Terminal attack trajectories of peregrine falcons are described by the proportional navigation guidance law of missiles.

The ability to intercept uncooperative targets is key to many diverse flight behaviors, from courtship to predation. Previous research has looked for simple geometric rules describing the attack trajectories of animals, but the underlying feedback laws have remained obscure. Here, we use GPS loggers and onboard video cameras to study peregrine falcons, Falco peregrinus, attacking stationary targets, maneuvering targets, and live prey. We show that the terminal attack trajectories of peregrines are not described by any simple geometric rule as previously claimed, and instead use system identification techniques to fit a phenomenological model of the dynamical system generating the observed trajectories. We find that these trajectories are best-and exceedingly well-modeled by the proportional navigation (PN) guidance law used by most guided missiles. Under this guidance law, turning is commanded at a rate proportional to the angular rate of the line-of-sight between the attacker and its target, with a constant of proportionality (i.e., feedback gain) called the navigation constant (N). Whereas most guided missiles use navigation constants falling on the interval 3 ≤ N ≤ 5, peregrine attack trajectories are best fitted by lower navigation constants (median N < 3). This lower feedback gain is appropriate at the lower flight speed of a biological system, given its presumably higher error and longer delay. This same guidance law could find use in small visually guided drones designed to remove other drones from protected airspace.

Accuracy in Diagnosis of Celiac Disease Without Biopsies in Clinical Practice.

BACKGROUND & AIMS: The guidelines of the European Society of Pediatric Gastroenterology, Hepatology, and Nutrition allow for diagnosis of celiac disease without biopsies in children with symptoms and levels of immunoglobulin A against tissue-transglutaminase (TGA-IgA) 10-fold or more the upper limit of normal (ULN), confirmed by detection of endomysium antibodies (EMA) and positivity for HLA-DQ2/DQ8. We performed a large, international prospective study to validate this approach. METHODS: We collected data from consecutive pediatric patients (18 years or younger) on a gluten-containing diet who tested positive for TGA-IgA from November 2011 through May 2014, seen at 33 pediatric gastroenterology units in 21 countries. Local centers recorded symptoms; measurements of total IgA, TGA, and EMA; and histopathology findings from duodenal biopsies. Children were considered to have malabsorption if they had chronic diarrhea, weight loss (or insufficient gain), growth failure, or anemia. We directly compared central findings from 16 antibody tests (8 for TGA-IgA, 1 for TGA-IgG, 6 for IgG against deamidated gliadin peptides, and 1 for EMA, from 5 different manufacturers), 2 HLA-DQ2/DQ8 tests from 2 manufacturers, and histopathology findings from the reference pathologist. Final diagnoses were based on local and central results. If all local and central results were concordant for celiac disease, cases were classified as proven celiac disease. Patients with only a low level of TGA-IgA (threefold or less the ULN) but no other results indicating celiac disease were classified as no celiac disease. Central histo-morphometry analyses were performed on all other biopsies and cases were carefully reviewed in a blinded manner. Inconclusive cases were regarded as not having celiac disease for calculation of diagnostic accuracy. The primary aim was to determine whether the nonbiopsy approach identifies children with celiac disease with a positive predictive value (PPV) above 99% in clinical practice. Secondary aims included comparing performance of different serological tests and to determine whether the suggested criteria can be simplified. RESULTS: Of 803 children recruited for the study, 96 were excluded due to incomplete data, low level of IgA, or poor-quality biopsies. In the remaining 707 children (65.1% girls; median age, 6.2 years), 645 were diagnosed with celiac disease, 46 were found not to have celiac disease, and 16 had inconclusive results. Findings from local laboratories of TGA-IgA 10-fold or more the ULN, a positive result from the test for EMA, and any symptom identified children with celiac disease (n = 399) with a PPV of 99.75 (95% confidence interval [CI], 98.61-99.99); the PPV was 100.00 (95% CI, 98.68-100.00) when only malabsorption symptoms were used instead of any symptom (n = 278). Inclusion of HLA analyses did not increase accuracy. Findings from central laboratories differed greatly for patients with lower levels of antibodies, but when levels of TGA-IgA were 10-fold or more the ULN, PPVs ranged from 99.63 (95% CI, 98.67-99.96) to 100.00 (95% CI, 99.23-100.00). CONCLUSIONS: Children can be accurately diagnosed with celiac disease without biopsy analysis. Diagnosis based on level of TGA-IgA 10-fold or more the ULN, a positive result from the EMA tests in a second blood sample, and the presence of at least 1 symptom could avoid risks and costs of endoscopy for more than half the children with celiac disease worldwide. HLA analysis is not required for accurate diagnosis. Clinical Trial Registration no: DRKS00003555.

Osmotic and stimulant laxatives for the management of childhood constipation.

