the concurrent and construct validity of a revised SLEDAI-2K (SLED-R) that included these symptoms with the original SLEDAI-2K (SLED-O), using the physician global assessment of disease activity (PGA) as the reference. METHODS: Our revised SLED-R substituted the SLED-O's fever descriptor with a constitutional descriptor that included fever, fatigue, lymphadenopathy, and/or weight loss. SLED-O, SLED-R, PGA and patient global assessment (PtGA) scores were collected prospectively. Bland-Altman correlations for repeated measures were calculated and Meng's z-test was used to compare correlations between dependent and overlapping correlation coefficients. Associations between constitutional symptoms and disease activity measures were analyzed using Mann-Whitney U, Kruskal-Wallis, Chi-square tests and repeated measures correlations. RESULTS: 1123 SLED-O, SLED-R, PGA, and 1066 PtGA were collected in 239 subjects. The new descriptor was scored in 45 subjects (18.8%) and 92 instances (8.1%), while the original descriptor, fever, was scored in only 4 subjects (1.7%) and 5 instances (0.4%). Mean SLED-O, PGA and PtGA scores were higher when the constitutional descriptor was scored versus not (p < .001). The correlation between SLED-R and PGA was marginally higher than between SLED-O and PGA (p < .001). Fatigue contributed most to this increase (p = .001) and associated with both higher PGA and PtGA scores (p < .001). Mean SLED-O and PGA scores were higher when ≥1 constitutional symptom(s) were scored versus not (p < .002). Correlations between PGA and PtGA when the new descriptor was scored versus not were similar (p = .860). The frequency of concordance between PGA and PtGA was lower when the new descriptor was scored (55%) versus not (72.5%), with PGA > PtGA when the new descriptor was scored (p < .001). CONCLUSION: The addition of constitutional symptoms to SLEDAI-2K, particularly fatigue, resulted in a marginal increase in its correlation with PGA, and new constitutional symptoms associated with higher SLED-O and PGA scores. As fatigue is subjective and difficult to attribute to SLE, its validity and inter-rater reliability in scoring remains uncertain. The clinical utility of SLED-R remains unclear, and further studies of its validity and reliability are needed.
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Fadiga , Lúpus Eritematoso Sistêmico , Índice de Gravidade de Doença , Redução de Peso , Humanos , Projetos Piloto , Feminino , Masculino , Adulto , Pessoa de Meia-Idade , Fadiga/etiologia , Lúpus Eritematoso Sistêmico/diagnóstico , Lúpus Eritematoso Sistêmico/fisiopatologia , Linfadenopatia/diagnóstico , Estudos Prospectivos , Febre/diagnóstico , Reprodutibilidade dos TestesRESUMO
STUDY OBJECTIVE: Emergency practitioners use ultrasound-guided nerve blocks to alleviate pain. This study represents the largest registry of single-injection ultrasound-guided nerve blocks performed in an emergency department (ED) to date. We wished to assess the safety and pain score reductions associated with ED-performed ultrasound-guided nerve blocks. The main outcomes of interest were ultrasound-guided nerve block complication rates and change in patient-reported pain (0 to 10 on the VAS) pre and post ultrasound-guided nerve blocks. Other variables of interest were ultrasound-guided nerve block types and indications during the study period. METHODS: This is a retrospective analysis of 420 emergency practitioner-performed ultrasound-guided nerve blocks through chart review over 1 year in the Highland ED. Four emergency physician abstractors reviewed all templated ultrasound-guided nerve block notes and nursing records over the study period. Inter-rater reliability was assessed using 10 randomly selected charts with 100% agreement for 70 key variables (Kappa=1, P<.001). RESULTS: Seventy-five unique emergency practitioners performed 420 ultrasound-guided nerve blocks. Ultrasound-guided nerve blocks were most often performed by emergency residents (61.9%), advanced practice practitioners (21.2%), ultrasound fellowship-trained faculty (8.3%), interns (3.6%), nonultrasound fellowship-trained faculty (3.3%), and not recorded (1.7%). One complication occurred during the study (arterial puncture recognized through syringe aspiration without further sequelae). Among the 261 ultrasound-guided nerve blocks with preblock and postblock pain scores, there was an improvement in postblock pain scores. The mean pain scores decreased from 7.4 to 2.8 after an ultrasound-guided nerve block (difference 4.6, 95% confidence interval 3.9 to 5.2). CONCLUSIONS: This 1-year retrospective study supports that emergency practitioner-performed ultrasound-guided nerve blocks have a low complication rate and are associated with reduced pain.
