Apelin signalling in the periaqueductal grey matter alleviates capsaicin-evoked pulpal nocifensive behaviour and capsaicin-induced spatial learning and memory impairments in rat.

AIM: Pulpal pain is a common orofacial health issue that has been linked to cognitive impairment. Because of its prominent role in pain modulation and cognitive impairment, apelin (Apl) is regarded as a promising target for clinical pain management. The role of Apl in orofacial pain, however, is unknown. The purpose of this study was to determine the effects of intra-periaqueductal grey matter (PAG) administrations of Apl-13 on capsaicin-evoked pulpal nocifensive behaviour and capsaicin-induced spatial learning and memory impairments in rats. METHODOLOGY: Forty-nine male Wistar rats (200-250 g) were randomly divided into seven groups (n = 7 per group). The groups included: untreated intact, capsaicin (Caps) only, three Caps+Apl groups that received different dosages of intra-PAG injection of Apl-13 (1, 2 and 3 µg/rat) 20 min prior to capsaicin application, and two Apl+antagonist groups that received Apl receptor antagonist or naloxone (a µ opioid receptor) 20 min before Apl injection. Learning and memory were assessed using the Morris water maze test. One-way analysis of variance followed by Tukey post hoc tests was used for statistical analysis. RESULTS: Intra-PAG administration of Apl-13 significantly reduced the capsaicin-induced nocifensive behaviour (p < .01). This antinociception effect was inhibited by F13A and naloxone. Apl-13 inhibited nociception-induced learning and memory deficits (p < .01). The cognitive effects were also blocked by pre-treatment administration of F13A (3 µg/rat). CONCLUSIONS: These findings indicated that Apl-13, via Apl receptors (AR or APJ) and µ opioid receptors, alleviated capsaicin-induced dental nocifensive behaviour and protected against nociception-induced learning and memory impairments. As a result of our findings, Apl appears to be a promising analgesic option for further research in orofacial pain models and clinical trials.

Biodistribution and Activity of EGFR Targeted Polymeric Micelles Delivering a New Inhibitor of DNA Repair to Orthotopic Colorectal Cancer Xenografts with Metastasis.

The disruption of polynucleotide kinase/phosphatase (PNKP) in colorectal cancer (CRC) cells deficient in phosphatase and tensin homolog (PTEN) is expected to lead to the loss of cell viability by a process known as synthetic lethality. In previous studies, we have reported on the encapsulation of a novel inhibitor of PNKP, namely, A83B4C63, in polymeric micelles and its activity in slowing the growth of PTEN-deficient CRC cells as well as subcutaneous xenografts. In this study, to enhance drug delivery and specificity to CRC tumors, the surface of polymeric micelles carrying A83B4C63 was modified with GE11, a peptide targeting epidermal growth factor receptor (EGFR) overexpressed in about 70% of CRC tumors. Using molecular dynamics (MD) simulations, we assessed the binding site and affinity of GE11 for EGFR. The GE11-modified micelles, tagged with a near-infrared fluorophore, showed enhanced internalization by EGFR-overexpressing CRC cells in vitro and a trend toward increased primary tumor homing in an orthotopic CRC xenograft in vivo. In line with these observations, the GE11 modification of polymeric micelles was shown to positively contribute to the improved therapeutic activity of encapsulated A83B4C63 against HCT116-PTEN-/- cells in vitro and that of orthotopic CRC xenograft in vivo. In conclusion, our results provided proof of principle evidence for the potential benefit of EGFR targeted polymeric micellar formulations of A83B4C63 as monotherapeutics for aggressive and metastatic CRC tumors but at the same time highlighted the need for the development of EGFR ligands with improved physiological stability and EGFR binding.

Decreased serum testosterone level was not significantly correlated with lipid indices in elderly men.