BACKGROUND: Constipation within childhood is an extremely common problem. Despite the widespread use of osmotic and stimulant laxatives by health professionals to manage constipation in children, there has been a long standing paucity of high quality evidence to support this practice. OBJECTIVES: We set out to evaluate the efficacy and safety of osmotic and stimulant laxatives used to treat functional childhood constipation. SEARCH METHODS: We searched MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials, and the Cochrane IBD Group Specialized Trials Register from inception to 10 March 2016. There were no language restrictions. We also searched the references of all included studies, personal contacts and drug companies to identify studies. SELECTION CRITERIA: Randomised controlled trials (RCTs) which compared osmotic or stimulant laxatives to placebo or another intervention, with participants aged 0 to 18 years old were considered for inclusion. The primary outcome was frequency of defecation. Secondary endpoints included faecal incontinence, disimpaction, need for additional therapies and adverse events. DATA COLLECTION AND ANALYSIS: Relevant papers were identified and two authors independently assessed the eligibility of trials, extracted data and assessed methodological quality using the Cochrane risk of bias tool. The primary outcome was frequency of defecation. Secondary endpoints included faecal incontinence, disimpaction, need for additional therapies and adverse events. For continuous outcomes we calculated the mean difference (MD) and 95% confidence interval (CI) using a fixed-effect model. For dichotomous outcomes we calculated the risk ratio (RR) and 95% CI using a fixed-effect model. The Chi(2) and I(2) statistics were used to assess statistical heterogeneity. A random-effects model was used in situations of unexplained heterogeneity. We assessed the overall quality of the evidence supporting the primary and secondary outcomes using the GRADE criteria. MAIN RESULTS: Twenty-five RCTs (2310 participants) were included in the review. Fourteen studies were judged to be at high risk of bias due to lack of blinding, incomplete outcome data and selective reporting. Meta-analysis of two studies (101 patients) comparing polyethylene glycol (PEG) with placebo showed a significantly increased number of stools per week with PEG (MD 2.61 stools per week, 95% CI 1.15 to 4.08). Common adverse events in the placebo-controlled studies included flatulence, abdominal pain, nausea, diarrhoea and headache. Participants receiving high dose PEG (0.7 g/kg) had significantly more stools per week than low dose PEG (0.3 g/kg) participants (1 study, 90 participants, MD 1.30, 95% 0.76 to 1.84). Meta-analysis of 6 studies with 465 participants comparing PEG with lactulose showed a significantly greater number of stools per week with PEG (MD 0.70 , 95% CI 0.10 to 1.31), although follow-up was short. Patients who received PEG were significantly less likely to require additional laxative therapies. Eighteen per cent (27/154) of PEG patients required additional therapies compared to 31% (47/150) of lactulose patients (RR 0.55, 95% CI 0.36 to 0.83). No serious adverse events were reported with either agent. Common adverse events in these studies included diarrhoea, abdominal pain, nausea, vomiting and pruritis ani. Meta-analysis of 3 studies with 211 participants comparing PEG with milk of magnesia showed that the stools per week were significantly greater with PEG (MD 0.69, 95% CI 0.48 to 0.89). However, the magnitude of this difference was quite small and may not be clinically significant. One child was noted to be allergic to PEG, but there were no other serious adverse events reported. One study found a significant difference in stools per week favouring milk of magnesia over lactulose (MD -1.51, 95% CI -2.63 to -0.39, 50 patients), Meta-analysis of 2 studies with 287 patients comparing liquid paraffin (mineral oil) with lactulose revealed a relatively large statistically significant difference in the number of stools per week favouring liquid paraffin (MD 4.94 , 95% CI 4.28 to 5.61). No serious adverse events were reported. Adverse events included abdominal pain, distention and watery stools. No statistically significant differences in the number of stools per week were found between PEG and enemas (1 study, 90 patients, MD 1.00, 95% CI -1.58 to 3.58), dietary fibre mix and lactulose (1 study, 125 patients, P = 0.481), senna and lactulose (1 study, 21 patients, P > 0.05), lactitol and lactulose (1 study, 51 patients, MD -0.80, 95% CI -2.63 to 1.03), hydrolyzed guar gum and lactulose (1 study, 61 patients, MD 1.00, 95% CI -1.80 to 3.80), PEG and flixweed (1 study, 109 patients, MD 0.00, 95% CI -0.33 to 0.33), PEG and dietary fibre (1 study, 83 patients, MD 0.20, 95% CI -0.64 to 1.04), and PEG and liquid paraffin (2 studies, 261 patients, MD 0.35, 95% CI -0.24 to 0.95). AUTHORS' CONCLUSIONS: The pooled analyses suggest that PEG preparations may be superior to placebo, lactulose and milk of magnesia for childhood constipation. GRADE analyses indicated that the overall quality of the evidence for the primary outcome (number of stools per week) was low or very low due to sparse data, inconsistency (heterogeneity), and high risk of bias in the studies in the pooled analyses. Thus, the results of the pooled analyses should be interpreted with caution because of quality and methodological concerns, as well as clinical heterogeneity, and short follow-up. There is also evidence suggesting the efficacy of liquid paraffin (mineral oil). There is no evidence to demonstrate the superiority of lactulose when compared to the other agents studied, although there is a lack of placebo controlled studies. Further research is needed to investigate the long term use of PEG for childhood constipation, as well as the role of liquid paraffin. The optimal dose of PEG also warrants further investigation.