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Bloqueio Nervoso , Ultrassonografia de Intervenção , Humanos , Estudos Retrospectivos , Reprodutibilidade dos Testes , Dor/etiologiaRESUMO
BACKGROUND: Recently the Society for Vascular Surgery (SVS) and Society for Thoracic Surgeons (STS) published contemporary guidelines clearly defining complicated versus uncomplicated acute type B aortic dissections (TBADs) with an additional high-risk grouping. Few studies have evaluated outcomes associated with "high-risk" TBADs. The objective of this study was to assess differences in demographics, clinical presentation, symptom onset, and outcomes in high-risk patients that underwent either thoracic endovascular aortic repair (TEVAR) or best medical management for acute TBAD compared to those with complicated and uncomplicated acute TBAD. METHODS: Patients admitted with acute TBADs from a single academic medical center from October 2011 to March 2020 were analyzed. Per the STS/SVS 2020 guidelines, high risk was defined as refractory pain/hypertension, bloody pleural effusion, aortic diameter >4 cm, false lumen diameter >22 mm, radiographic malperfusion, and early readmission, and complicated was defined as ruptured/malperfusion presentation. Uncomplicated patients were those without malperfusion/rupture and without high-risk features. The primary end-point was inpatient mortality. Secondary end-points included complications, reintervention, and survival. RESULTS: Of the 159 patients identified with acute TBAD, 63 (40%) met the high-risk criteria. In the high-risk cohort, 38 (60%) underwent TEVAR (HR-TEVAR), with refractory pain as the most common indication, while 25 (40%) were managed medically (HR-medical). Malperfusion or rupture was present in 63 (40%) patients (complicated TBAD (C-TBAD)), all of whom underwent TEVAR. An additional 33 patients had no high-risk features and were all managed medically (uncomplicated TBAD). There were no differences in age, body mass index, and race between groups. Among the 4 groups, there were variable distributions in sex, insurance status, and incidence of several baseline comorbidities including congestive heart failure, chronic obstructive pulmonary disease, and renal dysfunction (P < 0.05 for all). C-TBAD had increased length of stay (12, interquartile range [IQR] 9-22) compared to HR-TEVAR (11.5, IQR 7-15), HR-medical (6, IQR 5-8), and uncomplicated TBAD (7, IQR 5-10) (P < 0.01). C-TBAD had decreased days from admission to repair (0, IQR 0-2) compared to HR-TEVAR (3.5, IQR 1-8) (P < 0.01). C-TBAD patients had worse 3-year survival compared to other groups (log-rank P < 0.01), although when in-hospital mortality was excluded, survival was similar among groups (P = 0.37). Of patients initially managed medically, outpatient TEVAR was performed in 6 (24%) HR-medical and 4 (12%) uncomplicated patients, with no difference between rate of intervention between groups (P = 0.22). CONCLUSIONS: High-risk features, as defined in updated SVS/STS guidelines, are common in patients presenting with acute TBAD. High-risk patients had acceptable outcomes when managed either surgically or medically. High-risk patients that underwent TEVAR had improved perioperative outcomes and mortality compared to those undergoing TEVAR for C-TBAD, a finding which may help guide preoperative risk stratification and patient counseling.
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Aneurisma da Aorta Torácica , Dissecção Aórtica , Implante de Prótese Vascular , Procedimentos Endovasculares , Mortalidade Hospitalar , Humanos , Dissecção Aórtica/cirurgia , Dissecção Aórtica/mortalidade , Dissecção Aórtica/diagnóstico por imagem , Masculino , Feminino , Fatores de Risco , Procedimentos Endovasculares/mortalidade , Procedimentos Endovasculares/efeitos adversos , Resultado do Tratamento , Idoso , Pessoa de Meia-Idade , Estudos Retrospectivos , Medição de Risco , Fatores de Tempo , Implante de Prótese Vascular/mortalidade , Implante de Prótese Vascular/efeitos adversos , Doença Aguda , Aneurisma da Aorta Torácica/cirurgia , Aneurisma da Aorta Torácica/mortalidade , Aneurisma da Aorta Torácica/diagnóstico por imagem , Complicações Pós-Operatórias/mortalidade , Complicações Pós-Operatórias/etiologia , Bases de Dados FactuaisRESUMO
BACKGROUND: Venous thromboembolism (VTE) incidence after thoracic and fenestrated endovascular aortic repair (TEVAR/FEVAR) is high (up to 6-7%) relative to other vascular procedures; however, the etiology for this discrepancy remains unknown. Notably, patients undergoing TEVAR/FEVAR commonly receive cerebrospinal fluid drains (CSFDs) for neuroprotection, requiring interruption of perioperative anticoagulation and prolonged immobility. We hypothesized that CSFDs are a risk factor for VTE after TEVAR/FEVAR. METHODS: Consecutive TEVAR/FEVAR patients at a single center were reviewed (2011-2020). Cerebrospinal fluid drains (CSFDs) were placed based on surgeon preference preoperatively or for spinal cord ischemia (SCI) rescue therapy postoperatively. The primary end-point was VTE occurrence, defined as any new deep venous thrombosis (DVT) or pulmonary embolism (PE) confirmed on imaging within 30 days postoperatively. Routine postoperative VTE screening was not performed. Patients with and without VTE, and subjects with and without CSFDs were compared. Logistic regression was used to explore associations between VTE incidence and CSFD exposure. RESULTS: Eight hundred ninety-seven patients underwent TEVAR/FEVAR and 43% (n = 387) received a CSFD at some point during their care (preoperative: 94% [n = 365/387]; postoperative SCI rescue therapy: 6% [n = 22/387]). CSFD patients were more likely to have previous aortic surgery (44% vs. 37%; P = 0.028) and received more postoperative blood products (780 vs. 405 mL; P = 0.005). The overall VTE incidence was 2.2% (n = 20). 