Iron(III)-Catalyzed Carboannulations of Homopropargylic Alcohols: A One-Pot General Synthesis of 4-(2,2-Diarylvinyl)quinolines and 4-(2,2-Diarylvinyl)-2H-chromenes.

A simple and efficient approach for the general synthesis of 4-(2,2-diarylvinyl)quinolines 5 and 4-(2,2-diarylvinyl)-2H-chromenes 6 has been developed using Fe(III)-catalyzed intramolecular annulations of homopropargyl substrates 1 and 2, respectively. The high yields (up to 98%) achieved using simple substrates, an environmentally benign low-cost catalyst, and less hazardous reaction conditions make the methodology inherently attractive.

Substrate-Controlled Product Divergence in Iron(III)-Catalyzed Reactions of Propargylic Alcohols: Easy Access to Spiro-indenyl 1,4-Benzoxazines and 2-(2,2-Diarylvinyl)quinoxalines.

We report herein unprecedented cascade reactions of O-propargyl-N-tosyl-amino phenols with 10 mol% FeCl3 in DCE at room temperature for 0.67-3 h to form spiro-indenyl 1,4-benzoxazines with 38-89 % yield. Replacing the substrates' oxygen atom by a N-tosylimine group followed by treatment with the same catalyst and solvent at 80 °C produced 2-(2,2-diarylvinyl)quinoxalines in 12-20 h with up to 62 % yield. Mechanistic understanding provided an insight into the transformations. The use of simple substrates and an environmentally benign low-cost catalyst, broad substrate scope and tolerance of diverse functional groups makes the methodology inherently attractive.

Palladium(ii) catalysed cascade strategy for the synthesis of dibenzo[5,6:7,8]cycloocta[1,2-b]indol-10-ols/-10(15H)-ones: easy access to 1,3,5,7-cyclooctatetraenes (COTs).

An atom-economic Pd(ii)-catalysed cascade cyclisation of 2-(biphenylethynyl)anilines tethered to an aldehyde or cyano group leads to the formation of dibenzo[5,6:7,8]cycloocta[1,2-b]indol-10-ols 6 or dibenzo[5,6:7,8]cycloocta[1,2-b]indol-10(15H)-ones 8 with high yields (up to 95%). The reaction proceeds via amino-palladation of the alkyne followed by nucleophilic addition onto the aldehyde/cyano group. Treatment of 6 with p-TsOH·H2O smoothly provided cyclooctatetraene (COT) derivatives 7.

Palladium(II)-Catalyzed Cascade Reactions of Ene-Ynes Tethered to Cyano/Aldehyde: Access to Naphtho[1,2-b]furans and Benzo[g]indoles.

An efficient palladium(II)-catalyzed cascade reaction of ene-yne substrates carrying cyano/aldehyde group is described. It involves successive hetero- and benz-annulations in one pot via trans-oxo/aminopalladation onto alkyne, followed by 1,2-addition to cyano/aldehyde, providing a convenient synthesis of both naphtho[1,2-b]furans and benzo[g]indoles. The reaction constitutes a fast intramolecular assembly through several carbon-carbon and carbon-heteroatom bond formations taking place in one pot. The reactions are operationally simple, compatible with a range of functional groups and atom-economical in nature.

Research priorities for childhood chronic conditions: a workshop report.

BACKGROUND: Chronic conditions are the leading cause of mortality, morbidity and disability in children. However, children and caregivers are rarely involved in identifying research priorities, which may limit the value of research in supporting patient-centred practice and policy. OBJECTIVE: To identify priorities of patients, caregivers and health professionals for research in childhood chronic conditions and describe the reason for their choices. SETTING: An Australian paediatric hospital and health consumer organisations. METHODS: Recruited participants (n=73) included patients aged 8 to 14 years with a chronic condition (n=3), parents/caregivers of children aged 0 to 18 years with a chronic condition (n=19), representatives from consumer organisations (n=13) and health professionals including clinicians, researches (n=38) identified and discussed research priorities. Transcripts were thematically analysed. RESULTS: Seventy-eight research questions were identified. Five themes underpinned participants' priorities: maintaining a sense of normality (enabling participation in school, supporting social functioning, promoting understanding and acceptance), empowering self-management and partnership in care (overcoming communication barriers, gaining knowledge and skills, motivation for treatment adherence, making informed decisions, access and understanding of complementary and alternative therapies),strengthening ability to cope (learning to have a positive outlook, preparing for home care management, transitioning to adult services), broadening focus to family (supporting sibling well-being, parental resilience and financial loss, alleviating caregiver burden), and improving quality and scope of health and social care (readdressing variability and inequities, preventing disease complications and treatment side effects, identifying risk factors, improving long-term outcomes, harnessing technology, integrating multidisciplinary services). CONCLUSION: Research priorities identified by children, caregivers and health professionals emphasise a focus on life participation, psychosocial well-being, impact on family and quality of care. These priorities may be used by funding and policy organisations in establishing a paediatric research agenda.

