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Background Pulmonary arterial hypertension (PAH) has a delay in diagnosis that makes time since diagnosis of interest in this population. Objectives To assess psychological conditions, perceived stress, QOL, and interpersonal support and to explore whether these factors may correlate with time since diagnosis in patients with PAH. Methods Participants at an academic medical center ( n = 108) completed psychological questionnaires (Cambridge Pulmonary Hypertension Outcome Review, Patient Health Questionnaire-9, Perceived Stress Scale-10, and Interpersonal Support Evaluation List-Short Form). Results Prevalence of psychiatric disorder, major depression, and “other depressive disorder” were 29.6%, 15.7%, and 9.3%, respectively. Participants reported adequate social support, high perceived stress, and average quality of life. Time since diagnosis was positively associated with greater perceived social support (ρ = 0.174, p = .075) and greater perceived stress (ρ = 0.191, p = .048), but no other psychological factor. Conclusions Routine psychological assessment and timely referral for mental health services are suggested. Social support may buffer patients from stress. [ABSTRACT FROM AUTHOR]

The natural vitamin E family is composed of 8 members equally divided into 2 classes: tocopherols (TCP( and tocotrienols (TE). A growing body of evidence suggests TE possess potent biological activity not shared by TCP. The primary objective of this work was to determine the concentrations of TE (200 mg mixed TE, b.i.d.) and TCP [200 mg α-TCP, b.i.d.)] in vital tissues and organs of adults receiving oral supplementation. Eighty participants were studied. Skin and blood vitamin E concentrations were determined from healthy participants following 12 wk of oral supplementation of TE or TCP. Vital organ vitamin E levels were determined by HPLC in adipose, brain, cardiac muscle, and liver of surgical patients following oral TE or TCP supplementation (mean duration, 20 wk; range, 1-96 wk). Oral supplementation of TE significantly increased the TE tissue concentrations in blood, skin, adipose, brain, cardiac muscle, and liver over time. a-TE was delivered to human brain at a concentration reported to be neuroprotective in experimental models of stroke. In prospective liver transplantation patients, oral TE lowered the model for end-stage liver disease (MELD) score in 50% of patients supplemented, whereas only 20% of TCP-supplemented patients demonstrated a reduction in MELD score. This work provides, to our knowledge, the first evidence demonstrating that orally supplemented TE are transported to vital organs of adult humans. The findings of this study, in the context of the current literature, lay the foundation for Phase II clinical trials testing the efficacy of TE against stroke and end-stage liver disease in humans. [ABSTRACT FROM AUTHOR]

Summary: Objective: Asthma is one of the most common medical conditions complicating pregnancy. Despite the presence of published guidelines outlining the care of the pregnant patient with asthma, disparities in the treatment of acute asthma exacerbations in the emergency department related to pregnancy status are known to exist. We sought to determine if pregnancy status affected the treatment of women presenting to a tertiary emergency department for care of acute asthma exacerbations. Methods: We retrospectively compared the emergency department treatment of acute asthma exacerbations in 123 pregnant women to 123 non-pregnant controls. Asthma exacerbations were classified by severity according to pre-determined criteria. Results: In the emergency department (ED), pregnant women were significantly less likely to be treated with systemic corticosteroids than non-pregnant controls (50.8% versus 72.4%, p = 0.001). Similarly, 41% of pregnant women received prescriptions for prednisone at the time of discharge from the ED compared to 69.2% of non-pregnant women (p < 0.001). Conclusions: In this population of asthmatics presenting to a tertiary emergency department with acute asthma exacerbations, pregnant women were less likely to receive appropriate therapy with systemic corticosteroids. [ABSTRACT FROM AUTHOR]

Abstract: To protect against ricin intoxication, a genetically derived ricin A chain vaccine candidate (RVEc) was developed lacking the toxic N-glycosidase activity (). The vaccine protects animals against an aerosolized ricin holotoxin (RT) challenge (). In the current study, the RVEc vaccine was evaluated for its interaction and effect on human endothelial cells. RVEc was tested in an in vitro cellular-based bioassay, consisting of primary human endothelial cells cultured on collagen-coated inserts, to which concentrations of the vaccine candidate (0.6, 2, 2.5 or 9μM) were added. RVEc showed no signs of adverse activity on the cells (e.g., cytotoxicty activity) as measured by changes in trans-endothelial electrical resistance (TEER). In contrast, ricin toxin (RT) cytotoxicity was observed at all concentrations tested. Under light microscopy, no cytotoxicity was visible at 24h with 0.6 or 9μM of RVEc. However, cytotoxicity was observed for RT and to a lesser degree for RTA. Flow cytometric analysis showed binding of RT, slight binding of RTA, and no binding of the RVEc vaccine to endothelial cells. The presence of RTB as a contaminant contributing to the cytotoxicity in the RTA preparation was ruled out by a RTB-specific ELISA. In addition, RTA at 9μM produced a cytotoxic activity that could not be explained exclusively by the presence of azide in the RTA buffer. In the current study, the model demonstrated no discernable adverse events of the RVEc vaccine on human endothelial cells, when compared to the toxicity caused by holotoxin or native RTA preparations. [Copyright &y& Elsevier]