Pharmaceutical portfolio management: global disease burden and corporate performance metrics.

BACKGROUND: Biopharmaceutical companies face multiple external pressures. Shareholders demand a profitable company while governments, nongovernmental third parties, and the public at large expect a commitment to improving health in developed and, in particular, emerging economies. Current industry commercial models are inadequate for assessing opportunities in emerging economies where disease and market data are highly limited. OBJECTIVE: The purpose of this article was to define a conceptual framework and build an analytic decision-making tool to assess and enhance a company's global portfolio while balancing its business needs with broader social expectations. METHODS: Through a case-study methodology, we explore the relationship between business and social parameters associated with pharmaceutical innovation in three distinct disease areas. The global burden of disease-based theoretical framework using disability-adjusted life-years provides an overview of the burden associated with particular diseases. The social return on investment is expressed as disability-adjusted life-years averted as a result of the particular pharmaceutical innovation. Simultaneously, the business return on investment captures the research and development costs and projects revenues in terms of a profitability index. CONCLUSIONS: The proposed framework can assist companies as they strive to meet the medical needs of populations around the world for decades to come.

Azathioprine and 6-mercaptopurine for maintenance of surgically-induced remission in Crohn's disease.

BACKGROUND: Crohn's disease (CD) is a chronic relapsing inflammatory condition. Many patients fail to achieve remission with medical management and require surgical interventions. Purine analogues have been used to maintain surgically-induced remission in CD, but the effectiveness of these agents is unclear. OBJECTIVES: The objectives were to evaluate the efficacy and safety of purine analogues for maintenance of surgically-induced remission in CD. SEARCH METHODS: We searched the following databases from inception to 30 April 2014: PubMed, MEDLINE, EMBASE, CENTRAL, and the Cochrane Inflammatory Bowel Disease and Functional Bowel Disorders Group Specialized Trials Register). We also searched the reference lists of all included studies, and contacted personal sources and drug companies to identify additional studies. The searches were not limited by language. SELECTION CRITERIA: Randomised controlled trials (RCTs) that compared purine analogues to placebo or another intervention, with treatment durations of at least six months were considered for inclusion. Participants were patients of any age with CD in remission following surgery. DATA COLLECTION AND ANALYSIS: Two authors independently assessed trial eligibility and extracted data. Methodological quality was assessed using the Cochrane risk of bias tool. The primary outcome measures were clinical and endoscopic relapse as defined by the primary studies. Secondary outcomes included adverse events, withdrawal due to adverse events and serious adverse events. Data were analysed on an intention-to-treat basis where patients with missing final outcomes were assumed to have relapsed. We calculated the risk ratio (RR) and corresponding 95% confidence interval (95% CI) for dichotomous outcomes. The Chi(2) and I(2) statistics were used to assess heterogeneity. The overall quality of the evidence supporting the primary outcomes and selected secondary outcomes was assessed using the GRADE criteria. MAIN RESULTS: Seven RCTs (n = 584 patients) were included in the review. Three studies compared azathioprine to 5-aminosalicylic acid (5-ASA). One small study compared azathioprine to both 5-ASA and adalimumab. One study compared azathioprine to placebo and another study compared 6-mercaptopurine to 5-ASA and placebo. One small study compared azathioprine to infliximab. Three studies were judged to be at low risk of bias. Four studies were judged to be at high risk of bias due to blinding. The study (n = 22) comparing azathioprine to infliximab found that the effects on the proportion of patients who had a clinical (RR 2.00, 95% CI 0.21 to 18.98) or endoscopic relapse (RR 4.40, 95% CI 0.59 to 3.07) were uncertain. One study (n = 33) found decreased clinical (RR 5.18, 95% CI 1.35 to 19.83) and endoscopic relapse (RR 10.35, 95% CI 1.50 to 71.32) rates favouring adalimumab over azathioprine. A pooled analysis of two studies (n = 168 patients) showed decreased clinical relapse rates at one or two years favouring purine analogues over placebo. Forty-eight per cent of patients in the purine analogue group experienced a clinical relapse compared to 63% of placebo patients (RR 0.74, 95% CI 0.58 to 0.94). A GRADE analysis indicated that the overall quality of the evidence supporting this outcome was low due to high risk of bias (one study was single-blind) and sparse data (93 events). One study (87 patients) found a reduction in endoscopic relapse rates favouring 6-mercaptopurine over placebo. Seventeen per cent of 6-mercaptopurine patients had an endoscopic relapse at two years compared to 42% of placebo patients (RR 0.40, 95% CI 0.19 to 0.83). A GRADE analysis indicated that the overall quality of the evidence for this outcome was low due to very sparse data (25 events). A pooled analysis of five studies (n = 425 patients) showed no difference in clinical relapse rates at one or two years between purine analogues and 5-ASA agents. Sixty-three per cent of patients in the purine analogues group experienced a clinical relapse compared to 54% of 5-ASA patients (RR 1.15, 95% CI 0.99 to 1.34). A GRADE analysis indicated that the overall quality of the evidence supporting this outcome was very low due to high risk of bias (two open-label studies), sparse data (249 events) and moderate heterogeneity (I(2) = 45%). There was no difference in endoscopic relapse at 12 months between azathioprine and 5-ASA (RR 0.78, 95% CI 0.52 to 1.17; 1 study, 35 patients). A GRADE analysis indicated that the overall quality of the evidence for this outcome was very low due to high risk of bias (open-label study) and very sparse data (26 events). There was a reduction in endoscopic relapse at 24 months favouring 6-mercaptopurine over 5-ASA patients. Seventeen per cent of 6-mercaptopurine patients had an endoscopic relapse compared to 48% of 5-ASA patients (RR 0.36, 95% CI 0.18 to 0.72; 1 study, 91 patients). A GRADE analysis indicated that the overall quality of the evidence for this outcome was low due to very sparse data (29 events). Adverse events that required withdrawal were more common in the purine analogue group compared to 5-ASA. Twenty per cent of patients in the purine analogue group withdrew due to adverse events compared to 10% of 5-ASA patients (RR 2.07, 95% CI 1.26 to 3.39; 5 studies, 423 patients).The results for withdrawal due to adverse events between purine analogues and placebo or for other comparisons were uncertain. Commonly reported adverse events across all studies included leucopenia, arthralgia, abdominal pain or severe epigastric intolerance, elevated liver enzymes, nausea and vomiting, pancreatitis, anaemia, exacerbation of Crohn's disease, nasopharyngitis, and flatulence. AUTHORS' CONCLUSIONS: Purine analogues may be superior to placebo for maintenance of surgically-induced remission in patients with CD, although this is based on two small studies. The results for efficacy outcomes between purine analogues and 5-ASA agents were uncertain. However, patients taking purine analogues were more likely than 5-ASA patients to discontinue therapy due to adverse events. No firm conclusions can be drawn from the two small studies that compared azathioprine to infliximab or adalimumab. Adalimumab may be superior to azathioprine but further research is needed to confirm these results. Further research investigating the efficacy and safety of azathioprine and 6-mercaptopurine in comparison to other active medications in patients with surgically-induced remission of CD is warranted.