BACKGROUND: Aging in men causes a gradual decline in endogenous testosterone levels, which may have detrimental effects on their health status. Testosterone deficiency is thought to promote atherosclerosis by modulating lipid metabolism. Therefore, this study was conducted to evaluate the serum testosterone level and its correlation with lipid profile in men aged ≥60 years old. METHODS: All elderly men aged ≥60, residing in Amirkola and participating in a phase of the comprehensive project on "investigating the health status of the elderly in Amirkola" were entered into this descriptive cross-sectional study. After fasting over 12 hours, the venous blood samples were taken. Serum concentration of testosterone was determined using ELISA method. Moreover, HDL-LDL, total cholesterol, triglyceride and fasting blood glucose were measured. RESULTS: The prevalence of hypogonadism was 91.28% among the 792 participants of this study with a cut-off point of 9.72 nmol/L (95% confidence interval, 93.25-89.31) and the prevalence of severe hypogonadism with a cut-off point of 5.2 nmol/L was reported 71.59% (95% confidence interval, 74.73-68.44%). Based on the results, there was no significant statistical correlation between the serum level of testosterone and triglyceride (r=0.03, P=0.34). Furthermore, there was a negative correlation between testosterone and HDL, which was not statistically significant(r=-0.05, P=0.13). No significant statistical correlation was found between testosterone and LDL (P=0.98). There was a negative correlation between testosterone and cholesterol, which was not statistically significant (r=-0.02, P=0.49). CONCLUSION: According to the study results, 91% of men aged ≥60 years old had hypogonadism, no correlation was found between testosterone and lipid indices.

Decoration of Anti-CD38 on Nanoparticles Carrying a STAT3 Inhibitor Can Improve the Therapeutic Efficacy Against Myeloma.

STAT3 is an oncoprotein which has been shown to contribute to drug resistance in multiple myeloma (MM). Nonetheless, the clinical utility of STAT3 inhibitors in treating MM has been limited, partly related to some of their pharmacologic properties. To overcome these challenges, our group had previously packaged STAT3 inhibitors using a novel formulation of nanoparticles (NP) and found encouraging results. In this study, we aimed to further improve the pharmacologic properties of these NP by decorating them with monoclonal anti-CD38 antibodies. NP loaded with S3I-1757 (a STAT3 inhibitor), labeled as S3I-NP, were generated. S3I-NP decorated with anti-CD38 (labeled as CD38-S3I-NP) were found to have a similar nanoparticular size, drug encapsulation, and loading as S3I-NP. The release of S3I-1757 at 24 h was also similar between the two formulations. Using Cy5.5 labeling of the NP, we found that the decoration of anti-CD38 on these NP significantly increased the cellular uptake by two MM cell lines (p < 0.001). Accordingly, CD38-S3I-NP showed a significantly lower inhibitory concentration at 50% (IC50) compared to S3I-NP in two IL6-stimulated MM cell lines (p < 0.001). In a xenograft mouse model, CD38-S3I-NP significantly reduced the tumor size by 4-fold compared to S3I-NP on day 12 after drug administration (p = 0.006). The efficacy of CD38-S3I-NP in suppressing STAT3 phosphorylation in the xenografts was confirmed by using immunocytochemistry and Western blot analysis. In conclusion, our study suggests that the decoration of anti-CD38 on NP loaded with STAT3 inhibitors can further improve their therapeutic effects against MM.

A systematic review examining the impact of redirecting low-acuity patients seeking emergency department care: is the juice worth the squeeze?

OBJECTIVES: Diverting patients away from the emergency department (ED) has been proposed as a solution for mitigating overcrowding. This systematic review examined the impact of interventions designed to either bypass the ED or direct patients to other alternative care after ED presentation. METHODS: Seven electronic databases and the grey literature were searched. Eligible studies included randomised/controlled trials or cohort studies that assessed the effectiveness of pre-hospital or ED-based diversion interventions. Two reviewers independently screened the studies for relevance, inclusion and risk of bias. Pooled statistics were calculated as relative risks (RR) with 95% confidence intervals (CI) using a random effects model. RESULTS: Fifteen studies were included evaluating pre-hospital (n=11) or ED-based (n=4) diversion interventions. The quality of the studies ranged from moderate to low. Patients deemed suitable for diversion among the pre-hospital studies (n=3) ranged from 19.2% to 90.4% and from 19% to 36% in ED-based studies (n=4). Of the eligible patients, the proportion of patients diverted via ED-based diversion tended to be higher (median 85%; IQR 76-93%) compared with pre-hospital diversion (median 40%; IQR 24-57%). Overall, pre-hospital diversion did not decrease the proportion of patients transferred to the ED compared with standard care (RR 0.92; 95% CI 0.80 to 1.06). There was no significant decrease in subsequent ED utilisation among patients diverted via pre-hospital diversion compared with non-diverted patients (RR 1.09; 95% CI 0.99 to 1.21). Of the three pre-hospital studies completing a cost analysis, none found a significant difference in total healthcare costs between diverted and non-diverted patients. CONCLUSION: There was no conclusive evidence regarding the impact of diversion strategies on ED utilisation and subsequent healthcare utilisation. The overall quality of the research limited the ability of this review to draw definitive conclusions and more research is required prior to widespread implementation.