Background: Zinc deficiency is a cause of immune dysfunction and infection. Previous human studies have shown that the activation of the acute phase response alters zinc metabolism. Whether the alteration in zinc metabolism is predictive of disease severity in the setting of critical illness is unclear. Objective: We sought to determine whether differences occur in zinc metabolism at the onset of critical illness between infected (septic) and noninfected subjects. Design: We conducted this prospective study in an adult medical intensive care unit (MICU) at a tertiary care hospital. Subjects were enrolled within 24 h of intensive care unit admission. Subjects who did not meet sepsis criteria were considered for the critically ill control (CIC) arm. After patient consent, blood was immediately collected to measure plasma zinc and cytokine concentrations and zinc transporter gene expression in peripheral blood monocytes. Clinical data during the MICU stay were also recorded. Results: A total of 56 patients were evaluated (22 septic, 22 CIC, and 12 healthy subjects). Plasma zinc concentrations were below normal in CIC patients and further reduced in the septic cohort (57.2 ± 18.2 compared with 45.5 ± 18.1 μg/dL). Cytokine concentrations increased with decreasing plasma zinc concentrations (P = 0.05). SLC39A8 gene expression was highest in patients with the lowest plasma zinc concentrations and the highest severity of illness. Conclusions: The alteration of zinc metabolism was more pronounced in septic patients than in noninfected critically ill patients. Specifically, sepsis was associated with lower plasma zinc concentrations and higher SLC39A8 mRNA expression, which correlated with an increased severity of illness, including cardiovascular dysfunction. [ABSTRACT FROM AUTHOR]

Abstract: This study investigated the cytotoxic potential of novel activated carbon adsorbents (MAST Carbon International Ltd.) developed for medical applications such as extracorporeal therapies. Carbon adsorbents were assessed for their in vitro cytotoxicity against a V79 cell line using a material extraction method in combination with a colony formation assay. Results were compared to those from a commercially available cellulose-coated carbon adsorbent, developed for direct haemoperfusion. Initial findings demonstrated an inhibition of colony formation and an apparent cytotoxic effect. However, it was found that this inhibition occurred as a result of protein and ion adsorption by carbon materials possessing large surface area and highly developed porous structure. Consequently, these essential nutrients were unavailable to the cells during colony formation. Modifications to the cytotoxicity assessment methods were required in order to take into account nutrient loss. Subsequently it was determined that the carbon materials do not show a cytotoxic response towards the V79 cell line under the modified conditions employed. The suggested approach may be useful in the assessment of other biomaterials such as carbon nanotubes and other nanoparticles which possess large surface area. The preliminary data support the ongoing investigation of these adsorbents as candidates for use in extracorporeal therapies. [Copyright &y& Elsevier]

Purpose: We conducted this study to determine if preoperative magnetic resonance imaging (MRI) cross-sectional area measurements would correlate with intraoperative graft size in hamstring anterior cruciate ligament (ACL) reconstructions. Methods: We retrospectively reviewed ACL reconstructions performed by a single surgeon using a quadruple-looped hamstring allograft. Preoperative MRI axial images were used to determine the combined cross-sectional area of the semitendinosis and gracilis tendons. These cross-sectional areas were correlated to the intraoperative graft size. Results: We found a strong correlation between the MRI cross-sectional areas and graft size. If the combined cross-sectional areas were ≥18mm2, there was an 88% probability of obtaining a graft of sufficient size at the time of surgery. Conclusions: We conclude that our technique is a reliable option to assist the surgeon with preoperative determination of graft size. This is valuable to the orthopaedist to more accurately discuss graft options with the patient and improve preoperative preparation with respect to graft choice. Level of Evidence: Level II, development of diagnostic criteria on the basis of consecutive patients with universally applied gold standard. [Copyright &y& Elsevier]