Validating cognitive screening in young people with first-episode psychosis: The CogScreen protocol.

AIM: Cognitive impairments are a core feature of first-episode psychosis (FEP) and one of the strongest predictors of long-term psychosocial functioning. Cognition should be assessed and treated as part of routine clinical care for FEP. Cognitive screening offers the opportunity to rapidly identify and triage those in most need of cognitive support. However, there are currently no validated screening measures for young people with FEP. CogScreen is a hybrid effectiveness-implementation study which aims to evaluate the classification accuracy (relative to a neuropsychological assessment as a reference standard), test-retest reliability and acceptability of two cognitive screening tools in young people with FEP. METHODS: Participants will be 350 young people (aged 12-25) attending primary and specialist FEP treatment centres in three large metropolitan cities (Adelaide, Sydney, and Melbourne) in Australia. All participants will complete a cross-sectional assessment over two sessions including two cognitive screening tools (Screen for Cognitive Impairment in Psychiatry and Montreal Cognitive Assessment), a comprehensive neuropsychological assessment battery, psychiatric and neurodevelopmental assessments, and other supplementary clinical measures. To determine the test-retest reliability of the cognitive screening tools, a subset of 120 participants will repeat the screening measures two weeks later. RESULTS: The protocol, rationale, and hypotheses for CogScreen are presented. CONCLUSIONS: CogScreen will provide empirical evidence for the validity and reliability of two cognitive screening tools when compared to a comprehensive neuropsychological assessment. The screening measures may later be incorporated into clinical practice to assist with rapid identification and treatment of cognitive deficits commonly experienced by young people with FEP.

Gastrostomy feeding versus oral feeding alone for children with cerebral palsy.

BACKGROUND: Children with cerebral palsy can be significantly disabled in terms of their ability to suck, chew and swallow. This can lead to significant impairment in feeding and, eventually, to undernutrition. It can also result in aspiration of food into the lungs. Length of feeding time may be considerably increased and, instead of being an enjoyable experience, mealtimes may be distressing for both child and carer. For children unable to maintain a normal nutritional state feeding by mouth, gastrostomy or jejunostomy tubes are increasingly being used to provide the digestive system with nutrients. A gastrostomy tube is a feeding tube inserted surgically through the abdominal wall directly into the stomach. A jejunostomy feeding tube is inserted into the jejunum, part of the small intestine, either directly or via a previous gastrostomy. Although gastrostomy or jejunostomy placement may greatly facilitate the feeding of children with cerebral palsy, many carers find it very emotionally difficult to accept this intervention. Moreover, the intervention is costly and there is the possibility of complications. The effectiveness and safety of the treatment requires further assessment. This review is an update of one previously published in 2004. OBJECTIVES: To assess the effects of nutritional supplementation given via gastrostomy or jejunostomy to children with feeding difficulties due to cerebral palsy. SEARCH METHODS: For this update, we searched the following databases in July 2012: CENTRAL, MEDLINE , Embase, CINAHL, Science Citation Index, Conference Proceedings Citation Index, LILACS and Zetoc. We searched for trials in ICTRP and Clinicaltrials.gov, and for theses in WorldCat and Proquest Index to Theses. We also contacted other researchers and experts in this field. SELECTION CRITERIA: We looked for randomised controlled trials that compared delivery of nutrition via a gastrostomy or jejunostomy tube compared with oral feeding alone for children up to the age of 16 years. DATA COLLECTION AND ANALYSIS: Screening of search results was undertaken independently by two review authors. No data extraction was possible as there were no included studies. MAIN RESULTS: No trials were identified that met the inclusion criteria for this review. AUTHORS' CONCLUSIONS: Considerable uncertainty about the effects of gastrostomy for children with cerebral palsy remains. A well designed and conducted randomised controlled trial should be undertaken to resolve the current uncertainties about medical management for children with cerebral palsy and physical difficulties in eating.