Prevalence, patient and consultation characteristics of enuresis in Australian paediatric practice.

AIM: To describe the prevalence and consultation characteristics of enuresis in Australian paediatric practice and assess for changes over a period of 5 years. METHODS: Data collected prospectively by paediatricians (outpatient settings) in 2008 and 2013, as part of the Children Attending Paediatricians Study. Consultations on children aged 5 years or over were included. Consultations in each cohort (2008 and 2013) categorised as either listing or not listing enuresis. Characteristics of the 'enuresis' versus 'non-enuresis' subgroup in each cohort were compared as were the enuresis subgroups 2008 versus 2013. RESULTS: Of 4175 and 4181 consultations in 2008 and 2013, enuresis was reported in 178 (4.3% - 2008) and 193 (4.6% - 2013). Constipation and encopresis were more prevalent in the enuresis versus non-enuresis subgroups (46 (25.8%) vs. 136 (3.4%) for constipation and 25 (14%) vs. 65 (1.6%) for encopresis in 2008; 52 (26.9%) vs. 160 (4%) for constipation and 25 (13%) vs. 78 (2%) for encopresis in 2013, both P < 0.001). The enuresis subgroup had more referrals to multidisciplinary teams (19 (10.7%) vs. 148 (3.7%) - 2008 and 21 (10.9%) vs. 163 (4.1%) - 2013, both P < 0.001) and allied health professionals (29 (16.3%) vs. 230 (5.8%) - 2008; 27 (14%) vs. 178 (4.5%) - 2013, both P < 0.001). CONCLUSION: The overall frequency of presentation of children for management of enuresis was low. Prevalence/Consultation characteristics of enuresis were comparable over 5 years. Constipation and encopresis were significantly more prevalent in the enuresis subgroups.

Lack of Accuracy of Body Temperature for Detecting Serious Bacterial Infection in Febrile Episodes.

BACKGROUND: Body temperature is a time-honored marker of serious bacterial infection, but there are few studies of its test performance. The aim of our study was to determine the accuracy of temperature measured on presentation to medical care for detecting serious bacterial infection. METHODS: Febrile children 0-5 years of age presenting to the emergency department of a tertiary care pediatric hospital were sampled consecutively. The accuracy of the axillary temperature measured at presentation was evaluated using logistic regression models to generate receiver operating characteristic curves. Reference standard tests for serious bacterial infection were standard microbiologic/radiologic tests and clinical follow-up. Age, clinicians' impression of appearance of the child (well versus unwell) and duration of illness were assessed as possible effect modifiers. RESULTS: Of 15,781 illness episodes 1120 (7.1%) had serious bacterial infection. The area under the receiver operating characteristic curve for temperature was 0.60 [95% confidence intervals (CI): 0.58-0.62]. A threshold of ≥ 38°C had a sensitivity of 0.67 (95% CI: 0.64-0.70), specificity of 0.45 (95% CI: 0.44-0.46), positive likelihood ratio of 1.2 (95% CI: 1.2-1.3) and negative likelihood ratio of 0.7 (95% CI: 0.7-0.8). Age and illness duration had a small but significant effect on the accuracy of temperature increasing its "rule-in" potential. CONCLUSION: Measured temperature at presentation to hospital is not an accurate marker of serious bacterial infection in febrile children. Younger age and longer duration of illness increase the rule-in potential of temperature but without substantial overall change in its test accuracy.

Republished: value of white cell count in predicting serious bacterial infection in febrile children under 5 years of age.

