The murine acquired immunodeficiency syndrome (MAIDS) is caused in susceptible C57BL/6 (B6) mice by a defective murine leukemia virus (MuLV) and resembles human AIDS in several respects. The disease ...is characterized by hypergammaglobulinemia, polyclonal B cell activation, lymphadenopathy, and generalized immunosuppression within 5-8 weeks postinfection. The virus has been shown to infect B cells and macrophages and both T and B cells are required for MAIDS development. The manner in which T cells contribute to the disease process is not known. We report here that this retroviral infection leads to induction of a Thy-CD4+T cell subpopulation capable of transferring all the symptoms of MAIDS disease to normal B6 and B6 nu/nu. Essentially 100% of T cells recovered from B6 nu/nu mice, injected with CD4+ T cells from B6 MAIDS animal, is of the Thy-CD4+ phenotype. The proliferation of these T cells in culture and their ability to cause MAIDS in SCID mice is totally dependent on the presence of B cells. These T cells do not exhibit significant V beta restriction of their T cell receptors (TCR) and, by PCR analysis, have defective virus-specific sequences in the cellular genome. By several criteria, however, these cells do not produce the infectious virus. These results suggest that a B-cell-dependent population of CD4+ T cells from MAIDS animals, in the absence of detectable infectious virus production, has the ability to transfer MAIDS-like disease.
Abstract only
Introduction:
To better understand the cardioprotective mechanisms of regular physical activity (PA), we examined its association with plasma bioactive lipids (BAL) and prospective ...cardiovascular disease (CVD) events and evaluated the extent to which BMI might mediate this association.
Hypothesis: 1)
Higher PA associates with a bioactive lipid profile related to lower CVD risk;
2)
BMI mediates the PA-BAL and BAL-CVD associations.
Methods:
Using linear models (adjusted for age, sex, race, smoking, LDL, and total cholesterol), self-reported PA was examined with BAL assayed by an untargeted metabolomics platform in VITAL (N=1032) with validation in JUPITER (N=589). After performing mediation analysis through BMI (same adjustments), we evaluated both BMI-mediated and non-mediated PA-BAL associations with incident CVD using similarly adjusted conditional logistic regression in two nested CVD case-control studies: VITAL-CVD (770 pairs, followed by mediation analysis) and JUPITER-CVD (415 case-control pairs - validation)
Results:
We detected 237 significant PA-BAL associations in VITAL with replication in JUPITER (FDR<.1). Mediation analysis revealed 146 BMI-mediated associations (indirect effect p<.05), of which 53 showed a relationship with incident CVD in VITAL-CVD. Of those, 22 significant CVD-BAL associations were found in JUPITER-CVD (20 from 49 BMI-mediated and 2 from 4 non-BMI-mediated associations in VITAL-CVD). No relationship with CVD was found from the set of PA-BAL associations not mediated by BMI (indirect effect p≥.05). Notably, BALs related to decreased risk of CVD were positively associated with PA and
vice-versa
.
Conclusion:
We identified a signature of 22 PA-related BAL, which were also associated with incident CVD in two independent case-control studies. Although BMI-mediated associations were predominant, non-mediated effects were also detected, implying that more than one pathway may play a role in the PA-CVD relationship.
Despite the established role of the critical care pharmacist on the ICU multiprofessional team, critical care pharmacist workloads are likely not optimized in the ICU. Medication regimen complexity ...(as measured by the Medication Regimen Complexity-ICU MRC-ICU scoring tool) has been proposed as a potential metric to optimize critical care pharmacist workload but has lacked robust external validation. The purpose of this study was to test the hypothesis that MRC-ICU is related to both patient outcomes and pharmacist interventions in a diverse ICU population.
This was a multicenter, observational cohort study.
Twenty-eight ICUs in the United States.
Adult ICU patients.
Critical care pharmacist interventions (quantity and type) on the medication regimens of critically ill patients over a 4-week period were prospectively captured. MRC-ICU and patient outcomes (i.e., mortality and length of stay LOS) were recorded retrospectively.
A total of 3,908 patients at 28 centers were included. Following analysis of variance, MRC-ICU was significantly associated with mortality (odds ratio, 1.09; 95% CI, 1.08-1.11; p < 0.01), ICU LOS (β coefficient, 0.41; 95% CI, 00.37-0.45; p < 0.01), total pharmacist interventions (β coefficient, 0.07; 95% CI, 0.04-0.09; p < 0.01), and a composite intensity score of pharmacist interventions (β coefficient, 0.19; 95% CI, 0.11-0.28; p < 0.01). In multivariable regression analysis, increased patient: pharmacist ratio (indicating more patients per clinician) was significantly associated with increased ICU LOS (β coefficient, 0.02; 0.00-0.04; p = 0.02) and reduced quantity (β coefficient, -0.03; 95% CI, -0.04 to -0.02; p < 0.01) and intensity of interventions (β coefficient, -0.05; 95% CI, -0.09 to -0.01).
