The sternal brace: a novel osteopathic diagnostic screening tool to rule out cardiac chest pain in the emergency department.

CONTEXT: Chest pain is one of the most common emergency medicine complaints in the United States, yet no reliable physical examination finding exists to help differentiate cardiac chest pain (CCP) from noncardiac chest pain (non-CCP). OBJECTIVES: This is a diagnostic accuracy study of the sternal brace, a novel physical examination maneuver to rule out cardiac-related chest pain from non-CCP. METHODS: We performed this double-blind prospective diagnostic accuracy pilot study on 34 adults in the Newark Beth Israel emergency department with a chief complaint of chest pain. We utilized the Numerical Rating Scale 0-10 (NRS) to quantify chest pain severity before and after the maneuver. Eligible for inclusion were adults over 18 years old who were able to provide written informed consent. We performed the sternal brace on all consenting adults meeting these criteria, and the researchers were blinded between test results and final diagnosis. Cardiac ischemia in the US with a disease prevalence of 0.029 was utilized. RESULTS: A total of 34 patients were included, of whom 11 had a final diagnosis of cardiac-related chest pain. The cutoff value was a decrease in pain severity of 2 or greater between pretest and posttest. Sensitivity was 81.8 % (95 % confidence interval [CI], 48.2-97.7 %); specificity 34.8 % (95 % CI, 16.4-57.3 %), the positive predictive value was 3.6 % (95 % CI, 0.1-20.3 %), and the negative predictive value was 98.4 % (95 % CI, 66.8-100.0 %). CONCLUSIONS: The sternal brace is a good screening test because if a person with chest pain has an NRS that decreases by 2 or more with the maneuver, then there is a 98.5 % chance that the chest pain is noncardiac, given the prevalence of cardia ischemia. In addition, if the disease is present, then it is 81.8 % likely that their NRS will not decrease by more than 2.

Clinical Outcomes and Inpatient Mortality Among Hospitalized Patients With Concomitant Autoimmune Hepatitis and Systemic Lupus Erythematosus.

Background Autoimmune hepatitis (AIH) is an inflammatory disease of the liver that is characterized by a broad disease spectrum, circulating autoantibodies, and elevated serum globulin levels. Systemic lupus erythematosus (SLE) is a chronic disease that is characterized by a high inflammatory state and is associated with multiorgan system involvement. Despite a well-known association between AIH and other autoimmune diseases, the literature is deficient on the associations between AIH-related outcomes and complications in SLE patients. This study aims to evaluate the effects of SLE on clinical outcomes and inpatient mortality in patients with AIH. Method The National Inpatient Sample (NIS) database was used to identify AIH-related hospitalizations from 2012 to 2014 using International Classification of Diseases Ninth Edition Revision (ICD-9) codes. Patients were divided into two groups, those with and without SLE. Primary outcomes were mortality, hospital charges, and length of stay (LOS). Secondary outcomes were complications associated with AIH: cirrhosis, gastrointestinal (GI) bleed, acute liver failure (ALF), cholangitis, pancreatitis, and sepsis. Chi-squared tests for categorical data and independent t-test for continuous data were used to compare outcomes. Multivariate analysis was performed to assess the primary outcomes after adjusting for confounding variables. Results There were 17,050 AIH-related hospitalizations from 2012 to 2014 and 1,115 patients had SLE. In patients with SLE and AIH, 1,035 were female with average age of 48.6. The average LOS was 6.3 days, mortality rate was 1.35%, and total hospital charges were $48,146. SLE was associated with a statistically significant lower mortality rate compared to the control. LOS, hospital cost, and CCI (Charlson Comorbidity Index) were not found to be significantly different. For secondary outcomes, SLE was statistically significant for having higher pancreatitis rates. SLE patients had statistically significant lower cholangitis, and ALF. Differences in complications such as sepsis and GI bleed were non-significant. Conclusion SLE is known to have a high inflammatory state so it was hypothesized that there would be higher rates of complications and a higher mortality rate in those with concomitant AIH. This study showed that the mortality rate was lower in SLE patients with lower rates of complications including ALF and cholangitis. We postulate that SLE patient outcomes are likely affected by the treatment regimen involved with SLE, including corticosteroids. This would provide an immunosuppressive state, limiting the autoreactivity cascade in AIH, in effect leading to better outcomes and a mortality benefit. This study identifies a lower mortality rate and lower complication rates in patients with AIH and SLE overlap as compared to patients with AIH alone and future studies are needed to confirm these associations.

A Rare Presentation of Infective Endocarditis Due to Serratia marcescens.