Modulation of Hypoxia-Induced Chemoresistance to Polymeric Micellar Cisplatin: The Effect of Ligand Modification of Micellar Carrier Versus Inhibition of the Mediators of Drug Resistance.

Hypoxia can induce chemoresistance, which is a significant clinical obstacle in cancer therapy. Here, we assessed development of hypoxia-induced chemoresistance (HICR) against free versus polymeric cisplatin micelles in a triple negative breast cancer cell line, MDA-MB-231. We then explored two strategies for the modulation of HICR against cisplatin micelles: a) the development of actively targeted micelles; and b) combination therapy with modulators of HICR in MDA-MB-231 cells. Actively targeted cisplatin micelles were prepared through surface modification of acetal-poly(ethylene oxide)-poly(α-carboxyl-ε-caprolactone) (acetal-PEO-PCCL) micelles with epidermal growth factor receptor (EGFR)-targeting peptide, GE11 (YHWYGYTPQNVI). Our results showed that hypoxia induced resistance against free and cisplatin micelles in MDA-MB-231 cells. A significant increase in micellar cisplatin uptake was observed in MDA-MB-231 cells that overexpress EGFR, following surface modification of micelles with GE11. This did not lead to increased cytotoxicity of micellar cisplatin, however. On the other hand, the addition of pharmacological inhibitors of key molecules involved in HICR in MDA-MB-231 cells, i.e., inhibitors of hypoxia inducing factor-1 (HIF-1) and signal transducer and activator of transcription 3 (STAT3), substantially enhanced the cytotoxicity of free and cisplatin micelles. The results indicated the potential benefit of combination therapy with HIF-1 and STAT3 inhibitors in overcoming HICR to free or micellar cisplatin.

eMental Healthcare Technologies for Anxiety and Depression in Childhood and Adolescence: Systematic Review of Studies Reporting Implementation Outcomes.

BACKGROUND: Anxiety disorders and depression are frequent conditions in childhood and adolescence. eMental healthcare technologies may improve access to services, but their uptake within health systems is limited. OBJECTIVE: The objective of this review was to examine and describe how the implementation of eMental healthcare technologies for anxiety disorders and depression in children and adolescents has been studied. METHODS: We conducted a search of 5 electronic databases and gray literature. Eligible studies were those that assessed an eMental healthcare technology for treating or preventing anxiety or depression, included children or adolescents (<18 years), or their parents or healthcare providers and reported findings on technology implementation. The methodological quality of studies was evaluated using the Mixed Methods Appraisal Tool. Outcomes of interest were based on 8 implementation outcomes: acceptability (satisfaction with a technology), adoption (technology uptake and utilization), appropriateness ("fitness for purpose"), cost (financial impact of technology implementation), feasibility (extent to which a technology was successfully used), fidelity (implementation as intended), penetration ("spread" or "reach" of the technology), and sustainability (maintenance or integration of a technology within a healthcare service). For extracted implementation outcome data, we coded favorable ratings on measurement scales as "positive results" and unfavorable ratings on measurement scales as "negative results." Those studies that reported both positive and negative findings were coded as having "mixed results." RESULTS: A total of 46 studies met the inclusion criteria, the majority of which were rated as very good to excellent in methodological quality. These studies investigated eMental healthcare technologies for anxiety (n=23), depression (n=18), or both anxiety and depression (n=5). Studies of technologies for anxiety evaluated the following: (1) acceptability (78%) reported high levels of satisfaction, (2) adoption (43%) commonly reported positive results, and (3) feasibility (43%) reported mixed results. Studies of technologies for depression evaluated the following: (1) appropriateness (56%) reported moderate helpfulness and (2) acceptability (50%) described a mix of both positive and negative findings. Studies of technologies designed to aid anxiety and depression commonly reported mixed experiences with acceptability and adoption and positive findings for appropriateness of the technologies for treatment. Across all studies, cost, fidelity, and penetration and sustainability were the least measured implementation outcomes. CONCLUSIONS: Acceptability of eMental healthcare technology is high among users and is the most commonly investigated implementation outcome. Perceptions of the appropriateness and adoption of eMental healthcare technology were varied. Implementation research that identifies, evaluates, and reports on costs, sustainability, and fidelity to clinical guidelines is crucial for making high-quality eMental healthcare available to children and adolescents.