70% (14) patients with VTE had DVT, 50% (10) had PE, and 20% (4) had DVT and PE. Among TEVAR/FEVAR patients with VTE, 65% (n = 13) were symptomatic. Most VTEs (90%, n = 18) were identified inhospital and the median time to diagnosis was 12.5 (interquartile range 7.5-18) days postoperatively. Patients with VTE were more likely to have nonelective surgery (95% vs. 41%; P < 0.001), had higher American Society of Anesthesiologists classification (4.1 vs. 3.7; P < 0.001), required longer intensive care unit admission (24 vs. 12 days; P < 0.001), and received more blood products (1,386 vs. 559 mL; P < 0.001). Venous thromboembolism (VTE) incidence was 1.8% in CSFD patients compared to 3.5% in non-CSFD patients (odds ratio 0.70 [95% confidence interval 0.28-1.78, P = 0.300). However, patients receiving CSFDs postoperatively for SCI rescue therapy had significantly greater VTE incidence (9.1% vs. 1.1%; P = 0.044). CONCLUSIONS: CSFD placement was not associated with an increased risk of VTE in patients undergoing TEVAR/FEVAR. Venous thromboembolism (VTE) risk was greater in patients undergoing nonelective surgery and those with complicated perioperative courses. Venous thromboembolism (VTE) risk was greater in patients receiving therapeutic CSFDs compared to prophylactic CSFDs, highlighting the importance of careful patient selection for prophylactic CSFD placement.
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Procedimentos Endovasculares , Embolia Pulmonar , Isquemia do Cordão Espinal , Tromboembolia Venosa , Humanos , Correção Endovascular de Aneurisma , Tromboembolia Venosa/diagnóstico por imagem , Tromboembolia Venosa/epidemiologia , Procedimentos Endovasculares/efeitos adversos , Procedimentos Endovasculares/métodos , Resultado do Tratamento , Fatores de Risco , Isquemia do Cordão Espinal/diagnóstico , Isquemia do Cordão Espinal/epidemiologia , Isquemia do Cordão Espinal/etiologia , Embolia Pulmonar/etiologia , Estudos RetrospectivosRESUMO
INTRODUCTION: Proper pain in acute scapular fractures can be challenging to achieve due to their anatomy and location. While the current mainstay of treatment relies on opioids, the Rhomboid Intercostal Block (RIB) has been utilized for anesthesia to effectively treat pain for scapular fractures. However, it has not yet been utilized in the emergency department (ED). CASE REPORT: In this case report, we present the first documented use of RIB to treat pain safely and effectively in a 69-year-old male with a scapula fracture following a ground-level fall in the ED. The RIB was performed under ultrasound guidance, providing precise localization and administration of the nerve block. CONCLUSION: The RIB demonstrated successful pain management in the ED. Although hopeful, further research is needed to understand limitations, potential side effects, length of pain control, and overall clinical outcomes of the RIB in the ED.
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Fraturas das Costelas , Traumatismos Torácicos , Masculino , Humanos , Idoso , Dor/etiologia , Fraturas das Costelas/complicações , Fraturas das Costelas/diagnóstico por imagem , Fraturas das Costelas/terapia , Serviço Hospitalar de Emergência , Traumatismos Torácicos/complicações , Ultrassonografia de Intervenção , Escápula/diagnóstico por imagem , Costelas/diagnóstico por imagemRESUMO
The objective of the present study was to determine if treatment with N-acetylcysteine (NAC) could reduce access-related limb dysfunction in mice. Male and female C57BL6J mice were fed an adenine-supplemented diet to induce chronic kidney disease (CKD) prior to the surgical creation of an arteriovenous fistula (AVF) in the iliac vascular bundle. AVF creation significantly increased peak aortic and infrarenal vena cava blood flow velocities, but NAC treatment had no significant impact, indicating that fistula maturation was not impacted by NAC treatment. Hindlimb muscle and paw perfusion recovery and muscle capillary density in the AVF limb were unaffected by NAC treatment. However, NAC treatment significantly increased the mass of the tibialis anterior (P = 0.0120) and soleus (P = 0.0452) muscles post-AVF. There was a significant main effect of NAC treatment on hindlimb grip strength at postoperative day 12 (POD 12) (P = 0.0003), driven by significantly higher grip strength in both male (P = 0.0273) and female (P = 0.0031) mice treated with NAC. There was also a significant main effect of NAC treatment on the walking speed at postoperative day 12 (P = 0.0447), and post hoc testing revealed an improvement in NAC-treated male mice (P = 0.0091). The area of postsynaptic acetylcholine receptors (P = 0.0263) and motor endplates (P = 0.0240) was also increased by NAC treatment. Interestingly, hindlimb skeletal muscle mitochondrial oxidative phosphorylation trended higher in NAC-treated female mice but was not statistically significant (P = 0.0973). Muscle glutathione levels and redox status were not significantly impacted by NAC treatment in either sex. In summary, NAC treatment attenuated some aspects of neuromotor pathology in mice with chronic kidney disease following AVF creation.NEW & NOTEWORTHY Hemodialysis via autogenous arteriovenous fistula (AVF) is the preferred first-line modality for renal replacement therapy in patients with end-stage kidney disease. However, patients undergoing AVF surgery frequently experience a spectrum of hand disability symptoms postsurgery including weakness and neuromotor dysfunction. Unfortunately, no treatment is currently available to prevent or mitigate these symptoms. Here, we provide evidence that daily N-acetylcysteine supplementation can attenuate some aspects of limb neuromotor function in a preclinical mouse model of AVF.