Osmotic and stimulant laxatives for the management of childhood constipation.

BACKGROUND: Constipation within childhood is an extremely common problem. Despite the widespread use of osmotic and stimulant laxatives by health professionals to manage constipation in children, there has been a long standing paucity of high quality evidence to support this practice. OBJECTIVES: We set out to evaluate the efficacy and safety of osmotic and stimulant laxatives used to treat functional childhood constipation. SEARCH METHODS: The search (inception to May 7, 2012) was standardised and not limited by language and included electronic searching (MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, Cochrane Inflammatory Bowel Disease and Functional Bowel Disorders Group Specialized Trials Register), reference searching of all included studies, personal contacts and drug companies. SELECTION CRITERIA: Randomised controlled trials (RCTs) which compared osmotic or stimulant laxatives with either placebo or another intervention, with patients aged 0 to 18 years old were considered for inclusion. The primary outcome was frequency of defecation. Secondary endpoints included faecal incontinence, disimpaction, need for additional therapies and adverse events. DATA COLLECTION AND ANALYSIS: Relevant papers were identified and the authors independently assessed the eligibility of trials. Methodological quality was assessed using the Cochrane risk of bias tool.The Cochrane RevMan software was used for analyses. Patients with final missing outcomes were assumed to have relapsed. For continuous outcomes we calculated a mean difference (MD) and 95% confidence interval (CI) using a fixed-effect model. For dichotomous outcomes we calculated an odds ratio (OR) and 95% confidence intervals (95% CI) using a fixed-effect model. The chi square and I(2) statistics were used to assess statistical heterogeneity. A random-effects model was used in situations of unexplained heterogeneity MAIN RESULTS: Eighteen RCTs (1643 patients) were included in the review. Nine studies were judged to be at high risk of bias due to lack of blinding, incomplete outcome data and selective reporting. Meta-analysis of two studies (101 patients) comparing polyethylene glycol (PEG) with placebo showed a significantly increased number of stools per week with PEG (MD 2.61 stools per week, 95% CI 1.15 to 4.08). Common adverse events in the placebo-controlled studies included flatulence, abdominal pain, nausea, diarrhoea and headache. Meta-analysis of 4 studies with 338 participants comparing PEG with lactulose showed significantly greater stools per week with PEG (MD 0.95 stools per week, 95% CI 0.46 to 1.44), although follow up was short. Patients who received PEG were significantly less likely to require additional laxative therapies. Eighteen per cent of PEG patients required additional therapies compared to 30% of lactulose patients (OR 0.49, 95% CI 0.27 to 0.89). No serious adverse events were reported with either agent. Common adverse events in these studies included diarrhoea, abdominal pain, nausea, vomiting and pruritis ani. Meta-analysis of 3 studies with 211 participants comparing PEG with milk of magnesia showed that the stools/wk was significantly greater with PEG (MD 0.69 stools per week, 95% CI 0.48 to 0.89). However, the magnitude of this difference is quite small and may not be clinically significant. One child was noted to be allergic to PEG, but there were no other serious adverse events reported. Meta-analysis of 2 studies with 287 patients comparing liquid paraffin (mineral oil) with lactulose revealed a relatively large statistically significant difference in the number of stools per week favouring paraffin (MD 4.94 stools per week, 95% CI 4.28 to 5.61). No serious adverse events were reported. Adverse events included abdominal pain, distention and watery stools. No statistically significant differences in the number of stools per week were found between PEG and enemas (1 study, 90 patients, MD 1.00, 95% CI -1.58 to 3.58), dietary fibre mix and lactulose (1 study, 125 patients, P = 0.481), senna and lactulose (1 study, 21 patients, P > 0.05), lactitol and lactulose (1 study, 51 patients, MD -0.80, 95% CI -2.63 to 1.03), and PEG and liquid paraffin (1 study, 158 patients, MD 0.70, 95% CI -0.38 to 1.78). AUTHORS' CONCLUSIONS: The pooled analyses suggest that PEG preparations may be superior to placebo, lactulose and milk of magnesia for childhood constipation. GRADE analyses indicated that the overall quality of the evidence for the primary outcome (number of stools per week) was low or very low due to sparse data, inconsistency (heterogeneity), and high risk of bias in the studies in the pooled analyses. Thus, the results of the pooled analyses should be interpreted with caution because of quality and methodological concerns, as well as clinical heterogeneity, and short follow up. However, PEG appears safe and well tolerated. There is also evidence suggesting the efficacy of liquid paraffin (mineral oil), which was also well tolerated.There is no evidence to demonstrate the superiority of lactulose when compared to the other agents studied, although there is a lack of placebo controlled studies. Further research is needed to investigate the long term use of PEG for childhood constipation, as well as the role of liquid paraffin.