Review: The impact of pediatric mental health care provided outpatient, primary care, community and school settings on emergency department use - a systematic review.

BACKGROUND: Increases in emergency department (ED) visits for pediatric mental health care point to a need to understand the impact of mental health services in relation to emergency-based care. This systematic review examined the impact of mental health services delivered in outpatient, primary care, community and/or school settings on ED use and costs for ED-based mental health care. METHOD: Two electronic databases and gray literature were searched. Eligible studies consisted of randomized/controlled clinical trials or cohort studies examining the effects of mental health services on ED use and costs for this care. Two reviewers independently screened the studies for relevance and study quality. Relative risks (RR), risk differences (RD), or mean differences (MD) were calculated for each study's primary outcome with 95% confidence intervals (CI). Meta-analysis was deferred due to substantial heterogeneity. RESULTS: Six studies were included. Overall risk of bias in the studies ranged from low, unclear, to high. The majority of programs had no effect on ED visits for mental health care. A school-based program was found to reduce the risk of ED visits for any reason during use (RD, -8.0%; 95% CI: -15.2%, -0.9%); however, these visits were not specific to mental health. Three studies examined costs. A wrap-around clinical management program was associated with higher average ED costs per patient per month ($20.07 US dollars) compared to usual outpatient care; other studies reported no cost differences. CONCLUSIONS: At this time, there is limited evidence to suggest outpatient, primary care, community and/or school-based mental health services impact ED use and costs for mental health care. Additional studies are needed.

Traceable PEO-poly(ester) micelles for breast cancer targeting: The effect of core structure and targeting peptide on micellar tumor accumulation.

Traceable poly(ethylene oxide)-poly(ester) micelles were developed through chemical conjugation of a near-infrared (NIR) dye to the poly(ester) end by click chemistry. This strategy was tried for micelles with poly(ε-caprolactone) (PCL) or poly(α-benzyl carboxylate-ε-caprolactone) (PBCL) cores. The surface of both micelles was also modified with the breast cancer targeting peptide, P18-4. The results showed the positive contribution of PBCL over PCL core on micellar thermodynamic and kinetic stability as well as accumulation in primary orthotopic MDA-MB-231 tumors within 4-96 h following intravenous administration in mice. This was in contrast to in vitro studies where better uptake of PEO-PCL versus PEO-PBCL micelles by MDA-MB-231 cells was observed. The presence of P18-4 enhanced the in vitro cell uptake and homing of both polymeric micelles in breast tumors, but only at early time points. In conclusion, the use of developed NIR labeling technique provided means for following the fate of PEO-poly(ester) based nano-carriers in live animals. Our results showed micellar stabilization through the use of PBCL over PCL cores, to have a more significant effect in enhancing the level and duration of nano-carrier accumulation in primary breast tumors than the modification of polymeric micellar surface with breast tumor targeting peptide, P18-4.

Pediatric eMental healthcare technologies: a systematic review of implementation foci in research studies, and government and organizational documents.