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Fístula Arteriovenosa , Derivação Arteriovenosa Cirúrgica , Falência Renal Crônica , Insuficiência Renal Crônica , Masculino , Feminino , Animais , Camundongos , Acetilcisteína/farmacologia , Diálise Renal , Insuficiência Renal Crônica/terapia , Insuficiência Renal Crônica/etiologia , Falência Renal Crônica/terapia , Derivação Arteriovenosa Cirúrgica/efeitos adversos , Estudos RetrospectivosRESUMO
The human KIR genes encode a family of class I MHC receptors that are expressed on subsets of NK cells. The expression of KIR proteins is controlled by a stochastic process, and competition between sense and antisense promoter elements has been suggested to program the variegated expression of these genes. Previous studies have demonstrated distinct roles of distal, intermediate, and proximal sense promoter/enhancer elements in gene activation and expression. Conversely, proximal and intronic antisense promoter transcripts have been associated with gene silencing at different stages of NK cell development. In the current study, we examine the effect of intermediate promoter deletion on KIR2DL1 expression in the YTS cell line. Homozygous deletion of the KIR2DL1 intermediate element did not affect proximal promoter activity but resulted in increased detection of upstream transcripts. No significant changes in alternative mRNA splicing or expression levels of KIR2DL1 protein were observed. However, intermediate element deletion was associated with a reduced frequency of gene activation by 5-azacytidine. Taken together, these results indicate that the intermediate element is not an enhancer required for KIR expression; however, it is required for the efficient activation of the gene.
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Receptores KIR , Humanos , Ativação Transcricional , Homozigoto , Deleção de Sequência , Receptores KIR2DL1/genética , Linhagem Celular , Regiões Promotoras Genéticas , Receptores KIR/genéticaRESUMO
Emergency departments (EDs) are common access points for patients who are at high risk for unintended pregnancy. Low-barrier access to effective contraception represents a crucial and low-cost intervention to address this public health need. Same-day initiation of contraception during an ED visit is a unique opportunity to provide reproductive health care for high-risk patients with otherwise limited health care access. We collaborated with our obstetrics and gynecology (OB/GYN) department, pharmacists, and a team of community health advocates to support emergency clinicians (namely, emergency physicians and advanced practice providers) in assessing pregnancy and contraceptive readiness, increasing proficiency in contraception counseling, prescribing hormonal contraception, counseling on barrier and emergency contraception, and inserting (and removing) the Nexplanon implant, a form of long-acting reversible contraception. With this novel approach, we found that emergency clinicians voluntarily participated in trainings on contraception, including low-threshold long-acting reversible contraception initiation; and, after completing these trainings, clinicians integrated these skills into their workflow in the ED. We report our results after screening 38 patients during our current Pilot Phase of implementing this program.
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Anticoncepção Pós-Coito , Gravidez , Feminino , Humanos , Anticoncepcionais , Acessibilidade aos Serviços de Saúde , Aconselhamento , Serviço Hospitalar de EmergênciaRESUMO
STUDY OBJECTIVE: We implemented a whole person care-informed intervention delivered by substance use navigators (SUN) for emergency department (ED) patients with substance use disorders. METHODS: This was an implementation study of adult patients discharged from 3 public hospital EDs between September 1, 2021 through January 31, 2022 with cocaine, methamphetamine, alcohol, and opioid use-related diagnoses. The primary effectiveness outcome was treatment engagement within 30 days of ED discharge among patients with and without the SUN intervention. We used logistic regression and nearest neighbor propensity score matching without replacement to control for confounding effects. RESULTS: There were 1,328 patients in the cohort, and 119 (9.0%) received the SUN intervention; 50.4% of patients in the SUN intervention group and 15.9% of patients without the SUN intervention were engaged in outpatient treatment within 30 days of ED discharge (difference in proportions: 34.5%, 95% confidence interval [CI] 25.3% to 43.8%). In the unadjusted analysis, the SUN intervention was associated with higher rates of treatment engagement after ED discharge for patients with alcohol, opioid, and cocaine-related diagnoses; patients with methamphetamine-related diagnoses had low engagement rates with or without the SUN intervention. In addition, the SUN intervention was associated with higher odds of treatment engagement in the multivariable model (aOR 3.7, 95% CI 2.4 to 5.8) and in the propensity score-matched analysis (OR 2.1, 95% CI 1.2 to 3.5). CONCLUSION: A whole person care-informed intervention delivered by SUNs for ED patients with substance use disorders was strongly associated with higher engagement rates in addiction treatment after discharge.