Increased medication regimen complexity, defined by the MRC-ICU, is associated with increased mortality, LOS, intervention quantity, and intervention intensity. Further, these results suggest that increased pharmacist workload is associated with decreased care provided and worsened patient outcomes, which warrants further exploration into staffing models and patient outcomes.
Our study aimed to describe the population pharmacokinetics (PK) of vancomycin in critically ill patients receiving extracorporeal membrane oxygenation (ECMO), including those receiving concomitant ...renal replacement therapy (RRT). Dosing simulations were used to recommend maximally effective and safe dosing regimens. Serial vancomycin plasma concentrations were measured and analyzed using a population PK approach on
. The final model was used to identify dosing regimens that achieved target exposures of area under the curve (AUC
) of 400-700 mg · h/liter at steady state. Twenty-two patients were enrolled, of which 11 patients received concomitant RRT. In the non-RRT patients, the median creatinine clearance (CrCL) was 75 ml/min and the mean daily dose of vancomycin was 25.5 mg/kg. Vancomycin was well described in a two-compartment model with CrCL, the presence of RRT, and total body weight found as significant predictors of clearance and central volume of distribution (
). The mean vancomycin renal clearance and
were 3.20 liters/h and 29.7 liters respectively, while the clearance for patients on RRT was 0.15 liters/h. ECMO variables did not improve the final covariate model. We found that recommended dosing regimens for critically ill adult patients not on ECMO can be safely and effectively used in those on ECMO. Loading doses of at least 25 mg/kg followed by maintenance doses of 12.5-20 mg/kg every 12 h are associated with a 97-98% probability of efficacy and 11-12% probability of toxicity, in patients with normal renal function. Therapeutic drug monitoring along with reductions in dosing are warranted for patients with renal impairment and those with concomitant RRT. (This study is registered with the Australian New Zealand Clinical Trials Registry ANZCTR under number ACTRN12612000559819.).
Perianal Crohn's disease is associated with poor outcomes and high medical costs. It is notoriously difficult to treat despite therapeutic advancements for luminal disease. A large animal model that ...mimics human perianal disease is needed to test innovative therapies.
This study aimed to create a swine model that replicates the inflammatory component and therapeutic challenges found in patients with perianal Crohn's disease.
This was an animal preclinical study.
The experiments were performed at the animal laboratory at the Johns Hopkins University.
Four sus scrufus female pigs were included in the study.
Four female pigs underwent creation of 3 surgical perianal fistulas each, 1 rectovaginal and 2 perianal. Size 24 French setons were placed to maintain patency of the fistula tracts for 4 weeks. After removal of the setons, trinitrobenzene sulfonic acid was administered into the fistula tract to create and maintain local inflammation mimicking perianal Crohn's disease.
An MRI was obtained to assess the fistulas and the pigs were euthanized to review histopathology.
Three inflammatory chronic fistula tracts were successfully created in each pig as confirmed by MRI and examination under anesthesia. This is the first report of maintaining patent fistulas in swine 2 weeks after removal of setons. For the first time, we reported that 2 pigs developed branching fistulas and small abscesses reminiscent of human perianal Crohn's disease. The corresponding histopathologic examination found significant chronic active inflammation on standard hematoxylin and eosin staining.
The fistulas were surgically induced and did not occur naturally.
A chronic perianal fistula model in pigs that strongly resembles human perianal Crohn's disease was successfully created. This model can be used to test novel therapeutics and techniques to pave the path for human trials. See Video Abstract at http://links.lww.com/DCR/B969 .