OBJECTIVE: The leukocyte count is frequently used to evaluate suspected bacterial infections but estimates of its test performance vary considerably. We evaluated its accuracy for the detection of serious bacterial infections in febrile children. DESIGN: Prospective cohort study. SETTING: Paediatric emergency department. PATIENTS: Febrile 0-5-year-olds who had a leukocyte count on presentation. OUTCOME MEASURES: Accuracy of total white blood cell and absolute neutrophil counts for the detection of urinary tract infection, bacteraemia, pneumonia and a combined ('any serious bacterial infection') category. Logistic regression models were fitted for each outcome. Reference standards were microbiological/radiological tests and clinical follow-up. RESULTS: Serious bacterial infections were present in 714 (18.3%) of 3893 illness episodes. The area under the receiver operating characteristic curve for 'any serious bacterial infection' was 0.653 (95% CI 0.630 to 0.676) for the total white blood cell count and 0.638 (95% CI 0.615 to 0.662) for absolute neutrophil count. A white blood cell count threshold >15×10(9)/L had a sensitivity of 47% (95% CI 43% to 50%), specificity 76% (95% CI 74% to 77%), positive likelihood ratio 1.93 (95% CI 1.75 to 2.13) and negative likelihood ratio 0.70 (95% CI 0.65 to 0.75). An absolute neutrophil count threshold >10×10(9)/L had a sensitivity of 41% (95% CI 38% to 45%), specificity 78% (95% CI 76% to 79%), positive likelihood ratio 1.87 (95% CI 1.68 to 2.09) and negative likelihood ratio 0.75 (95% CI 0.71 to 0.80). CONCLUSIONS: The total white blood cell count and absolute neutrophil count are not sufficiently accurate triage tests for febrile children with suspected serious bacterial infection.

Improved insulin sensitivity and body composition, irrespective of macronutrient intake, after a 12 month intervention in adolescents with pre-diabetes; RESIST a randomised control trial.

BACKGROUND: A higher protein to carbohydrate ratio in the diet may potentiate weight loss, improve body composition and cardiometabolic risk, including glucose homeostasis in adults. The aim of this randomised control trial was to determine the efficacy of two structured lifestyle interventions, differing in dietary macronutrient content, on insulin sensitivity and body composition in adolescents. We hypothesised that a moderate-carbohydrate (40-45% of energy), increased-protein (25-30%) diet would be more effective than a high-carbohydrate diet (55-60%), moderate-protein (15%) diet in improving outcomes in obese, insulin resistant adolescents. METHODS: Obese 10-17 year olds with either pre-diabetes and/or clinical features of insulin resistance were recruited at two hospitals in Sydney, Australia. At baseline adolescents were prescribed metformin and randomised to one of two energy restricted diets. The intervention included regular contact with the dietician and a supervised physical activity program. Outcomes included insulin sensitivity index measured by an oral glucose tolerance test and body composition measured by dual-energy x-ray absorptiometry at 12 months. RESULTS: Of the 111 adolescents recruited, 85 (77%) completed the intervention. BMI expressed as a percentage of the 95th percentile decreased by 6.8% [95% CI: -8.8 to -4.9], ISI increased by 0.2 [95% CI: 0.06 to 0.39] and percent body fat decreased by 2.4% [95% CI: -3.4 to -1.3]. There were no significant differences in outcomes between diet groups at any time. CONCLUSION: When treated with metformin and an exercise program, a structured, reduced energy diet, which is either high-carbohydrate or moderate-carbohydrate with increased-protein, can achieve clinically significant improvements in obese adolescents at risk of type 2 diabetes. TRIAL REGISTRATION: Australian New Zealand Clinical Trail Registry ACTRN12608000416392 . Registered 25 August 2008.

Parental perspectives on evaluation and management of fever in young infants: an interview study.

BACKGROUND: Young febrile infants typically undergo meticulous evaluation to rule out serious bacterial infection. Parental perspectives on the process of evaluation and management of febrile infants can influence treatment satisfaction and outcomes. This study aimed to describe the perspectives of parents of young infants presenting to hospital with fever. METHODS: We conducted semistructured, face-to-face interviews with parents of healthy, term infants aged less than 3 months, admitted to a tertiary children's hospital in Sydney, Australia, during the management of a febrile illness. The interview transcripts were thematically analysed. RESULTS: 36 parents of 27 infants participated. All infants underwent a complete sepsis work up, received empiric antibiotics and made a complete recovery. Parental empowerment was central to the three themes identified: expecting reassurance and support (overwhelming responsibility, heightened vulnerability), facilitators for parental empowerment (medical attentiveness, medical partnership, gaining closure and a sense of validation), and barriers to empowerment (unexpected medical seriousness, relinquished control, failed expectations of support and limited capacity for advocacy). CONCLUSIONS: Caring for a febrile infant is overwhelming for parents. When confronted by unexpected tests and hospitalisation, they fear the possibility of a severe illness, experience a sense of helplessness and loss of control as their infant undergoes painful tests, and doubt their own ability to meet their infant's needs. Family-centred care strategies that inform and support parents, acknowledging their concerns and distress, while involving them in the medical management, may promote parental empowerment and build better alliances between parents and healthcare providers.