BACKGROUND: Researchers, healthcare planners, and policymakers convey a sense of urgency in using eMental healthcare technologies to improve pediatric mental healthcare availability and access. Yet, different stakeholders may focus on different aspects of implementation. We conducted a systematic review to identify implementation foci in research studies and government/organizational documents for eMental healthcare technologies for pediatric mental healthcare. METHODS: A search of eleven electronic databases and grey literature was conducted. We included research studies and documents from organization and government websites if the focus included eMental healthcare technology for children/adolescents (0-18 years), and implementation was studied and reported (research studies) or goals/recommendations regarding implementation were made (documents). We assessed study quality using the Mixed Methods Appraisal Tool and document quality using the Appraisal of Guidelines for Research & Evaluation II. Implementation information was grouped according to Proctor and colleagues' implementation outcomes-acceptability, adoption, appropriateness, cost, feasibility, fidelity, penetration, and sustainability-and grouped separately for studies and documents. RESULTS: Twenty research studies and nine government/organizational documents met eligibility criteria. These articles represented implementation of eMental healthcare technologies in the USA (14 studies), United Kingdom (2 documents, 3 studies), Canada (2 documents, 1 study), Australia (4 documents, 1 study), New Zealand (1 study), and the Netherlands (1 document). The quality of research studies was excellent (n = 11), good (n = 6), and poor (n = 1). These eMental health studies focused on the acceptability (70%, n = 14) and appropriateness (50%, n = 10) of eMental healthcare technologies to users and mental healthcare professionals. The quality of government and organizational documents was high (n = 2), medium (n = 6), and low (n = 1). These documents focused on cost (100%, n = 9), penetration (89%, n = 8), feasibility (78%, n = 7), and sustainability (67%, n = 6) of implementing eMental healthcare technology. CONCLUSION: To date, research studies have largely focused on acceptability and appropriateness, while government/organizational documents state goals and recommendations regarding costs, feasibility, and sustainability of eMental healthcare technologies. These differences suggest that the research evidence available for pediatric eMental healthcare technologies does not reflect the focus of governments and organizations. Partnerships between researchers, healthcare planners, and policymakers may help to align implementation research with policy development, decision-making, and funding foci.

Micellar nano-carriers for the delivery of STAT3 dimerization inhibitors to melanoma.

The objective of this research was to develop polymeric micellar formulations of inhibitors of signal transducer and activator of transcription 3 (STAT3) dimerization, i.e., S3I-1757 and S3I-201, and evaluate the activity of successful formulations in B16-F10 melanoma, a STAT3 hyperactive cancer model, in vitro and in vivo. STAT3 inhibitory agents were encapsulated in methoxy poly(ethylene oxide)-b-poly(ε-caprolactone) (PEO114-b-PCL22) and methoxy poly(ethylene oxide)-b-poly(α-benzyl carboxylate-ε-caprolactone) (PEO114-b-PBCL20) micelles using co-solvent evaporation. Polymeric micelles of S3I-1757 showed high encapsulation efficiency (>88%), slow release profile (<32% release in 24 h) under physiological conditions, and a desirable average diameter for tumor targeting (33-54 nm). The same formulations showed low encapsulation efficiencies and rapid drug release for S3I-201. Further studies evidenced the delivery of functional S3I-1757 by polymeric micelles to B16-F10 melanoma cells, leading to a dose-dependent inhibition of cell growth and vascular endothelial growth factor (VEGF) production comparable with that of free drug. Encapsulation of S3I-1757 in polymeric micelles significantly reduced its cytotoxicity in normal bone marrow-derived dendritic cells (DCs). Micelles of S3I-1757 were able to significantly improve the function of B16-F10 tumor-exposed immunosuppressed DCs in the production of IL-12, an indication for functionality in the induction of cell-mediated immune response. In a B16-F10 melanoma mouse model, S3I-1757 micelles inhibited tumor growth and enhanced the survival of tumor-bearing mice more than free S3I-1757. Our findings show that both PCL- and PBCL-based polymeric micelles have potential for the solubilization and delivery of S3I-1757, a potent STAT3 inhibitory agent.

A Systematic Review of Instruments to Identify Mental Health and Substance Use Problems Among Children in the Emergency Department.

