Does discharging asthma patients after one hour of treatment if clinically well affect emergency department length of stay.

AIM: Asthma is a major contributor to direct and indirect health-care costs and resource use. In May 2015, the Royal Children's Hospital (RCH) amended its clinical practice guideline for acute asthma management from discharging patients if the anticipated salbutamol requirement was every 3-4 h to discharging patients who were clinically well at 1 h after initial treatment. Our objective was to examine the impact of the new discharge recommendation on emergency department (ED) length of stay (LOS), rates of admission and representation. METHODS: We retrospectively audited the case notes of children presenting with mild or moderate asthma to the RCH ED over the equivalent 2-week periods in winter 2014 (pre-implementation of the new guideline) and 2015 (post-implementation). RESULTS: A total of 105 patients in 2014 and 92 patients in 2015 were included. In both years, all patients who initially presented with mild or moderate asthma either improved or stayed within the same severity classification at the 1-h assessment. For patients who were clinically well by the 1-h assessment, there was a significant reduction in admissions between 2014 and 2015 (40 vs. 10%, P = 0.001). There was also a reduction for these patients in median LOS from 3 h 13 min in 2014 to 2 h 31 min in 2015 (P = 0.03). In both years, all patients who were moderate at 1 h were admitted. There was no difference in the rate of representation or subsequent deterioration in those patients who were discharged at 1 h between the 2 years. CONCLUSION: Early discharge of patients who are clinically well 1 h after initial therapy may be associated with a reduction in LOS and admission rate without an apparent compromise in patient safety. Further evaluation of this intervention is required to determine whether this is a true causal relationship.

Comparison of supine and prone craniospinal irradiation in children with medulloblastoma.

PURPOSE: To compare port film rejection and treatment outcome according to craniospinal irradiation (CSI) position for medulloblastoma. METHODS AND MATERIALS: We retrospectively searched for patients ≤19 years treated with CSI for medulloblastoma at 1 department. We collected the following data: age; sex; risk group; need for general anesthesia; radiation therapy (RT) dose and fractionation; and the acceptance or rejection of weekly port films during treatment. We also collected data on outcomes, including neuraxis recurrence and possible complications such as myelitis. RESULTS: Of 46 children identified, 23 were treated prone (median age, 8.1 years) and 23 supine (median age, 7.2 years). High-risk disease was seen in 26% of prone and 35% of supine patients (P = .25). There was no difference in use of general anesthesia between those treated prone versus supine (57% vs 61%). The rejection rate of cranial port films in the prone position was 35%, which was significantly higher than the rate of 8% in patients treated supine (P < .0001). The 5-year progression-free (P = .37) and overall survival (P = .18) rates were 62% and 67% for prone and 76% and 84% for supine patients. There were no isolated junctional failures or radiation myelitis in either CSI position. CONCLUSIONS: The supine position for CSI was found to have similar survival outcomes compared with the prone position. A higher proportion of rejected cranial port films was seen in children treated in the prone position.

Vitamin D status in critically ill children.

BACKGROUND: Hypovitaminosis D is an independent risk factor for cardiovascular disease, muscle weakness, impaired metabolism, immune dysfunction, and compromised lung function. Hypovitaminosis D is common in critically ill adults and has been associated with adverse outcomes. The prevalence of hypovitaminosis D and its significance in critically ill children are unclear. METHODS: We performed a prospective study to determine the prevalence of hypovitaminosis D in 316 critically ill children, and examined its association with physiological and biochemical variables, length of pediatric intensive care unit (PICU) stay, and hospital mortality. RESULTS: The prevalence of hypovitaminosis D [25(OH)D(3) <50 nmol/L] was 34.5 %. Hypovitaminosis D was more common in postoperative cardiac patients than in general medical ICU patients (40.5 versus 22.6 %, p = 0.002), and the cardiac patients had a higher inotrope score [2.5 (1.9-3.3) versus 1.4 (1.1-1.9), p = 0.006]. Additionally, ionized calcium within the first 24 h was lower in patients with 25(OH)D(3) <50 nmol/L [1.07 (0.99-1.14) mmol/L] compared with patients with normal vitamin D(3) [1.17 (1.14-1.19) mmol/L, p = 0.02]. Hypovitaminosis D was not associated with longer PICU stay or increased hospital mortality. CONCLUSIONS: Hypovitaminosis D is common in critically ill children, and is associated with higher inotropes in the postoperative cardiac population, but not with PICU length of stay or hospital survival.