Oral 5-aminosalicylic acid for maintenance of surgically-induced remission in Crohn's disease.

BACKGROUND: The use of 5-aminosalicylates (5-ASAs) in Crohn's disease (CD) is controversial.  A recent Cochrane review found that 5-ASAs are not effective for the maintenance of medically-induced remission in CD, but their role in the maintenance of surgically-induced remission is unclear. OBJECTIVES: The objectives were to evaluate the efficacy and safety of 5-ASA agents for the maintenance of surgically-induced remission in CD. SEARCH STRATEGY: The search was standardised and not limited by language and included electronic searching (MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, Cochrane Inflammatory Bowel Disease Group Specialized Trials Register), reference searching of all included studies, abstracts from major meetings, personal contacts and drug companies. SELECTION CRITERIA: Randomised controlled trials (RCTs) which compared 5-ASAs with either placebo or another intervention, with treatment durations of at least 6 months were considered for inclusion. Participants were patients of any age with CD in remission following surgery. Primary outcome measures were clinical relapse or endoscopic recurrence as defined by the primary studies. Secondary endpoints were the occurrence of adverse events. DATA COLLECTION AND ANALYSIS: Relevant papers were identified and the authors independently assessed the eligibility of trials. Methodological quality was assessed using the Cochrane risk of bias tool.The Cochrane RevMan software was used for analyses. Patients with final missing outcomes were assumed to have relapsed. Odds ratio (OR) and 95% confidence intervals (95% CI) were calculated based on the fixed effects model. The chi square and I(2) statistics were used to assess statistical heterogeneity. MAIN RESULTS: Nine RCTs were included in the review. Seven studies compared oral 5-ASA with placebo and two compared oral 5-ASA with purine antimetabolites (azathioprine or 6-mercaptopurine). 5-ASA was significantly more effective than placebo for preventing relapse (OR 0.68, 95% CI, 0.52 to 0.90). There was no statistically significant heterogeneity among the 8 trials comparing 5-ASA with placebo (P=0.47). No statistically significant difference in adverse events was found for 5-ASA versus placebo (OR 1.02, 95%CI, 0.60 to 1.76). No statistically significant difference was found between 5-ASA and purine antimetabolites for preventing relapses (OR 1.08 95% CI, 0.63 to 1.85). AUTHORS' CONCLUSIONS: The pooled analyses suggest that 5-ASA preparations may be superior to placebo for the maintenance of surgically-induced remission in patients with CD. The results of the pooled analyses should be interpreted with caution because adequately powered studies demonstrated no difference and publication bias (failure to publish negative studies) may be an issue. The potential benefit provided by 5-ASA drugs is modest with a number needed to treat of approximately 16 to 19 patients to avoid one relapse which raises issues about the cost-effectiveness of this therapy. However, 5-ASA drugs are safe and well tolerated. The incidence of adverse events was not different in patients receiving 5-ASA compared with those receiving placebo. There is insufficient evidence to allow any conclusions on how 5-ASA preparations compare with azathioprine or 6-mercaptopurine.

Probiotics for maintenance of remission in ulcerative colitis.