OBJECTIVE: Specialized instruments to screen and diagnose mental health problems in children and adolescents are not yet standard components of clinical assessments in emergency departments (EDs). We conducted a systematic review to investigate the psychometric properties, accuracy, and performance metrics of instruments used in the ED to identify pediatric mental health and substance use problems. METHODS: We searched seven electronic databases and the gray literature for psychometric validation studies, diagnostic studies, and cohort studies that assessed any instrument to screen for or diagnose mental illness, emotional or behavioral problems, or substance use disorders. Studies had to include children and adolescents with mental health presentations or positive screens for substance use. Two reviewers independently screened studies for relevance and quality. Diagnostic study quality was assessed with the four QUADAS-2 domains. Psychometric study quality was assessed with published criteria for instrument reliability, validity, and usability. We present a descriptive analysis of the reported psychometric properties and diagnostic performance of instruments for each study. RESULTS: Of the 4,832 references screened, 14 met inclusion criteria. Included studies evaluate 18 instruments for identifying suicide risk (six studies), alcohol use disorders (six studies), mood disorders (one study), and ED decision making (need for assessment, admission; one study). Nine studies include a psychometric focus but quality varies, with no studies fully meeting criteria for reliability, validity, and usability. Seven studies examine diagnostic performance of an instrument, but no study has a low risk of bias for all QUADAS-2 domains. The HEADS-ED instrument has good inter-rater reliability (r = 0.785) for identifying general mental health problems and modest evidence for ruling in patients requiring hospital admission (positive likelihood ratio [LR+] = 6.30). Internal consistency (reliability) varies for instruments to screen for suicide risk (α = 0.46-0.97), and no instruments have both high sensitivity and high specificity. The Ask Suicide-Screening Questions (ASQ) is highly sensitive (98%) and has strong evidence for ruling out risk (negative likelihood ratio [LR-] = 0.04). Among screening instruments for alcohol use disorders, internal consistency is high for the consumption subscale of the Alcohol Use Disorders Identification Test (α = 0.83-0.88) and the Adolescent Drinking Index (α = 0.92). Both instruments also had sound internal validity. Diagnostically, a two-item instrument based on DSM-IV criteria is the most accurate in identifying patients with a disorder (area under the curve = 0.89) and has modest evidence for ruling in and out risk (LR+ = 8.80, LR- = 0.13). CONCLUSIONS: From available evidence, we recommend that ED clinicians use 1) the HEADS-ED to rule in ED admission among pediatric patients with visits for mental health care, 2) the ASQ to rule out suicide risk among pediatric patients with any visit type, and 3) the DSM-IV two-item instrument to rule in/rule out alcohol use disorders among pediatric patients currently using alcohol. These instruments require minimal to no training or time commitment. We also recommend that clinicians become familiar with each instrument's psychometric properties to understand the quality of the evidence base. In this review, however, we identify methodologic limitations in the evidence base. To develop a robust evidence base, additional research is necessary.

A systematic review of management strategies for children's mental health care in the emergency department: update on evidence and recommendations for clinical practice and research.

OBJECTIVE: Children with mental health crises require access to specialised resources and services which are not yet standard in general and paediatric EDs. In 2010, we published a systematic review that provided some evidence to support the use of specialised care models to reduce hospitalisation, return ED visits and length of ED stay. We perform a systematic review to update the evidence base and inform current policy statements. METHODS: Twelve databases and the grey literature were searched up to January 2015. Seven studies were included in the review (four newly identified studies). These studies compared ED-based strategies designed to assess, treat and/or therapeutically support or manage a mental health presentation. The methodological quality of six studies was assessed using the Cochrane Effective Practice and Organization of Care Risk of Bias tool (one interrupted time series study) and a modified Newcastle-Ottawa Scale (three retrospective cohort and two before-after studies). The Grading of Recommendations Assessment, Development and Evaluation (GRADE) system was applied to rate overall evidence quality (high, moderate, low or very low) for individual outcomes from these six studies. An additional study evaluated the psychometric properties of a clinical instrument and was assessed using criteria developed by the Society of Pediatric Psychology Assessment Task Force (well-established, approaching well-established or promising assessment). RESULTS: There is low to very low overall evidence quality that: (1) use of screening laboratory tests to medically clear mental health patients increases length of ED stay and costs, but does not increase the risk of clinical management or disposition change if not conducted; and (2) specialised models of ED care reduce lengths of ED stay, security man-hours and restraint orders. One mental health assessment tool of promising quality, the home, education, activities and peers, drugs and alcohol, suicidality, emotions and behaviour, discharge resources (HEADS-ED), has had good accuracy in predicting admission to inpatient psychiatry. CONCLUSIONS: Lower-quality data suggest benefits to the use of specialised resources and services for paediatric mental health care in general and paediatric EDs. Experimental evaluation of strategies and the inclusion of patient-reported outcomes will improve confidence in these findings. Additional psychometric studies are needed for the HEADS-ED tool to be considered well established.