The maternal diet is an important determinant of glutathione-related metabolism in rats. Glutathione (GSH) may play a major role in the detoxification of sulfur dioxide (SO2) within the lungs. The effects of fetal exposure to a low protein maternal diet upon later susceptibility to pulmonary injury induced by chronic SO2 exposure were evaluated in young adult rats. Pregnant rats were fed purified diets containing 180 g casein/kg (control diet) or 120, 90 or 60 g casein/kg (experimental diets). After parturition, all dams were fed a standard non-purified diet (189 g protein/kg diet). The pups thus differed only in terms of protein nutrition during gestation. At seven wk of age the male pups were housed in either room air or 286 microg SO2/m3 for 5 h/d during a 28-d period. At the end of the final SO2 treatment period, the rats exposed to 90 or 60 g casein/kg diets in utero exhibited significantly greater pulmonary injury, as assessed by bronchoalveolar lavage, than did those exposed to control diet in utero. Significant maternal diet-induced differences in activities of enzymes of the gamma-glutamyl cycle were noted in the lungs and livers of rats which had not undergone SO2 treatment. Furthermore, the response of these enzyme activities to SO2 treatment was determined by prior exposure to the maternal diet. SO2-treated rats exposed to control diet (180 g casein/kg) and low protein diet (60 g casein/kg), but not those exposed to 120 or 90 g casein/kg diets, tended to augment the activities, relative to rats not treated with SO2, of enzymes which maintain tissue GSH status either through synthesis or recycling. Differences in susceptibility to SO2-induced tissue injury may be related to programming of GSH metabolism by the maternal diet. Alternatively, impaired immune and acute phase responses to an inflammatory insult may account for a failure to resolve initial SO2-induced injury in rats exposed to low protein maternal diets. [ABSTRACT FROM AUTHOR]

Objective: Burnout is specific to the work domain and in physicians is indicative of emotional exhaustion, depersonalization in relationships with coworkers and detachment from patients, and a sense of inadequacy or low personal accomplishment. The purpose of this study was to determine the burnout rate among gynecologic oncologists and evaluate other personal, professional, and psychosocial factors associated with this condition.Study Design: This study used a cross-sectional design. Current members of the Society of Gynecologic Oncology were sent an anonymous email survey including 76 items measuring burnout, psychosocial distress, career satisfaction, and quality of life.Results: A total of 1086 members were invited, 436 (40.1%) responded, and 369 (84.6%) of those completed the survey. Of physicians, 30% scored high for emotional exhaustion, 10% high for depersonalization, and 11% low for personal accomplishment. Overall, 32% of physicians scored above clinical cutoffs indicating burnout. In all, 33% screened positive for depression, 13% endorsed a history of suicidal ideation, 15% screened positive for alcohol abuse, and 34% reported impaired quality of life. Nonetheless, 70% reported high levels of personal accomplishment, and results suggested most were satisfied with their careers, as 89% would enter medicine again and 61% would encourage their child to enter medicine. Respondents with high burnout scores were less likely to report they would become a physician again (P = .002) or encourage a child to enter medicine (P < .001), and more likely to screen positive for depression (P < .001), alcohol abuse (P = .006), history of suicidal ideation (P < .001), and impaired quality of life (P < .001).Conclusion: Burnout is a significant problem associated with psychosocial distress and lower levels of career satisfaction in gynecologic oncologists. Burnout in obstetrics-gynecology and gynecologic oncology is of particular concern as young age and female gender are often identified as risk factors for this significant problem. Interventions targeted at improving quality of life, treatment of depression, or alcohol abuse may have an impact on burnout. However, significant barriers may exist as 44.5% of respondents in this study reported that they would be reluctant to seek medical care for depression, substance use, or other mental health issues due to concerns about their medical license. [ABSTRACT FROM AUTHOR]