Serratia marcescens is an opportunistic organism that can commonly cause respiratory tract infections in immunocompromised individuals. It has also been shown to cause urinary tract infections and soft tissue infections. It has several virulence factors including fimbriae-like adhesions that allow for surface attachment and biofilm formation to increase the likelihood of infections in humans. However, it has rarely been shown to cause infective endocarditis but has an increased mortality compared to the usual microbial agents associated with it (Staphylococcus and Streptococcus). Therefore, a high index of suspicion is necessary to accurately diagnose and treat patients at risk. Most published cases of S. marcescens endocarditis show that almost all described patients had chronic medical conditions or cardiovascular abnormalities. Furthermore, treatment has become difficult as S. marcescens has been shown to exhibit antibacterial resistance with beta-lactamase production. Here, we present a complicated case of S. marcescens pneumonia and infective endocarditis with a good prognosis. Our patient had a rapid onset of complications (i.e. including joint infections, splenic abscesses, myositis, and septic arthritis), despite the initial benign presentation concerning for pneumonia. However, the patient had a favorable outcome due to the prompt work-up and treatment that was initiated. Therefore, S. marcescens bacteremia in a patient with risk factors should prompt further investigation with a thorough evaluation of source followed by immediate management. This case highlights the fastidious nature of S. marcescens. Further investigation needs to be done to elucidate the pathogenesis of the organism that can serve as a target for future therapeutic intervention.

Physical Activity After Treatment for Symptomatic Peripheral Artery Disease.

The association of invasive versus noninvasive treatment and physical activity level in patients with claudication remains unclear. Participants with claudication were enrolled from US vascular clinics. Treatment was categorized as invasive (surgical or endovascular treatment <3 months of initial visit) versus noninvasive. Self-reported leisure time (LTPA) and work related physical activity (WRPA) (sedentary, mild, moderate/strenuous), and health status (peripheral artery questionnaire summary score [PAQ SS]) was measured at baseline and 12 months. Change in PA was also categorized as increased, decreased, persistent sedentary [reference] and persistent active based on activity status at baseline and 12 months. Multivariable logistic regression assessed the association of treatment with 12-month LTPA and WRPA. Multivariable linear regression examined the association between 12-month change in PA with a 12-month change in PAQ. A total of 196of 656 patients (29.9%) underwent invasive treatment. There was no association between treatment and 12-month LTPA (p = 0.77) or WRPA (p = 0.26). Compared with being persistently sedentary, increased LTPA was associated with increased PAQ SS (OR 11.1 95% CI [4.4 to 17.7], p <0.01). In conclusion, there was no association between invasive treatment and physical activity at follow up despite a greater health status change in the invasive group. As increased physical activity was associated with more health status gains than remaining sedentary, additional ways to improve physical activity levels could potentially improve PAD outcomes.

Physical Activity in Patients with Symptomatic Peripheral Artery Disease: Insights from the PORTRAIT Registry.

OBJECTIVE: A physically active lifestyle reduces the risk of cardiovascular events and functional impairment in patients with peripheral artery disease (PAD). There are limited data on the patterns of physical activity in patients with PAD compared between countries. METHODS: Self reported physical activity (sedentary vs. not) was obtained at enrolment, 3, 6, and 12 months in the US and Netherlands' cohorts of the Patient-centered Outcomes Related to Treatment Practices in Peripheral Arterial Disease: Investigating Trajectories (PORTRAIT) registry of patients with new or worsening claudication. Multivariable repeated measures using modified Poisson regression analysis compared the proportion of sedentary participants over time between countries to identify factors that attenuate intercountry differences. RESULTS: Of 1 098 participants, 743 (67.7%) and 355 (32.3%) were recruited from the USA and the Netherlands respectively. Compared with the Netherlands, participants from the US were older (mean age 68.6 vs. 65.3 years; p < .001), more obese (41.3% vs. 20.5%; p < .001), and more likely to be female (41.3% vs. 31.4%; p = .002). There were fewer current smokers (30.1% vs. 52.8%; p < .001) and supervised exercise referrals (1.6% vs. 63.9%; p < .001) in the US compared with the Netherlands. US participants were more sedentary at baseline (43.7% vs. 34.1%; p < .001). Sedentary behaviour decreased after three months in both countries, then diverged with an increase in sedentary participants in the USA. Risk of sedentary behaviour was significantly greater in the USA compared with the Netherlands at 12 months, after adjustment of sociodemographic, lifestyle factors, and comorbidities (relative risk [RR] 1.56, 95% confidence interval [CI] 1.08-2.25; p = .020) but was attenuated after accounting for referral to supervised exercise (RR 1.20, 95% CI 0.67-2.16; p = .54). CONCLUSION: Referral to supervised exercise was key in explaining the observed difference in the physical activity levels between patients with PAD in the USA and the Netherlands. Further promotion of supervised exercise for PAD may improve physical activity in patients with PAD and modify cultural norms of inactivity in the US.