Predicting time to emergency department re-visits and inpatient hospitalization among adolescents who visited an emergency department for psychotic symptoms: a retrospective cohort study.

BACKGROUND: Adolescents experiencing psychosis may enter the mental health system by a pathway to care that includes or is initiated at the emergency department (ED). However, a better understanding of the pathway to care involving EDs is required to ensure these patients receive the care they require. This study explores physician-based care factors associated with adolescent ED re-visits and inpatient hospitalization following an index ED visit for psychotic symptoms. METHODS: Using administrative data from Alberta, Canada, we identified a cohort of adolescents aged 13-17 years who were discharged after an ED visit for psychotic symptoms between April 1, 2002 and September 29, 2010. Multivariable models estimated times to ED re-visit and inpatient hospitalization for mental health care in a 90-day period after ED discharge. RESULTS: The cohort was comprised of 208 adolescents. Reduced times to ED re-visit and inpatient hospitalization were associated with: 1) multiple physician visits after discharge (ED re-visit: hazard ratio [HR] 5.93, 95 % confidence interval [CI] 2.09-16.82; inpatient hospitalization: HR 9.43, 95 % CI 1.24-72.00), and 2) post-ED physician care provided in a hospital-based outpatient clinic (ED re-visit: HR 3.07, 95 % CI 1.77-5.29; inpatient hospitalization: HR 3.48, 95 % CI 1.54-7.88). A follow-up visit to a pediatrician, compared to other physician specialties, was associated with earlier inpatient hospitalization (HR 4.45, 95 % CI 1.43-13.87). There was a significant interaction between sex and First Nations status in both models. Females with First Nations status re-visited the ED sooner (HR 3.19; 95 % CI 1.41-7.22) and were hospitalized sooner (HR 4.18; 95 % CI 1.24-14.06). CONCLUSIONS: This study identifies predictors of time to care for adolescents with psychotic symptoms that are worthy of additional investigation. To ensure the pathway to care for these adolescents reduces the duration of untreated problems, health care aspects that require urgent investigation include the type assessments and clinical decisions made during post-ED physician visits.

Vaccination with autologous dendritic cells pulsed with multiple tumor antigens for treatment of patients with malignant melanoma: results from a phase I/II trial.

BACKGROUND AND AIM: Dendritic cells are regarded as the most effective antigen presenting cells and coordinators of the immune response and therefore suitable as vaccine basis. Here we present results from a clinical study in which patients with malignant melanoma (MM) with verified progressive disease received vaccination with autologous monocyte-derived mature dendritic cells (DC) pulsed with p53, survivin and telomerase-derived peptides (HLA-A2+ patients) or with autologous/allogeneic tumor lysate (HLA-A2(−) patients) in combination with low-dose interleukin (IL)-2 and interferon (IFN)-alpha2b. RESULTS: Of 46 patients who initiated treatment, 10 stopped treatment within 1-4 weeks because of rapid disease progression and deterioration. After 8 weeks, 36 patients were evaluable: no patient had an objective response, 11 patients had stable disease (SD); six had continued SD after 4 months, and three patients had prolonged SD for more than 6 months. The mean overall survival time was 9 months, with a significantly longer survival (18.4 months) of patients who attained SD compared with patients with progressive disease (PD) (5 months). Induction of antigen-specific T-cell responses was analyzed by multidimensional encoding of T cells using HLA-A2 major histocompatibility complex (MHC) multimers. Immune responses against five high-affinity vaccine peptides were detectable in the peripheral blood of six out of 10 analyzed HLA-A2+ patients. There was no observed correlation between the induction of immune responses and disease stabilization. A significant lower blood level of regulatory T cells (CD25(high) CD4 T cells) was demonstrable after six vaccinations in patients with SD compared with PD. CONCLUSIONS: Vaccination was feasible and safe. Treatment-associated SD was observed in 24% of the patients. SD correlated with prolonged survival suggesting a clinical benefit. Differences in the level of regulatory T cells among SD and PD patients could indicate a significant role of these immune suppressive cells.