La enfermedad de Crohn perianal se asocia con malos resultados y altos costos médicos. Es notoriamente difícil de tratar a pesar de los avances terapéuticos para la enfermedad luminal. Se precisa de un modelo animal grande que imite la enfermedad perianal humana para probar terapias innovadoras.OBJETIVO:Nuestro objetivo de este estudio fue crear un modelo porcino que replique el componente inflamatorio y los desafíos terapéuticos que se encuentran en los pacientes con enfermedad de Crohn perianal.DISEÑO:Este fue un estudio preclínico en animales.AJUSTES:Los experimentos se realizaron en el laboratorio de animales de la Universidad Johns Hopkins.PACIENTES:Se incluyeron en el estudio cuatro cerdas sus scrofa.INTERVENCIONES:Cuatro cerdas fueron sometidas a la creación de 3 fístulas perianales quirúrgicas cada una: 1 recto vaginal y 2 perianales. Se colocaron sedales de 24 French para mantener la permeabilidad de los trayectos fistulosos durante 4 semanas. Tras el retiro de los sedales, se administró ácido trinitrobenceno sulfónico en el trayecto de la fístula para crear y mantener la inflamación local simulando la enfermedad de Crohn perianal.PRINCIPALES MEDIDAS DE RESULTADOS:Se obtuvo una resonancia magnética para evaluar las fístulas y los cerdos fueron sacrificados para revisar la histopatología.RESULTADOS:Se crearon de manera exitosa tres trayectos fistulosos inflamatorios crónicos en cada cerdo, confirmados por imágenes de resonancia magnética y examen bajo anestesia. Este es el primer informe de preservación de fístulas permeables en cerdos 2 semanas tras el retiro de los setones. Por primera vez, informamos que dos cerdos desarrollaron fístulas ramificadas y pequeños abscesos que recuerdan a la enfermedad de Crohn perianal humana. El examen histopatológico correspondiente encontró una significativa inflamación crónica activa en la tinción estándar de hematoxilina y eosina.LIMITACIONES:Las fístulas se indujeron quirúrgicamente y no se produjeron de forma natural.CONCLUSIONES:Se logro recrear con éxito un modelo de fístula perianal crónica en cerdos que se asemeja mucho a la enfermedad de Crohn perianal humana. Este modelo se puede utilizar para probar nuevas terapias y técnicas para allanar el camino para los ensayos en humanos. Consulte Video Resumen en http://links.lww.com/DCR/B969 . (Traducción-Dr Osvaldo Gauto).
The extent to which co-occurrence of cardiovascular disease (CVD) and cancer is due to shared risk factors or other mechanisms is unknown.
This study investigated the association of standard CVD risk ...factors, CVD biomarkers, pre-existing CVD, and ideal cardiovascular (CV) health metrics with the development of future cancer.
This study prospectively followed Framingham Heart Study and PREVEND (Prevention of Renal and Vascular End-Stage Disease) study participants free of cancer at baseline and ascertained histology-proven cancer. This study assessed the association of baseline CV risk factors, 10-year atherosclerotic (ASCVD) risk score, established CVD biomarkers, prevalent CVD, and the American Heart Association (AHA) Life’s Simple 7 CV health score with incident cancer using multivariable Cox models. Analyses of interim CVD events with incident cancer used time-dependent covariates.
Among 20,305 participants (mean age 50 ± 14 years; 54% women), 2,548 incident cancer cases occurred over a median follow-up of 15.0 years (quartile 1 to 3: 13.3 to 15.0 years). Traditional CVD risk factors, including age, sex, and smoking status, were independently associated with cancer (p < 0.001 for all). Estimated 10-year ASCVD risk was also associated with future cancer (hazard ratio HR: 1.16 per 5% increase in risk; 95% confidence interval CI 1.14 to 1.17; p < 0.001). The study found that natriuretic peptides (tertile 3 vs. tertile 1; HR: 1.40; 95% CI: 1.03 to 1.91; p = 0.035) were associated with incident cancer but not high-sensitivity troponin (p = 0.47). Prevalent CVD and the development of interim CV events were not associated with higher risk of subsequent cancer. However, ideal CV health was associated with lower future cancer risk (HR: 0.95 per 1-point increase in the AHA health score; 95% CI: 0.92 to 0.99; p = 0.009).
CVD risk, as captured by traditional CVD risk factors, 10-year ASCVD risk score, and natriuretic peptide concentrations are associated with increased risk of future cancer. Conversely, a heart healthy lifestyle is associated with a lower risk of future cancer. These data suggest that the association between CVD and future cancer is attributable to shared risk factors.
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Background
Natriuretic peptides promote natriuresis, diuresis, and vasodilation. Experimental deficiency of natriuretic peptides leads to hypertension (HTN) and cardiac hypertrophy, conditions more ...common among African Americans. Hospital‐based studies suggest that African Americans may have reduced circulating natriuretic peptides, as compared to Caucasians, but definitive data from community‐based cohorts are lacking.
Methods and Results
We examined plasma N‐terminal pro B‐type natriuretic peptide (NTproBNP) levels according to race in 9137 Atherosclerosis Risk in Communities (ARIC) Study participants (22% African American) without prevalent cardiovascular disease at visit 4 (1996–1998). Multivariable linear and logistic regression analyses were performed adjusting for clinical covariates. Among African Americans, percent European ancestry was determined from genetic ancestry informative markers and then examined in relation to NTproBNP levels in multivariable linear regression analysis. NTproBNP levels were significantly lower in African Americans (median, 43 pg/mL; interquartile range IQR, 18, 88) than Caucasians (median, 68 pg/mL; IQR, 36, 124; P<0.0001). In multivariable models, adjusted log NTproBNP levels were 40% lower (95% confidence interval CI, −43, −36) in African Americans, compared to Caucasians, which was consistent across subgroups of age, gender, HTN, diabetes, insulin resistance, and obesity. African‐American race was also significantly associated with having nondetectable NTproBNP (adjusted OR, 5.74; 95% CI, 4.22, 7.80). In multivariable analyses in African Americans, a 10% increase in genetic European ancestry was associated with a 7% (95% CI, 1, 13) increase in adjusted log NTproBNP.