BACKGROUND: Ulcerative colitis is a chronic relapsing disease characterised by diffuse mucosal inflammation limited to the colon. Current maintenance treatments have multiple adverse events and an effective treatment with minimal adverse events is desired. Several studies have demonstrated the importance of intestinal flora in the pathogenesis of ulcerative colitis. It has been suggested that modifying the bacterial flora with probiotics may attenuate the inflammatory process and prevent relapses in ulcerative colitis. OBJECTIVES: The primary objectives were to determine the efficacy and safety of probiotics for the maintenance of remission in ulcerative colitis. SEARCH METHODS: The Cochrane Central Register of Controlled Tials (CENTRAL), MEDLINE (1966 to July 2011), EMBASE (1974 to July 2011), CINAHL (1982 to July 2011) and the Cochrane Inflammatory Bowel Disease and Functional Bowel Disorders Group Specialised Trial Register were searched. Manufacturers of probiotics were contacted to identify any unpublished trials. References of trials were also searched for any additional trials. SELECTION CRITERIA: Randomised controlled trials (RCTs) that compared probiotics against placebo or any other intervention for the maintenance of remission in ulcerative colitis were eligible for inclusion. DATA COLLECTION AND ANALYSIS: Data extraction and assessment of methodological quality of included studies were independently performed by two authors. The main outcome measure was the occurrence of clinical or endoscopic relapse. MAIN RESULTS: Four studies (n = 587) met the inclusion criteria and were included in the review. Three trials compared probiotics to mesalazine and one trial compared probiotics with placebo. The studies ranged in length from 3 to 12 months. The risk of bias was high in two studies due to incomplete outcome data and lack of blinding. The methods used for allocation concealment were unclear for all four studies. There was no statistically significant difference between probiotics and mesalazine for maintenance of remission in UC. Relapse was reported in 40.1% of patients in the probiotics group compared to 34.1% of patients in the mesalazine group (3 studies; 555 patients: OR 1.33; 95% CI 0.94 to 1.90 ; I(2) = 11%). There was no statistically significant difference in the incidence of adverse events. Twenty-six per cent of patients in the probiotics group experienced at least one adverse event compared to 24% of patients in the mesalazine group (2 studies; 430 patients OR 1.21; 95% CI 0.80 to 1.84; I(2) =27%). Adverse events reported in the mesalazine-controlled studies include diarrhea, mucous secretion, bloody stools, abdominal pain, flatulence and distension, nausea and vomiting and headache. A small placebo controlled trial (n = 32) found no statistically significant difference in efficacy. Seventy-five per cent of probiotic patients relapsed at one year compared to 92% of placebo patients (OR 0.27; 95% CI 0.03 to 2.68). Adverse events reported in the placebo-controlled study include flatulence, abdominal bloating and pain, changes in faecal consistency, arthralgia, sacroiliitis, tiredness, incontinence, stress, oral blisters, eye dryness, headache, dizziness, influenza, gastroenteritis, cystitis and pneumonia. AUTHORS' CONCLUSIONS: Given the relatively small number of patients in the pooled analysis, the small number of events and the high risk and unclear risk of bias in the included studies, there is insufficient evidence to make conclusions about the efficacy of probiotics for maintenance of remission in UC. There is a lack of well-designed RCTs in this area and further research is needed.

Stratification of fertility potential according to cervical mucus symptoms: achieving pregnancy in fertile and infertile couples.

Women wishing to conceive are largely unaware of fertility symptoms at the time of ovulation. This study investigated the effectiveness of fertility-awareness in achieving pregnancy, particularly fertile mucus pattern, in the context of infertility. The 384 eligible participants were taken from consecutive women desiring pregnancy who attended 17 Australian Billings Ovulation Method® clinics from 1999-2003. This cohort included couples with infertility ≥12 months (51%) and female age >35 years (28%). Under fertility-awareness instruction, pregnancy was achieved by 240 couples (62.5%) after maximum follow-up of two years. Mucus symptom observations effectively stratified 'low pregnancy-potential' (35.2%) and 'high pregnancy-potential' groups. Pregnancy rates were ∼30% higher in the latter group (44.4% versus 72.3%) in addition to consistent effects observed on pregnancy achievements within subgroups defined by prognostic factors such as duration of infertility (p = 0.001) and increasing female age (p = 0.04). Fertile symptoms were also associated with significantly shorter time to conception (4.2 versus 6.4 months) in a survival analysis (p = 0.003). Billings Ovulation Method® observations strongly predicted successful conception. This has the capacity to provide a rapid, reliable and cost-effective approach to stratifying fertility potential, including directing timely and targeted investigations/management, and is accessible for women who may be remote from primary or specialist care.

Dynamic shapes of the zygote and two-cell mouse and human.

Mouse zygote morphokinetics were measured during interphase, the mitotic period, cytokinesis, and two-cell stage. Sequences of rounder-distorted-rounder shapes were revealed, as were changing patterns of cross section area. A calcium chelator and an actin-disrupting agent inhibited the area changes that occurred between pronuclear envelope breakdown and cytokinesis. During cell division, two vortices developed in each nascent cell and they rotated in opposite directions at each end of the cell, a pattern that sometimes persisted for up to 10 h. Exchange with the environment may have been promoted by these shape and area cycles and persisting circulation in the cytoplasm may have a similar function between a cell's interior and periphery. Some of these movements were sporadically also seen in human zygotes with abnormal numbers of pronuclei and the two-cell stages that developed from these compromised human zygotes.

Flying and swimming animals cruise at a Strouhal number tuned for high power efficiency.

Dimensionless numbers are important in biomechanics because their constancy can imply dynamic similarity between systems, despite possible differences in medium or scale. A dimensionless parameter that describes the tail or wing kinematics of swimming and flying animals is the Strouhal number, St = fA/U, which divides stroke frequency (f) and amplitude (A) by forward speed (U). St is known to govern a well-defined series of vortex growth and shedding regimes for airfoils undergoing pitching and heaving motions. Propulsive efficiency is high over a narrow range of St and usually peaks within the interval 0.2 < St < 0.4 (refs 3-8). Because natural selection is likely to tune animals for high propulsive efficiency, we expect it to constrain the range of St that animals use. This seems to be true for dolphins, sharks and bony fish, which swim at 0.2 < St < 0.4. Here we show that birds, bats and insects also converge on the same narrow range of St, but only when cruising. Tuning cruise kinematics to optimize St therefore seems to be a general principle of oscillatory lift-based propulsion.