Molecular dynamics study of the encapsulation capability of a PCL-PEO based block copolymer for hydrophobic drugs with different spatial distributions of hydrogen bond donors and acceptors.

Molecular dynamics simulation was used to study the potential of using a block copolymer containing three poly(epsilon-caprolactone) (PCL) blocks of equal length connected to one end of a poly(ethylene oxide) (PEO) block, designated as PEO-b-3PCL, to encapsulate two classes of hydrophobic drugs with distinctively different molecular structures. In particular, the first class of drugs consisted of two cucurbitacin drugs (CuB and CuI) that contain multiple hydrogen bond donors and acceptors evenly distributed on their molecules while the other class of drugs (fenofibrate and nimodipine) contain essentially only clustered hydrogen bond acceptors. In the case of cucurbitacin drugs, the results showed that PEO-b-3PCL lowered the Flory-Huggins interaction parameters (chi) considerably (i.e., increased the drug solubility) compared to the linear di-block copolymer PEO-b-PCL with the same PCL/PEO (w/w) ratio of 1.0. However, the opposite effect was observed for fenofibrate and nimodipine. Analysis of the intermolecular interactions indicates that the number of hydrogen bonds formed between the three PCL blocks and cucurbitacin drugs is significantly higher than that of the linear di-block copolymer. On the other hand, owing to the absence of hydrogen bond donors and the clustering of the hydrogen bond acceptors on the fenofibrate and nimodipine molecules, this significantly reduces the number of hydrogen bonds formed in the multi-PCL block environment, leading to unfavourable chi values. The findings of the present work suggest that multi-hydrophobic block architecture could potentially increase the drug loading for hydrophobic drugs with structures containing evenly distributed multiple hydrogen bond donors and acceptors.

Prediction of the solubility of cucurbitacin drugs in self-associating poly(ethylene oxide)-b-poly(alpha-benzyl carboxylate epsilon-caprolactone) block copolymer with different tacticities using molecular dynamics simulation.

Molecular dynamics (MD) simulation was used to investigate the solubility of two hydrophobic drugs Cucurbitacin B (CuB) and Cucurbitacin I (CuI) in poly(ethylene oxide)-b-poly(alpha-benzyl carboxylate epsilon-caprolactone) (PEO-b-PBCL) block copolymers with different tacticities. In particular, di-block copolymer with three different tacticities viz. PEO-b-iPBCL, PEO-b-sPBCL, and PEO-b-aPBCL were used. The solubility was quantified by calculating the corresponding Flory-Huggins interaction parameters (chi) using random binary mixture models with 10wt% of drug. The tacticity of the di-block copolymer was found to influence significantly the solubility of two drugs in it. In particular, based on MD simulation results, only PEO-b-sPBCL exhibited solubility while the other two did not. Given the fact that the drugs were shown to be soluble in PEO-b-PBCL experimentally, it is predicted that the tacticity of the di-block copolymer synthesized in experiment is syndiotactic. This predication matches well with the dominant ring opening polymerization of cyclic lactones to syndiotactic polymers by stannous octoate as catalyst used to prepare PEO-b-PBCL block copolymers in our previous experiments. The simulation results showed that the solubility of the drugs in PEO-b-sPBCL is attributed to the favorable intra-molecular interaction of the di-block copolymer and favorable intermolecular interaction between the di-block copolymer and the drugs. Radial distribution function analysis provides useful insights into the nature and type of the intermolecular interactions.

Roles of nonpolar and polar intermolecular interactions in the improvement of the drug loading capacity of PEO-b-PCL with increasing PCL content for two hydrophobic Cucurbitacin drugs.