Objective: Left ventricular dysfunction and preoperative hyponatremia are associated with adverse outcomes after cardiac surgery. However, the interactions between them are unknown. Thus, we evaluated the interaction of low left ventricular ejection fraction (<40%) and preoperative hyponatremia (Na <135 mEq/L) with morbidity and mortality after cardiac surgery. Methods: The interaction of hyponatremia and ejection fraction with hospital complications, length of stay, and mortality was analyzed using logistic and Cox regression analysis in 2247 patients who underwent cardiac surgery between 2005 and 2008 at The Ohio State University Wexner Medical Center. Results: Of the patients, 68.5% had normal ejection fraction. Hyponatremia was present in 18% of patients with normal ejection fraction and 35% of patients with low ejection fraction. Hyponatremic patients had higher rates of New York Heart Association class III and IV, more comorbidities, and higher Society of Thoracic Surgeons score and European System for Cardiac Operative Risk Evaluation irrespectively of their ejection fraction. The correlation between preoperative sodium and ejection fraction was weak (r 2  = 0.04). Hyponatremia increased the rate of postoperative complications and hospital stay, and decreased 1- and 3-year survivals in patients with both normal and low ejection fraction. Hyponatremia was independently associated with longer hospital stay for normal ejection fraction (multiplier, 1.18; confidence interval, 1.09-1.27; P < .001) and low ejection fraction (multiplier, 1.10; confidence interval, 1.0-1.21; P = .05), increased need for dialysis for normal ejection fraction (odds ratio, 2.16; confidence interval, 1.08-4.32; P = .03), and increased risk of mortality for normal ejection fraction (hazard ratio, 1.56; confidence interval, 1.20-2.05; P = .001), but not for patients with low ejection fraction (hazard ratio, 1.21; confidence interval, 0.89-1.65; P = .21). Conclusions: Hyponatremia is more common in patients with low ejection fraction. Although preoperative hyponatremia is independently associated with adverse outcomes in patients with normal ejection fraction, an association with adverse outcomes in patients with low ejection fraction was not demonstrated. [Copyright &y& Elsevier]

Drug release from chemoembolization microspheres stimulated by the presence of a chemically reducing environment may provide benefits for targeting drug resistant and metastatic hypoxic tumours. A water-soluble disulfide-based bifunctional cross-linker bis(acryloyl)-(l)-cystine (BALC) was synthesised, characterised and incorporated into a modified poly(vinyl) alcohol (PVA) hydrogel beads at varying concentrations using reverse suspension polymerisation. The beads were characterised to confirm the amount of cross-linker within each formulation and its effects on the bead properties. Elemental and UV/visible spectroscopic analysis confirmed the incorporation of BALC within the beads and sizing studies showed that in the presence of a reducing agent, all bead formulations increased in mean diameter. The BALC beads could be loaded with doxorubicin hydrochloride and amounts in excess of 300 mg of drug per mL of hydrated beads could be achieved but required conversion of the carboxylic acid groups of the BALC to their sodium carboxylate salt forms. Elution of doxorubicin from the beads demonstrated a controlled release via ionic exchange. Some formulations exhibited an increase in size and release of drug in the presence of a reducing agent, and therefore demonstrated the ability to respond to an in vitro reducing environment. [ABSTRACT FROM AUTHOR]

Summary: Background: Mortality from severe sepsis and septic shock differs across continents, countries, and regions. We aimed to use data from the Surviving Sepsis Campaign (SSC) to compare models of care and outcomes for patients with severe sepsis and septic shock in the USA and Europe. Methods: The SSC was introduced into more than 200 sites in Europe and the USA. All patients identified with severe sepsis and septic shock in emergency departments or hospital wards and admitted to intensive care units (ICUs), and those with sepsis in ICUs were entered into the SSC database. Patients entered into the database from its launch in January, 2005, through January, 2010, in units with at least 20 patients and 3 months of enrolment of patients were included in this analysis. Patients included in the cohort were limited to those entered in the first 4 years at every site. We used random-effects logistic regression to estimate the hospital mortality odds ratio (OR) for Europe relative to the USA. We used random-effects linear regression to find the relation between lengths of stay in hospital and ICU and geographic region. Findings: 25 375 patients were included in the cohort. The USA included 107 sites with 18 766 (74%) patients, and Europe included 79 hospital sites with 6609 (26%) patients. In the USA, 12 218 (65·1%) were admitted to the ICU from the emergency department whereas in Europe, 3405 (51·5%) were admitted from the wards. The median stay on the hospital wards before ICU admission was longer in Europe than in the USA (1·0 vs 0·1 days, difference 0·9, 95% CI 0·8–0·9). Raw hospital mortality was higher in Europe than in the USA (41·1%vs 28·3%, difference 12·8, 95% CI 11·5–14·7). The median length of stay in ICU (7·8 vs 4·2 days, 3·6, 3·3–3·7) and hospital (22·8 vs 10·5 days, 12·3, 11·9–12·8) was longer in Europe than in the USA. Adjusted mortality in Europe was not significantly higher than that in the USA (32·3%vs 31·3%, 1·0, −1·7 to 3·7, p=0·468). Complete compliance with all applicable elements of the sepsis resuscitation bundle was higher in the USA than in Europe (21·6%vs 18·4%, 3·2, 2·2–4·4). Interpretation: The significant difference in unadjusted mortality and the fact that this difference disappears with severity adjustment raise important questions about the effect of the approach to critical care in Europe compared with that in the USA. The effect of ICU bed availability on outcomes in patients with severe sepsis and septic shock requires further investigation. Funding: Eli Lilly Co, Baxter Lifesciences, Philips Medical Systems, the Society of Critical Care Medicine, and the European Society of Intensive Care Medicine. [Copyright &y& Elsevier]