2,6-Dichloro-1-[(1E)-2-(phenyl-sulfon-yl)ethen-yl]benzene.

In the title compound, C(14)H(10)Cl(2)O(2)S, the product of a base-catalyzed condensation followed by deca-rboxylation of the carboxyl-ate group of the sulfonyl derivative, the configuration of the alkene unit is E. The torsion angle between the alkene unit and the 2,6-dichloro-phenyl ring system is -40.8 (3)°. The dihedral angle between the rings is 80.39 (7)°.

Children Attending Paediatricians Study: a national prospective audit of outpatient practice from the Australian Paediatric Research Network.

OBJECTIVE: To audit general paediatric outpatient practice in Australia, including consultation characteristics and management patterns, diagnoses, factors associated with diagnoses, and billing practices. DESIGN, SETTING AND PARTICIPANTS: In October-November 2008, members of the Australian Paediatric Research Network (APRN; a national network of paediatricians established to facilitate multisite secondary care research) were invited to prospectively complete brief standardised data collection forms for 100 consecutive patients or all patients during a 2-week period, whichever came first. MAIN OUTCOME MEASURES: Length of consultation and type of diagnoses made; proportions recorded as having medications, investigations or referral; odds ratios for factors associated with diagnoses; and proportions of Medicare items billed. RESULTS: Of 300 APRN members, 199 (66%) completed data forms for 8345 consultations in which 15 375 diagnoses were made (mean, 1.8 diagnoses per consultation); 46.0%, 30.9% and 22.8% of consultations involved 1, 2 and ≥ 3 diagnoses, respectively. New and review consultations lasted a mean of 41 (SD, 20) and 26 (SD, 15) minutes, respectively. The most common diagnoses were attention deficit hyperactivity disorder (18.3%), baby checks (9.1%), and learning difficulties (7.5%). Patients seen in 47.5% of consultations had medications (eg, prescriptions, vaccinations) recorded, and patients in 27.2% of consultations were referred elsewhere, usually to a subspecialist or psychologist (31.6% and 26.6% of referrals, respectively). Male sex of the child and owning a Health Care Card were associated with most developmental-behavioural diagnoses. Paediatricians tended to bill for single disease/non-complex consultations, even when seeing a child with multiple problems. CONCLUSIONS: Australian paediatricians see children with a range of diagnoses that are often multiple and complex. Our findings provide directions for future secondary care research, and may inform workforce planning and paediatricians' training requirements.

Local control after craniospinal irradiation, intensity-modulated radiotherapy boost, and chemotherapy in childhood medulloblastoma.