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Analgésicos Opioides , Transtornos Relacionados ao Uso de Opioides , Adulto , Humanos , Analgésicos Opioides/uso terapêutico , Serviço Hospitalar de Emergência , Pacientes , Alta do Paciente , Transtornos Relacionados ao Uso de Opioides/tratamento farmacológicoRESUMO
BACKGROUND: Endovascular repair of thoracoabdominal aortic aneurysms (TAAA) and juxtarenal aortic aneurysms (JAA) with fenestrated and/or branched endografts (B/FEVAR) has become common. Physician modified endografts for patients presenting with symptomatic or contained ruptures has made B/FEVAR a feasible option in nonelective settings. The purpose of this study was to describe our 10-year institutional experience with endovascular interventions for TAAA in elective and nonelective cases to evaluate differences in outcomes and the clinical risk factors associated with nonelective presentation. METHODS: A prospectively maintained database was retrospectively queried for patients undergoing B/FEVAR for TAAA and JAA at a single tertiary care academic institution between 1/2011 and 12/2020. Data collected included demographics, comorbidities, presenting symptoms, aneurysm characteristics, and clinical outcomes. Nonelective repair was defined as any patient that presented through the Emergency Department, as a hospital transfer, or as a direct admission from clinic and had aortic repair performed during the same admission. Univariate analyses were used to compare patients. The primary outcomes were 30-day and 1-year mortality. Secondary outcomes included perioperative complications and nonhome discharge. RESULTS: Between 1/201 and 12/2020, a total of 208 patients underwent B/FEVAR for TAAA (173) and JAA (35). Nonelective repair was performed in 44 (21%) patients with 39 for TAAA (23%) and 5 for JAA (14%). Nonelective patients were younger (71 ± 11 vs. 74 ± 7 years, P = 0.03), more likely to be self-pay or have Medicaid (11% vs. 2%, P = 0.02) and had a different race distribution compared to the elective cohort (P < 0.01). Thirty-day mortality was 4% (n = 6) in elective repairs and 7% (n = 3) in nonelective repairs. One-year mortality was 13% (n = 22) in elective repairs and 18% (n = 8) in nonelective repairs. There were no differences between patients receiving elective versus nonelective repair in 30-day (P = 0.40) or 1-year mortality (P = 0.47). Nonelective patients had longer median duration of stay (11 interquartile range (IQR) 6-15 vs. 5 IQR 4-8, P < 0.01), postoperative length of stay (7 IQR 5-12 vs. 4 IQR 3-7, P < 0.01), and more intensive care unit days (6 IQR 3-8 vs. 3 IQR 2-5, P < 0.01). There were no differences in other secondary outcomes between elective and nonelective patients including inpatient and access-related complications, re-interventions, and nonhome discharge (P > 0.05 for all comparisons). A composite "any complication" occurred more frequently in patients with nonelective repair (50% vs. 35%, P = 0.03). CONCLUSIONS: Endovascular repair for TAAA or JAA is a good option in patients undergoing nonelective surgical intervention, with comparable 30-day mortality, 1-year mortality, and perioperative morbidity to that of patients undergoing elective B/FEVAR.