HER-2 is a member of the EGF receptor family and is overexpressed in 20-30% of breast cancers. HER-2 overexpression causes increased expression of VEGF at both the RNA and protein levels. HER-2 and VEGF are therefore considered good targets for cancer treatment, which has led to the development of two humanized monoclonal antibodies (mAb) pertuzumab and bevacizumab. Although passive immunotherapy with these Abs are approved for treatment of advanced breast cancer, a number of concerns exist. Treatment is expensive, has a limited duration of action, and is usually accompanied by serious side effects. We hypothesized that therapy with conformational peptide mimics aimed at blocking receptor-ligand interaction is potentially safer with little toxicity, cheaper with a longer half-life, and has greater penetrating abilities than mAbs. We designed and synthesized peptides based on the binding of HER-2 with pertuzumab and VEGF with VEGFR2. We show that treatment with the peptide mimics induces potent anti-tumor responses in vitro as determined by cell viability, proliferation, and HER2 phosphorylation assays. We also demonstrate in a transplantable BALB/c mouse tumor model that treatment with the peptide mimics resulted in a greater delay in tumor growth and development. Similarly, treatment with the peptide mimics inhibited angiogenesis in vivo as assessed by a Matrigel plug assay. To address the problem of degradability of L-amino acid peptides in vivo, we synthesized the retro-inverso D-peptide mimics that resulted in higher efficacy in treatment. Our study shows that combination treatment with HER-2 and VEGF peptide mimics provides greater efficacy than individual treatments. [ABSTRACT FROM AUTHOR]

We sought to reduce the risk of infectious complications and nonrelapse mortality (NRM) associated with the use of antithymocyte globulin (ATG) without compromising control of acute graft-versus-host disease (aGVHD) in patients undergoing reduced-intensity conditioning (RIC) transplantation. As part of an ongoing quality improvement effort, we lowered the dose of rabbit ATG from 7.5 mg/kg of ATG (R-ATG) (n = 39) to 6.0 mg/kg of ATG (r-ATG) (n = 33) in association with fludarabine (Flu) and busulfan (BU) RIC transplantation and then monitored patients for adverse events, relapse, and survival. Of the 72 mostly high risk (82%) patients studied, 89% received unrelated donor allografts, 25% of which were HLA-mismatched. No differences in posttransplantation full donor-cell chimerism rates were observed between the 2 ATG-dose groups (P > .05). When R-ATG versus r-ATG patients were compared, we observed no significant difference in the cumulative incidence of grade II-IV aGVHD (32% versus 27%; P = .73) or grade III-IV aGVHD (23% versus 11%; P = .28). However, the r-ATG group had significantly less cytomegalovirus (CMV) reactivation (64% versus 30%; P = .005) and bacterial infections (56% versus 18%; P = .001), a better 1-year cumulative incidence of NRM (18% versus 3%; P = .03), and a trend for better 1-year overall survival (OS) (64% versus 84%; P = .07) compared to R-ATG patients. A seemingly modest reduction in the dose of rabbit ATG did not compromise control of aGVHD or achievement of donor chimerism, but led to a significant decrease in the risk of serious infections and NRM in high-risk RIC allograft recipients. [Copyright &y& Elsevier]

Abstract: Discharge planning and linkage to appropriate aftercare services are crucial to successful outcomes following inpatient psychiatric care. Yet little is known about how aftercare decisions are made and what factors clinicians consider most important when making decisions about level of aftercare. Using comprehensive medical record data for 508 adolescents enrolled in Medicaid and admitted to three inpatient hospitals, this study examines the influence of both clinical and non-clinical factors on level of aftercare decisions. Results from the multinomial logistic regression analyses indicate that decisions about level of aftercare are largely driven by clinical need factors—illness severity and prior service history. However, non-clinical factors such as race/ethnicity, custody status, availability of services, and hospital provider also strongly influenced aftercare decisions, even after controlling for level of need. Study findings highlight the need for evidence-based decision-making guidelines to improve quality of care and ensure that youths are being referred to clinically effective and appropriate services. Further research is needed to understand how non-clinical factors affect clinical decision-making and the delivery of mental health care. [Copyright &y& Elsevier]