Molecular dynamics (MD) simulation was used to study the roles of nonpolar and polar intermolecular interactions in the improvement of the drug loading capacity of poly(ethylene oxide)-b-poly(epsilon-caprolactone) (PEO-b-PCL) with increasing PCL content for two water insoluble anticancer drugs: Cucurbitacin B (CuB) and Cucurbitacin I (CuI). In particular, random binary mixture models containing 10-12 wt % drug and remaining PEO-b-PCL with three different PCL/PEO (w/w) ratios (0.5, 1, and 2) were used to calculate their Flory-Huggins interaction parameters (chi). The MD simulation results show that, for both CuB and CuI, the computed chi decreases (i.e., affinity increases) with increasing PCL/PEO ratio. Such results are consistent with our experimental observation that increasing the PCL/PEO (w/w) ratio from 1 to 4.8 significantly increases the drug loading capacity of micelles formed by PEO-b-PCL for both drugs. Analysis of the energy data shows that increasing affinity (loading) at higher PCL/PEO ratio is attributed to the increase in favorable polar interactions and to the formation of additional hydrogen bonds (H-bonds) between the drugs and the PCL block rather than to the increase in the hydrophobic characteristics of the diblock copolymer as one would normally expect. In fact, the nonpolar intermolecular interactions became more unfavorable at higher PCL/PEO ratio. Analysis of the radial distribution functions of the model mixtures indicates that at high PCL/PEO ratio, multiple H-bond sites on the PCL block interacted with single H-bond sites on the drug molecules. However, at low PCL/PEO ratio, only single H-bonds formed between various H-bond sites on the drug molecules and those of the PCL and PEO blocks. It seems that formation of H-bonds between multiple H-bond sites on the PCL block and single H-bond sites on the drug molecules is responsible for inducing drug/PEO-b-PCL affinity. The finding also explains the experimental observation that release rates of both drugs decrease with increasing PCL/PEO ratio and that the decrease in the release rate of CuB is more pronounced than that of CuI. Our simulation results show that the number of H-bonds formed between CuB and the PCL block is much higher than that of CuI at high PCL/PEO ratio.

Self-associating poly(ethylene oxide)-b-poly(alpha-cholesteryl carboxylate-epsilon-caprolactone) block copolymer for the solubilization of STAT-3 inhibitor cucurbitacin I.

An increase in the degree of chemical compatibility between drug and polymeric structure in the core has been shown to raise the encapsulation efficiency and lower the rate of drug release from polymeric micelles. In this study, to achieve an optimized polymeric micellar delivery system for the solubilization and controlled delivery of cucurbitacin I (CuI), the Flory-Huggins interaction parameter (chi(sc)) between CuI and poly(epsilon-caprolactone) (PCL), poly(alpha-benzylcarboxylate-epsilon-caprolactone) (PBCL) and poly(alpha-cholesteryl carboxylate-epsilon-caprolactone) (PChCL) structures was calculated by group contribution method (GCM) as an indication for the degree of chemical compatibility between different micellar core structures and CuI. The results pointed to a better compatibility between CuI and PChCL core rationalizing the synthesis of self-associating methoxy poly(ethylene oxide)-b-poly(alpha-cholesteryl carboxylate-epsilon-caprolactone) block copolymer (MePEO-b-PChCL). Novel block copolymer of MePEO-b-PChCL was synthesized through, first, preparation of substituted monomer, that is, alpha-cholesteryl carboxylate-epsilon-caprolactone, and further ring opening polymerization of this monomer by methoxy PEO (5000 g mol(-1)) using stannous octoate as catalyst. Synthesized block copolymers were characterized for their molecular weight and polydispersity by (1)H NMR and gel permeation chromatography. Self-assembled MePEO-b-PChCL micelles were characterized for their size, morphology, critical micellar concentration (CMC), capacity for the physical encapsulation of CuI, and mode of CuI release in comparison to MePEO-b-PCL and MePEO-b-PBCL micelles. Overall, the experimental order for the level of CuI encapsulation in different polymeric micellar formulations was consistent with what was predicted by the Flory-Huggins interaction parameter. Although MePEO-b-PChCL micelles exhibited the highest level of CuI loading, this structure did not show any significant superiority over MePEO-b-PCL in controlling CuI release. The most efficient control over the rate of CuI release was achieved by MePEO-b-PBCL micelles that had more viscous cores than that of MePEO-b-PChCL, instead. The results point to a potential for MePEO-b-PChCL micelles for the solubilization of cholesterol compatible drugs. It also highlights the inadequacy of the Flory-Huggins interaction parameter calculated by GCM in predicting the order of drug release from different polymeric micellar structures.

Application of molecular dynamics simulation to predict the compatability between water-insoluble drugs and self-associating poly(ethylene oxide)-b-poly(epsilon-caprolactone) block copolymers.

In the present work, molecular dynamics (MD) simulation was applied to study the solubility of two water-insoluble drugs, fenofibrate and nimodipine, in a series of micelle-forming PEO-b-PCL block copolymers with combinations of blocks having different molecular weights. The solubility predictions based on the MD results were then compared with those obtained from solubility experiments and by the commonly used group contribution method (GCM). The results showed that Flory-Huggins interaction parameters computed by the MD simulations are consistent with the solubility data of the drug/PEO-b-PCL systems, whereas those calculated by the GCM significantly deviate from the experimental observation. We have also accounted for the possibility of drug solubilization in the PEO block of PEO-b-PCL.