Assuntos
Aneurisma da Aorta Abdominal , Aneurisma da Aorta Toracoabdominal , Implante de Prótese Vascular , Procedimentos Endovasculares , Humanos , Prótese Vascular/efeitos adversos , Implante de Prótese Vascular/efeitos adversos , Estudos Retrospectivos , Resultado do Tratamento , Procedimentos Endovasculares/efeitos adversos , Aneurisma da Aorta Abdominal/diagnóstico por imagem , Aneurisma da Aorta Abdominal/cirurgia , Aneurisma da Aorta Abdominal/complicações , Fatores de Risco , Complicações Pós-OperatóriasRESUMO
End-stage kidney disease, the most advanced stage of chronic kidney disease (CKD), requires renal replacement therapy or kidney transplant to sustain life. To accomplish durable dialysis access, the creation of an arteriovenous fistula (AVF) has emerged as a preferred approach. Unfortunately, a significant proportion of patients that receive an AVF experience some form of hand dysfunction; however, the mechanisms underlying these side effects are not understood. In this study, we used nuclear magnetic resonance spectroscopy to investigate the muscle metabolome following iliac AVF placement in mice with CKD. To induce CKD, C57BL6J mice were fed an adenine-supplemented diet for 3 wk and then randomized to receive AVF or sham surgery. Two weeks following surgery, the quadriceps muscles were rapidly dissected and snap frozen for metabolite extraction and subsequent nuclear magnetic resonance analysis. Principal component analysis demonstrated clear separation between groups, confirming a unique metabolome in mice that received an AVF. AVF creation resulted in reduced levels of creatine, ATP, and AMP as well as increased levels of IMP and several tricarboxylic acid cycle metabolites suggesting profound energetic stress. Pearson correlation and multiple linear regression analyses identified several metabolites that were strongly linked to measures of limb function (grip strength, gait speed, and mitochondrial respiration). In summary, AVF creation generates a unique metabolome profile in the distal skeletal muscle indicative of an energetic crisis and myosteatosis.NEW & NOTEWORTHY Creation of an arteriovenous fistula (AVF) is the preferred approach for dialysis access, but some patients experience hand dysfunction after AVF creation. In this study, we provide a detailed metabolomic analysis of the limb muscle in a murine model of AVF. AVF creation resulted in metabolite changes associated with an energetic crisis and myosteatosis that associated with limb function.
Assuntos
Fístula Arteriovenosa , Derivação Arteriovenosa Cirúrgica , Falência Renal Crônica , Insuficiência Renal Crônica , Animais , Camundongos , Adenina , Monofosfato de Adenosina , Trifosfato de Adenosina , Derivação Arteriovenosa Cirúrgica/efeitos adversos , Creatina , Músculos , Diálise Renal/métodos , Insuficiência Renal Crônica/etiologiaRESUMO
Neuropsychiatric lupus (NPSLE) is a debilitating manifestation of SLE which occurs in a majority of SLE patients and has a variety of clinical manifestations. In the central nervous system, NPSLE may result from ischemia or penetration of inflammatory mediators and neurotoxic antibodies through the blood brain barrier (BBB). Here we focus on cognitive dysfunction (CD) as an NPSLE manifestation; it is common, underdiagnosed, and without specific therapy. For a very long time, clinicians ignored cognitive dysfunction and researchers who might be interested in the question struggled to find an approach to understanding mechanisms for this manifestation. Recent years, however, propelled by a more patient-centric approach to disease, have seen remarkable progress in our understanding of CD pathogenesis. This has been enabled through the use of novel imaging modalities and numerous mouse models. Overall, these studies point to a pivotal role of an impaired BBB and microglial activation in leading to neuronal injury. These insights suggest potential therapeutic modalities and make possible clinical trials for cognitive impairment.
Assuntos
Disfunção Cognitiva , Lúpus Eritematoso Sistêmico , Vasculite Associada ao Lúpus do Sistema Nervoso Central , Animais , Camundongos , Vasculite Associada ao Lúpus do Sistema Nervoso Central/patologia , Disfunção Cognitiva/diagnóstico , Disfunção Cognitiva/etiologia , Barreira Hematoencefálica , Anticorpos , Lúpus Eritematoso Sistêmico/complicaçõesRESUMO
Swimming organisms may actively adjust their behavior in response to the flow around them. Ocean flows are typically turbulent and are therefore characterized by chaotic velocity fluctuations. While some studies have observed planktonic larvae altering their behavior in response to turbulence, it is not always clear whether a plankter is responding to an individual turbulence fluctuation or to the time-averaged flow. To distinguish between these two paradigms, we conducted laboratory experiments with larvae in turbulence. We observed veliger larvae of the gastropod Crepidula fornicata in a jet-stirred turbulence tank while simultaneously measuring two components of the fluid and larval velocity. Larvae were studied at two different stages of development, early and late, and their behavior was analyzed in response to different characteristics of turbulence: acceleration, dissipation and vorticity. Our analysis considered the effects of both the time-averaged flow and the instantaneous flow, around the larvae. Overall, we found that both stages of larvae increased their upward swimming speeds in response to increasing turbulence. However, we found that the early-stage larvae tended to respond to the time-averaged flow, whereas the late-stage larvae tended to respond to the instantaneous flow around them. These observations indicate that larvae can integrate flow information over time and that their behavioral responses to turbulence can depend on both their present and past flow environments.