Value of white cell count in predicting serious bacterial infection in febrile children under 5 years of age.

OBJECTIVE: The leukocyte count is frequently used to evaluate suspected bacterial infections but estimates of its test performance vary considerably. We evaluated its accuracy for the detection of serious bacterial infections in febrile children. DESIGN: Prospective cohort study. SETTING: Paediatric emergency department. PATIENTS: Febrile 0-5-year-olds who had a leukocyte count on presentation. OUTCOME MEASURES: Accuracy of total white blood cell and absolute neutrophil counts for the detection of urinary tract infection, bacteraemia, pneumonia and a combined ('any serious bacterial infection') category. Logistic regression models were fitted for each outcome. Reference standards were microbiological/radiological tests and clinical follow-up. RESULTS: Serious bacterial infections were present in 714 (18.3%) of 3893 illness episodes. The area under the receiver operating characteristic curve for 'any serious bacterial infection' was 0.653 (95% CI 0.630 to 0.676) for the total white blood cell count and 0.638 (95% CI 0.615 to 0.662) for absolute neutrophil count. A white blood cell count threshold >15×10(9)/L had a sensitivity of 47% (95% CI 43% to 50%), specificity 76% (95% CI 74% to 77%), positive likelihood ratio 1.93 (95% CI 1.75 to 2.13) and negative likelihood ratio 0.70 (95% CI 0.65 to 0.75). An absolute neutrophil count threshold >10×10(9)/L had a sensitivity of 41% (95% CI 38% to 45%), specificity 78% (95% CI 76% to 79%), positive likelihood ratio 1.87 (95% CI 1.68 to 2.09) and negative likelihood ratio 0.75 (95% CI 0.71 to 0.80). CONCLUSIONS: The total white blood cell count and absolute neutrophil count are not sufficiently accurate triage tests for febrile children with suspected serious bacterial infection.

Optimal macronutrient content of the diet for adolescents with prediabetes; RESIST a randomised control trial.

CONTEXT: Prediabetes and clinical insulin resistance in adolescents are rapidly emerging clinical problems with serious health outcomes. OBJECTIVE: The objective of this study was to determine the efficacy of 2 structured lifestyle interventions, both differing in diet macronutrient composition, on insulin sensitivity. DESIGN: This study was a randomized controlled trial, known as Researching Effective Strategies to Improve Insulin Sensitivity in Children and Teenagers, in 2 hospitals in Sydney, Australia. PARTICIPANTS: Participants included overweight or obese 10- to 17-year-olds with either prediabetes and/or clinical features of insulin resistance. INTERVENTION: At baseline adolescents were prescribed metformin and randomized to a structured diet, which was either high carbohydrate or moderate carbohydrate with increased protein. The program commenced with a 3-month dietary intervention, with the addition of an exercise intervention in the next 3 months. OUTCOMES: The outcomes included an insulin sensitivity, anthropometry, and cardiometabolic profile at 6 months. RESULTS: One hundred eleven subjects (66 girls) were recruited and 98 subjects (58 girls) completed the 6-month intervention. After 3 months the mean insulin sensitivity index increased by 0.3 [95% confidence interval (CI) 0.2-0.4]. After 6 months the mean insulin (picomoles per liter) to glucose ratio (millimoles per liter) decreased by 7.2 [95%CI -12.0 to -2.3], body mass index, expressed as a percentage of the 95th centile, decreased by 9% (95% CI -3 to -15), but there was no significant change in the lipids. There were no significant differences in outcomes between the diet groups at any time point. CONCLUSIONS: These results are in contrast with our hypothesis that adolescents randomized to the increased protein diet would have better outcomes. Further strategies are required to better address prediabetes and clinical features of insulin resistance in adolescents.

Accuracy of the "traffic light" clinical decision rule for serious bacterial infections in young children with fever: a retrospective cohort study.