BACKGROUND: The current study was conducted to determine whether the use of cochlear-sparing intensity-modulated radiotherapy (IMRT) boost results in excess local failures in children with medulloblastoma. METHODS: Fifty children with a median age of 7.8 years underwent resection, craniospinal irradiation (CSI), IMRT posterior fossa (PF) and/or tumor bed (TB) boost, and cisplatin-based chemotherapy for medulloblastoma. For standard-risk patients, the CSI dose was 18 to 23.4 grays (Gy) and was followed either by an IMRT PF boost to 36 Gy and a TB boost of 54 to 55.8 Gy (n = 29) or by an IMRT TB boost to 55.8 Gy (n = 4). For high-risk patients, the CSI dose was 36 to 39.6 Gy followed by an IMRT PF boost to 54 to 55.8 Gy (n = 8), an IMRT PF boost to 45 Gy and a TB boost to 55.8 Gy (n = 2), or an IMRT TB boost to 55.8 Gy (n = 7). For the TB boost, a 2-cm margin around the surgical bed was treated in most patients. RESULTS: The 5-year overall and progression-free survival rates (±standard deviation) were 72% ± 6.6% and 68.3% ± 6.8%, respectively, for all patients; 77.8% ± 7.4% and 75.1% ± 7.6%, respectively, for standard-risk patients; and 60.8% ± 12.8% and 55.4% ± 12.8%, respectively, for high-risk patients. The 5-year PF control rate was 90.5% ± 4.6%. TB failures occurred in 3 patients (including 2 patients who had distant failure), whereas an isolated non-TB PF failure occurred in 1 patient. CONCLUSIONS: The use of IMRT was associated with excellent local control and did not result in excess PF failures outside of the TB.

Adverse events associated with the use of complementary and alternative medicine in children.

OBJECTIVE: To determine the types of adverse events associated with the use of complementary and alternative medicine (CAM) that come to the attention of Australian paediatricians. DESIGN: Monthly active surveillance study of CAM-associated adverse events as reported to the Australian Paediatric Surveillance Unit between January 2001 and December 2003. RESULTS: There were 39 reports of adverse events associated with CAM use, including four reported deaths. Reports highlighted several areas of concern, including the risks associated with failure to use conventional medicine, the risks related to medication changes made by CAM practitioners and the significant dangers of dietary restriction. The reported deaths were associated with a failure to use conventional medicine in favour of a CAM therapy. CONCLUSION: CAM use has the potential to cause significant morbidity and fatal adverse outcomes. The diversity of CAM therapies and their associated adverse events demonstrate the difficulty addressing this area and the importance of establishing mechanisms by which adverse effects may be reported or monitored.

Ototoxicity after intensity-modulated radiation therapy and cisplatin-based chemotherapy in children with medulloblastoma.

PURPOSE: To report the incidence of Pediatric Oncology Group (POG) Grade 3 or 4 ototoxicity in a cohort of patients treated with craniospinal irradiation (CSI) followed by posterior fossa (PF) and/or tumor bed (TB) boost using intensity-modulated radiation therapy (IMRT). METHODS AND MATERIALS: From 1998 to 2006, 44 patients with medulloblastoma were treated with CSI followed by IMRT to the PF and/or TB and cisplatin-based chemotherapy. Patients with standard-risk disease were treated with 18 to 23.4 Gy CSI followed by either a (1) PF boost to 36 Gy and TB boost to 54 to 55.8 Gy or (2) TB boost to 55.8 Gy. Patients with high-risk disease received 36 to 39.6 Gy CSI followed by a (1) PF boost to 54 to 55.8 Gy, (2) PF boost to 45 Gy and TB boost to 55.8 Gy, or (3) TB boost to 55.8 Gy. Median audiogram follow-up was 41 months (range, 11-92.4 months). RESULTS: POG Grade Ototoxicity 0, 1, 2, 3. and 4 was found in 29, 32, 11, 13. and 3 ears. respectively, with POG Grade 3 or 4 accounting for 18.2% of cases. There was a statistically significant difference in mean radiation dose (D(mean)) cochlea according to degree of ototoxicity, with D(mean) cochlea increasing with severity of hearing loss (p = 0.027). CONCLUSIONS: Severe ototoxicity was seen in 18.2% of ears in children treated with IMRT boost and cisplatin-based chemotherapy. Increasing dose to the cochlea was associated with increasing severity of hearing loss.

Supine craniospinal irradiation using intrafractional junction shifts and field-in-field dose shaping: early experience at Methodist Hospital.