Assuntos
Gastrópodes , Plâncton , Animais , Comportamento Animal/fisiologia , Larva/fisiologia , Natação/fisiologiaRESUMO
BACKGROUND: Endovascular aneurysm repair conversion (EVAR-c) is increasingly reported and known to be technically complex and physiologically demanding. It has been proposed that pragmatic anthropomorphic measures such as psoas muscle area (PMA) may reliably quantify levels of preoperative frailty and be used to inform point of care clinical decision-making and patient discussions for a variety of complex operations. To date, there is mixed data supporting use of PMA as a prognostic factor in fenestrated endovascular and open abdominal aortic aneurysms (AAA) repairs; however, no literature exists evaluating the impact of preoperative PMA on EVAR-c results. Therefore, the purpose of this study was to review our EVAR-c experience and evaluate the association of PMA with perioperative and long-term mortality outcomes. METHODS: A retrospective single-center review of all AAA repairs was performed (2002-2019) and EVAR-c procedures were subsequently analyzed (n = 153). Cross-sectional PMA at the mid-body of the L3 vertebrae was measured. The lowest PMA tertile was used as a threshold value to designate patients as having "low" PMA (n = 51) and this cohort was subsequently compared to subjects with "normal" PMA (n = 102). Cox proportional hazards modeling was used to estimate covariate association with all-cause mortality. RESULTS: Patients with low PMA were older (77 vs. 72 years; P = 0.002), more likely to be female (27% vs. 5%; P < 0.001), and had reduced body mass index (26 vs. 29 kg/m2; P = 0.002). Time to conversion, total number of endovascular aneurysm repair (EVAR) reinterventions prior to conversion and elective EVAR-c presentation incidence were similar; however, patients with low PMA had larger aneurysms (8.3 vs. 7.5 cm; P = 0.01) and increased post-EVAR sac growth (2.3 vs. 1 cm; P = 0.005). Unadjusted inpatient mortality was significantly greater for low PMA patients (16% vs. normal PMA, 5%, P = 0.02). Similarly, the total number of complications was higher among low PMA subjects (1.5 ± 1.9 vs. normal PMA, 0.9 ± 1.5; P = 0.02). Although frequency of major adverse cardiovascular events and new onset inpatient hemodialysis were similar, low PMA patients had a more than four-fold increased likelihood of having persistent requirement of hemodialysis at discharge (18% vs. 4%,P = 0.01). The low PMA group had decreased survival at 1 and 5 years, respectively (77 ± 5%, 65 ± 6% vs. normal PMA, 86 ± 3%, 82% ± 5%; log-rank P = 0.03). Low PMA was an independent predictor of mortality with every 100 mm2 increase in PMA being associated with a 15% reduction in mortality (hazard ratio: 0.85,95% confidence interval:, 0.74-0.97; P = 0.02). CONCLUSIONS: Among EVAR-c patients, subjects with low preoperative PMA had higher rates of postoperative complications and worse overall survival. PMA assessments may be a useful adjunct to supplement traditional risk-stratification strategies when patients are being considered for EVAR-c.
Assuntos
Aneurisma da Aorta Abdominal , Implante de Prótese Vascular , Procedimentos Endovasculares , Humanos , Feminino , Masculino , Aneurisma da Aorta Abdominal/diagnóstico por imagem , Aneurisma da Aorta Abdominal/cirurgia , Aneurisma da Aorta Abdominal/complicações , Procedimentos Endovasculares/efeitos adversos , Estudos Retrospectivos , Músculos Psoas/diagnóstico por imagem , Estudos Transversais , Prognóstico , Fatores de Risco , Resultado do Tratamento , Fatores de Tempo , Complicações Pós-Operatórias/etiologiaRESUMO
BACKGROUND: Expanded access to HIV PrEP is a central pillar of the "Ending the HIV Epidemic" initiative. Identification of PrEP eligible individuals in EDs remains understudied. Our goal was to estimate the accuracy of the Denver HIV Risk Score (DHRS), a quantitative HIV risk tool, for determining PrEP eligibility, and to incorporate it into a novel screening algorithm to optimize sensitivity and specificity. METHODS: We performed a prospective cross-sectional study in two urban EDs. Patients were eligible if ≥18 years of age and without HIV. Research staff collected individual HIV risk, components of the DHRS, and PrEP eligibility per 2017 CDC guidelines. Accuracy estimates were calculated for the DHRS alone and the DHRS plus additional PrEP-specific questions. RESULTS: 1002 patients were enrolled with a median age of 39 years; 54.8% were male, 29.5% Black/non-Hispanic, and 22.5% Hispanic. Overall, 119 (11.9%, 95% CI: 9.9%-14.0%) were PrEP eligible; 5% endorsed history of sex with a partner at higher risk for HIV or condomless sex with multiple partners, 4% an STI, and 2% sharing IDU equipment. A DHRS ≥25 had a sensitivity of 92.4% (95% CI: 86.1%-96.5%) and a specificity of 17.2% (95% CI: 14.8%-19.9%) for PrEP eligibility. A 2-step algorithm, "DHRS-PrEP", beginning with a DHRS ≥25, followed by a step with questions specific to IDU, STI, and sexual partners improved the specificity to 100% (95% CI: 99.6%-100%). CONCLUSIONS: Among a heterogeneous ED sample, a substantial proportion was identified as PrEP eligible, and a 2-step algorithm had high sensitivity and specificity for identifying PrEP-eligible patients.