OBJECTIVES: To determine the accuracy of a clinical decision rule (the traffic light system developed by the National Institute for Health and Clinical Excellence (NICE)) for detecting three common serious bacterial infections (urinary tract infection, pneumonia, and bacteraemia) in young febrile children. DESIGN: Retrospective analysis of data from a two year prospective cohort study SETTING: A paediatric emergency department. PARTICIPANTS: 15,781 cases of children under 5 years of age presenting with a febrile illness. MAIN OUTCOME MEASURES: Clinical features were used to categorise each febrile episodes as low, intermediate, or high probability of serious bacterial infection (green, amber, and red zones of the traffic light system); these results were checked (using standard radiological and microbiological tests) for each of the infections of interest and for any serious bacterial infection. RESULTS: After combination of the intermediate and high risk categories, the NICE traffic light system had a test sensitivity of 85.8% (95% confidence interval 83.6% to 87.7%) and specificity of 28.5% (27.8% to 29.3%) for the detection of any serious bacterial infection. Of the 1140 cases of serious bacterial infection, 157 (13.8%) were test negative (in the green zone), and, of these, 108 (68.8%) were urinary tract infections. Adding urine analysis (leucocyte esterase or nitrite positive), reported in 3653 (23.1%) episodes, to the traffic light system improved the test performance: sensitivity 92.1% (89.3% to 94.1%), specificity 22.3% (20.9% to 23.8%), and relative positive likelihood ratio 1.10 (1.06 to 1.14). CONCLUSION: The NICE traffic light system failed to identify a substantial proportion of serious bacterial infections, particularly urinary tract infections. The addition of urine analysis significantly improved test sensitivity, making the traffic light system a more useful triage tool for the detection of serious bacterial infections in young febrile children.

Researching Effective Strategies to Improve Insulin Sensitivity in Children and Teenagers - RESIST. A randomised control trial investigating the effects of two different diets on insulin sensitivity in young people with insulin resistance and/or pre-diabetes.

BACKGROUND: Concomitant with the rise in childhood obesity there has been a significant increase in the number of adolescents with clinical features of insulin resistance and prediabetes. Clinical insulin resistance and prediabetes are likely to progress to type 2 diabetes and early atherosclerosis if not targeted for early intervention. There are no efficacy trials of lifestyle intervention in this group to inform clinical practice. The primary aim of this randomised control trial (RCT) is to determine the efficacy and effectiveness of two different structured lifestyle interventions differing in diet composition on insulin sensitivity, in adolescents with clinical insulin resistance and/or prediabetes treated with metformin. METHODS/DESIGN: This study protocol describes the design of an ongoing RCT. We are recruiting 108 (54 each treatment arm) 10 to 17 year olds with clinical features of insulin resistance and/or prediabetes, through physician referral, into a multi-centred RCT. All participants are prescribed metformin and participate in a diet and exercise program. The lifestyle program is the same for all participants except for diet composition. The diets are a high carbohydrate, low fat diet and a moderate carbohydrate, increased protein diet.The program commences with an intensive 3 month dietary intervention, implemented by trained dietitians, followed by a 3 month intensive gym and home based exercise program, supervised by certified physical trainers. To measure the longer term effectiveness, after the intensive intervention trial participants are managed by either their usual physician or study physician and followed up by the study dietitians for an additional 6 months. The primary outcome measure, change in insulin sensitivity, is measured at 3, 6 and 12 months. DISCUSSION: Clinical insulin resistance and prediabetes in the paediatric population are rapidly emerging clinical problems with serious health outcomes. With appropriate management these conditions are potentially reversible or at least their progression can be delayed. This research study is the first trial designed to provide much needed data on the effective dietary management for this cohort. This study will inform clinical practice guidelines for adolescents with clinical insulin resistance and may assist in preventing metabolic complications, type 2 diabetes and early cardiovascular disease. TRIAL REGISTRATION: Australian and New Zealand Clinical Trials Registration Number ACTRN12608000416392.

Overweight and obesity among children with developmental disabilities.

BACKGROUND: The aim of this study was to determine the prevalence of overweight and obesity in children with developmental disabilities attending a metropolitan Diagnosis and Assessment Service. METHOD: A retrospective chart review was carried out for 98 children (67 male) aged 2-18 years. Data on age, sex, weight, height, and severity of intellectual disability or global developmental delay were collected from medical records. Body mass index (BMI, weight/height2) was calculated, and overweight and obesity defined using standard international criteria. RESULTS: Data indicated that 24% of the children were overweight and a further 15% were obese (i.e., a total of 40% either overweight or obese), which is significantly higher than the prevalence rate for Australian school children in the New South Wales Schools Physical Activity and Nutrition Survey (SPANS) 2004, which found that 17% were overweight (p = .05) and 6% were obese (p = .0003) (i.e., 23% either overweight or obese, p = .0001). CONCLUSIONS: The prevalence of overweight and obesity is higher among children with developmental disabilities than in the general population. Community-based studies with larger sample sizes are required to confirm this finding. The results also highlight the need to develop health care strategies for the prevention, early identification and management of excess weight gain for this group.