PURPOSE: To describe our preliminary experience with supine craniospinal irradiation. The advantages of the supine position for craniospinal irradiation include patient comfort, easier access to maintain an airway for anesthesia, and reduced variability of the head tilt in the face mask. METHODS AND MATERIALS: The cranial fields were treated with near lateral fields and a table angle to match their divergence to the superior edge of the spinal field. The collimator was rotated to match the divergence from the superior spinal field. The spinal fields were treated using a source to surface distance (SSD) technique with the couch top at 100 cm. When a second spinal field was required, the table and collimator were rotated 90 degrees to allow for the use of the multileaf collimator and so the gantry could be rotated to match the divergence of the superior spinal field. The multileaf collimator was used for daily dynamic featherings and field-in-field dose control. RESULTS: With a median follow-up of 20.2 months, five documented failures and no cases of radiation myelitis occurred in 23 consecutive patients. No failures occurred in the junctions of the spine-spine or brain-spine fields. Two failures occurred in the primary site alone, two in the spinal axis alone, and one primary site failure plus distant metastasis. The median time to recurrence was 17 months. CONCLUSION: The results of our study have shown that supine approach for delivering craniospinal irradiation is not associated with increased relapses at the field junctions. To date, no cases of radiation myelitis have developed.

Design, synthesis, and biological evaluation of pyrazinones containing novel P1 needles as inhibitors of TF/VIIa.

Herein is described the design, synthesis, and enzymatic activity of a series of substituted pyrazinones as inhibitors of the TF/VIIa complex. These inhibitors were designed to explore replacement and variation of the P1 amidine described previously [J. Med. Chem.2003, 46, 4050]. The P1 needle replacements were selected based upon their reduced basicity compared to the parent phenyl amidine (pKa approximately 12). A contributing factor towards the oral bioavailability of a compound is the ionization state of the compound in the intestinal tract. The desired outcome of the study was to identify an orally bioavailable TF-VIIa inhibitor.

Structure-based design and synthesis of pyrazinones containing novel P1 'side pocket' moieties as inhibitors of TF/VIIa.

We describe the structure-based design, synthesis, and enzymatic activity of a series of substituted pyrazinones as inhibitors of the TF/VIIa complex. These inhibitors contain substituents meta to the P(1) amidine designed to explore additional interactions with the VIIa residues in the so-called 'S(1) side pocket'. A crystal structure of the designed inhibitors demonstrates the ability of the P(1) side pocket moiety to engage Lys192 and main chain of Gly216 via hydrogen bond interactions, thus, providing additional possibility for chemical modification to improve selectivity and/or physical properties of inhibitors.

A method for determining whether hypotension caused by novel compounds in preclinical development results from histamine release.

INTRODUCTION: Many therapeutic agents stimulate histamine release from mast cells, which results in a decrease in blood pressure. The purpose of this study is to establish a method to determine if the mechanism of action, or one of the mechanisms, of hypotensive compounds is related to the release of histamine. The method was developed using a novel hypotensive compound, SC-372. METHODS: In Inactin anesthetized rats, after intravenous administration of SC-372 (0.3-7 mg/kg), the 2 and 7 mg/kg resulted in a dose-dependent decrease in blood pressure. Histamine (0.1 and 1 mg/kg) was injected intravenously to establish whether histamine release was the mechanism of action for the hypotension induced by SC-372. Compound 48/80 (0.1 mg/kg, promotes histamine release) and Cromolyn (1 mg/kg/min, [5 min], prevents histamine release from mast cells) were characterized and used intravenously in combination with/or compared to SC-372. RESULTS: Histamine resulted in a decrease in blood pressure that was unaffected by Cromolyn (1 mg/kg). Administration of Compound 48/80 resulted in a rapid reduction of systemic blood pressure. Intravenous infusion of Cromolyn prior to the injection of Compound 48/80 significantly attentuated the hypotensive response and the increase in histamine levels in the plasma. Intravenous administration of SC-372 resulted in a rapid reduction in blood pressure with a profile similar to that of Compound 48/80. When the rats were treated with Cromolyn prior to the administration of SC-372, both the blood pressure and plasma histamine levels were maintained at their pretreatment control levels. DISCUSSION: These data indicate that Compound 48/80 and Cromolyn can be used in rats to screen for histamine release-dependent drug-induced hypotension and suggest that the rapid decrease in blood pressure caused by SC-372 may result from histamine release from mast cells.