Conclusions
African Americans have lower levels of plasma NTproBNP than Caucasians, which may be partially owing to genetic variation. Low natriuretic peptide levels in African Americans may contribute to the greater risk for HTN and its sequalae in this population.
Alterations in metabolism influence lifespan in experimental models, but data in humans are lacking. Here we use liquid chromatography/mass spectrometry to quantify 217 plasma metabolites and examine ...their relation to longevity in a large cohort of men and women followed for up to 20 years. We find that, higher concentrations of the citric acid cycle intermediate, isocitrate, and the bile acid, taurocholate, are associated with lower odds of longevity, defined as attaining 80 years of age. Higher concentrations of isocitrate, but not taurocholate, are also associated with worse cardiovascular health at baseline, as well as risk of future cardiovascular disease and death. None of the metabolites identified are associated with cancer risk. Our findings suggest that some, but not all, metabolic pathways related to human longevity are linked to the risk of common causes of death.
To determine whether a structured OPAT program supervised by an infectious disease physician and led by an OPAT nurse decreased hospital readmission rates and OPAT-related complications and whether ...it affected clinical cure. We also evaluated predictors of readmission while receiving OPAT.
A convenience sample of 428 patients admitted to a tertiary-care hospital in Chicago, Illinois, with infections requiring intravenous antibiotic therapy after hospital discharge.
In this retrospective, quasi-experimental study, we compared patients discharged on intravenous antimicrobials from an OPAT program before and after implementation of a structured ID physician and nurse-led OPAT program. The preintervention group consisted of patients discharged on OPAT managed by individual physicians without central program oversight or nurse care coordination. All-cause and OPAT-related readmissions were compared using the χ
test. Factors associated with readmission for OPAT-related problems at a significance level of
< .10 in univariate analysis were eligible for testing in a forward, stepwise, multinomial, logistic regression to identify independent predictors of readmission.
In total, 428 patients were included in the study. Unplanned OPAT-related hospital readmissions decreased significantly after implementation of the structured OPAT program (17.8% vs 7%;
= .003). OPAT-related readmission reasons included infection recurrence or progression (53%), adverse drug reaction (26%), or line-associated issues (21%). Independent predictors of hospital readmission due to OPAT-related events included vancomycin administration and longer length of outpatient therapy. Clinical cure increased from 69.8% before the intervention to 94.9% after the intervention (
< .001).
A structured ID physician and nurse-led OPAT program was associated with a decrease in OPAT-related readmissions and improved clinical cure.
Limited data exist regarding systolic blood pressure (SBP) through mid- to late-life and late-life cardiac function and heart failure (HF) risk. Among 4,578 HF-free participants in the ...Atherosclerosis Risk in Communities study attending the 5
th
Visit (2011-2013; age 75±5 years), time-averaged cumulative SBP was calculated as the sum of averaged SBPs from adjacent consecutive visits (Visits 1-5) indexed to total observation time (24±1 years). Calculations were performed using measured SBPs and also incorporating antihypertensive medication specific effect constants (‘underlying’ SBP). Outcomes included comprehensive echocardiography at Visit 5 and post-Visit 5 incident HF, HF with preserved ejection fraction (HFpEF), and reduced ejection fraction (HFrEF). Higher cumulative SBP was associated with greater LV mass and worse diastolic measures (all p <0.001), associations that were stronger with underlying compared to cumulative SBP (all p<0.05). At 5.6±1.2 years follow-up post-Visit 5, higher cumulative measured and underlying SBP were associated with incident HF (HR per 10 mmHg for measured: 1.12 1.01-1.24; underlying: 1.19 95%CI 1.10-1.30) and HFpEF (measured: 1.15 1.00-1.33; underlying: 1.28 1.14-1.45), but not HFrEF (measured: 1.11 0.94-1.32; underlying: 1.11 0.96-1.24). Associations with HF and HFpEF were more robust with cumulative underlying compared to measured SBP (all p <0.05). Time-averaged cumulative SBP in mid- to late-life is associated with worse cardiac function and risk of incident HF, especially HFpEF, in late-life. These associations were stronger considering underlying as opposed to measured SBP, highlighting the importance of prevention and effective treatment of hypertension to prevent late-life cardiac dysfunction and HF.
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