Assuntos
Algoritmos , Infecções por HIV/epidemiologia , Infecções por HIV/prevenção & controle , Profilaxia Pré-Exposição , Adulto , Estudos Transversais , Serviço Hospitalar de Emergência , Etnicidade/estatística & dados numéricos , Feminino , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Fatores de Risco , Sensibilidade e EspecificidadeRESUMO
Preclinical animal models of chronic kidney disease (CKD) are critical to investigate the underlying mechanisms of disease and to evaluate the efficacy of novel therapeutics aimed to treat CKD-associated pathologies. The objective of the present study was to compare the adenine diet and 5/6 nephrectomy (Nx) CKD models in mice. Male and female 10-wk-old C57BL/6J mice (n = 5-9 mice/sex/group) were randomly allocated to CKD groups (0.2-0.15% adenine-supplemented diet or 5/6 Nx surgery) or the corresponding control groups (casein diet or sham surgery). Following the induction of CKD, the glomerular filtration rate was reduced to a similar level in both adenine and 5/6 Nx mice (adenine diet-fed male mice: 81.1 ± 41.9 µL/min vs. 5/6 Nx male mice: 160 ± 80.9 µL/min, P = 0.5875; adenine diet-fed female mice: 112.9 ± 32.4 µL/min vs. 5/6 Nx female mice: 107.0 ± 45.7 µL/min, P = 0.9995). Serum metabolomics analysis indicated that established uremic toxins were robustly elevated in both CKD models, although some differences were observed between CKD models (i.e., p-cresol sulfate). Dysregulated phosphate homeostasis was observed in the adenine model only, whereas Ca2+ homeostasis was disturbed in male mice with both CKD models. Compared with control mice, muscle mass and myofiber cross-sectional areas of the extensor digitorum longus and soleus muscles were â¼18-24% smaller in male CKD mice regardless of the model but were not different in female CKD mice (P > 0.05). Skeletal muscle mitochondrial respiratory function was significantly decreased (19-24%) in CKD mice in both models and sexes. These findings demonstrate that adenine diet and 5/6 Nx models of CKD have similar levels of renal dysfunction and skeletal myopathy. However, the adenine diet model demonstrated superior performance with regard to mortality (â¼20-50% mortality for 5/6 Nx vs. 0% mortality for the adenine diet, P < 0.05 for both sexes) compared with the 5/6 Nx surgical model.NEW & NOTEWORTHY Numerous preclinical models of chronic kidney disease have been used to evaluate skeletal muscle pathology; however, direct comparisons of popular models are not available. In this study, we compared adenine-induced nephropathy and 5/6 nephrectomy models. Both models produced equivalent levels of muscle atrophy and mitochondrial impairment, but the adenine model exhibited lower mortality rates, higher consistency in uremic toxin levels, and dysregulated phosphate homeostasis compared with the 5/6 nephrectomy model.
Assuntos
Adenina/farmacologia , Taxa de Filtração Glomerular/genética , Músculo Esquelético/metabolismo , Insuficiência Renal Crônica/metabolismo , Animais , Modelos Animais de Doenças , Rim/metabolismo , Rim/patologia , Masculino , Camundongos Endogâmicos C57BL , Músculo Esquelético/patologia , Doenças Musculares/patologia , Doenças Musculares/fisiopatologia , Nefrectomia/métodos , Insuficiência Renal Crônica/tratamento farmacológico , Insuficiência Renal Crônica/patologia , Uremia/fisiopatologiaRESUMO
OBJECTIVES: Musculoskeletal pain and fatigue are common features in systemic lupus erythematosus (SLE). The cholinergic anti-inflammatory pathway is a physiological mechanism diminishing inflammation, engaged by stimulating the vagus nerve. We evaluated the effects of non-invasive vagus nerve stimulation in patients with SLE and with musculoskeletal pain. METHODS: 18 patients with SLE and with musculoskeletal pain ≥4 on a 10 cm Visual Analogue Scale were randomised (2:1) in this double-blind study to receive transcutaneous auricular vagus nerve stimulation (taVNS) or sham stimulation (SS) for 4 consecutive days. Evaluations at baseline, day 5 and day 12 included patient assessments of pain, disease activity (PtGA) and fatigue. Tender and swollen joint counts and the Physician Global Assessment (PGA) were completed by a physician blinded to the patient's therapy. Potential biomarkers were evaluated. RESULTS: taVNS and SS were well tolerated. Subjects receiving taVNS had a significant decrease in pain and fatigue compared with SS and were more likely (OR=25, p=0.02) to experience a clinically significant reduction in pain. PtGA, joint counts and PGA also improved. Pain reduction and improvement of fatigue correlated with the cumulative current received. In general, responses were maintained through day 12. Plasma levels of substance P were significantly reduced at day 5 compared with baseline following taVNS but other neuropeptides, serum and whole blood-stimulated inflammatory mediators, and kynurenine metabolites showed no significant change at days 5 or 12 compared with baseline. CONCLUSION: taVNS resulted in significantly reduced pain, fatigue and joint scores in SLE. Additional studies evaluating this intervention and its mechanisms are warranted.