Assessment of bleeding propensity in non-human primates by combination of selective tissue factor/VIIa inhibition and aspirin compared to warfarin and aspirin treatment.

This study in non-human primates was designed to evaluate the bleeding propensity of a selective, small molecule inhibitor of tissue factor (TF)/VIIa in combination with acetylsalicylic acid (ASA) in comparison to the combination of ASA and warfarin. Bleeding time was increased by ASA but was not prolonged further by the addition of the TF/VIIa inhibitor, PHA-927, at doses that elevated the prothrombin time to 8-fold. In contrast, bleeding time was prolonged by warfarin alone and further exacerbated by the presence of ASA. Acute blood loss at the bleeding site, while not significantly increased by either warfarin or PHA-927, was increased substantially in several individuals treated with a combination of warfarin and ASA but not by the combination of TF/VIIa inhibitor and ASA. These data predict that TF/VIIa inhibition, in the presence of chronic aspirin therapy in patients with cardiovascular risk factors, will be a safe therapy for thrombotic disorders.

Polymer-assisted solution-phase (PASP) Suzuki couplings employing an anthracene-tagged palladium catalyst.

A general method for polymer-assisted solution-phase (PASP) Suzuki reactions employing a combination of anthracene-tagged palladium catalyst and anthracene-tagged boronic acid with a polymer-supported carbonate base is reported. The anthracene-tagged catalyst allows for the easy removal of the Pd catalyst along with the dissociated phosphine ligand and phosphine oxide byproducts by sequestration through a chemoselective Diels-Alder reaction with a maleimide resin. The polymer-supported carbonate base facilitates the removal of excess boronic acid and the borane-containing byproducts present at the end of the coupling reaction. The Suzuki coupling reaction can be efficiently conducted by using combinations of the anthracene-tagged Pd catalyst, polymer-supported carbonate base, and anthracene-tagged boronic acid to yield the desired product in high purity and yield without the use of chromatography.

Synthesis and X-ray crystal structures of substituted fluorobenzene and benzoquinone inhibitors of the tissue factor VIIa complex.

Multistep syntheses of substituted benzenes and benzoquinone inhibitors of tissue Factor VIIa are reported. The benzene analogues were designed such that their substitution pattern would occupy and interact with the S(1), S(2), and S(3) pockets of the tissue Factor VIIa (TF/VIIa) enzyme. The compounds exhibited modest potency on TF/VIIa with selectivity over Factor Xa and thrombin. The X-ray crystal structures of the targeted fluorobenzene 12a and benzoquinone 14 inhibitors bound to TF/VIIa were obtained and will be described.

Design, synthesis, and crystal structure of selective 2-pyridone tissue factor VIIa inhibitors.

Targeted 2-pyridones were selected as tissue Factor VIIa inhibitors and prepared from 2,6-dibromopyridine via a multistep synthesis. A variety of chemical transformations, including regioselective nucleophilic addition, selective nitrogen alkylation, and a Suzuki coupling, afforded the targeted tissue Factor VIIa inhibitors. The pyridone core was selected as a replacement for the pyrazinone core of noncovalent tissue Factor VIIa inhibitors and designed such that their substitution pattern would occupy and interact with the S(1), S(2), and S(3) pockets of the tissue Factor VIIa enzyme. These compounds were tested in several serine protease enzyme assays involved in the coagulation cascade exhibiting modest activity on tissue Factor VIIa with excellent selectivity over thrombin and Factor Xa. Finally, an X-ray crystal structure of inhibitor 14a bound to tissue Factor VIIa was obtained and will be described.