Nurse-controlled analgesia (NCA) following major surgery in 10,000 patients in a children's hospital.

BACKGROUND AND OBJECTIVES: Patients who received NCA with morphine following major surgery between 1996 and 2008 at Great Ormond Street Hospital, London, UK, were prospectively studied in the postoperative period to determine effectiveness, morphine requirements, incidence of common side effects, and serious adverse events. METHODS: The morphine NCA regimen and monitoring was according to standard hospital protocols. Data were collected prospectively and subsequently entered by trained personnel into a secure database. Patient demographics, effectiveness and satisfaction rates, morphine requirements, side effects, and serious complications were recorded. RESULTS: 10,079 patients were included. The average age was 4 years old (range 1 day to 20.5 years, median 2.3 years). There were 510 neonates. The average NCA duration was 43.7 h. 1.8% of morphine NCAs were replaced by other methods because analgesia was unsatisfactory. Satisfaction ratings were 'good' or 'very good' for 98% of the remainder. Average daily morphine requirement (mcg x kg(-1) x h(-1)) was related to age, surgical category, and postoperative time. Side effects included PONV (25%), itching (9.4%), depression of respiration, and sedation (4.5%); incidences varied with age, morphine dose, and type of surgery. Serious, potentially life-threatening adverse effects (SAE) were 0.4%. There were no deaths. SAE were significantly greater in neonates (2.5%), relative risk 9.4, P < 0.001. Morphine dose in neonates who experienced SAE was not significantly different from other neonates. CONCLUSION: NCA with morphine is an acceptable, safe, and effective method of postoperative analgesia for a wide range of ages and types of surgery in our practice. Morphine requirements increase with age, but there was also considerable inter-individual variation within age groups. PONV, itching, sedation, and respiratory depression are expected side effects. SAE are uncommon but the incidence is greatest in neonates.

Photogrammetric reconstruction of high-resolution surface topographies and deformable wing kinematics of tethered locusts and free-flying hoverflies.

Here, we present a suite of photogrammetric methods for reconstructing insect wing kinematics, to provide instantaneous topographic maps of the wing surface. We filmed tethered locusts (Schistocerca gregaria) and free-flying hoverflies (Eristalis tenax) using four high-speed digital video cameras. We digitized multiple natural features and marked points on the wings using manual and automated tracking. Epipolar geometry was used to identify additional points on the hoverfly wing outline which were anatomically indistinguishable. The cameras were calibrated using a bundle adjustment technique that provides an estimate of the error associated with each individual data point. The mean absolute three-dimensional measurement error was 0.11 mm for the locust and 0.03 mm for the hoverfly. The error in the angle of incidence was at worst 0.51 degrees (s.d.) for the locust and 0.88 degrees (s.d.) for the hoverfly. The results we present are of unprecedented spatio-temporal resolution, and represent the most detailed measurements of insect wing kinematics to date. Variable spanwise twist and camber are prominent in the wingbeats of both the species, and are of such complexity that they would not be adequately captured by lower resolution techniques. The role of spanwise twist and camber in insect flight has yet to be fully understood, and accurate insect wing kinematics such as we present here are required to be sure of making valid predictions about their aerodynamic effects.

Aligning physician and hospital incentives: the approach at hospital for special surgery.

Healthcare administrators and physicians alike are navigating an increasingly complex and highly regulated healthcare environment. Unlike in the past, institutions now require strong collaboration among physician and administrative leaders. As providers and managers are trained and work differently, new methods are needed to provide the infrastructure and resources necessary to create, nurture, and sustain alignment between them. We describe four initiatives by administrators and physicians at Hospital for Special Surgery to work together in mutually beneficial relationships that help us achieve the highest level of patient care, satisfaction and safety. These initiatives include improving management efficiency through an orthopaedic service line structure, helping individual physicians grow their practices through the demand-office-operating room initiative of the Physicians Service Department, controlling costs through the supply effectiveness policy, and promoting teamwork in innovation through the technology transfer program.

Anesthesia in children with mastocytosis--a case based review.

INTRODUCTION: Mastocytosis is a rare heterogeneous disease of bone marrow origin which arises as a consequence of abnormal growth and/or accumulation of clonal mast cells in one or more organs. Sixty-five percent of patients with mastocytosis are children in whom it usually regresses around puberty. Adult patients with mastocytosis have been identified as at high risk of widespread mast cell degranulation in the perioperative period, this finding has not been reported in pediatric patients. This information has been repeated in mastocytosis websites where it has the potential to cause disproportionate alarm in parents. METHODS: We considered our experience of six children with mastocytosis together with a review of the literature to examine other reports of anesthesia in children with mastocytosis. Our literature search found 57 general anesthetics in 39 children with mastocytosis. In addition, we searched for information about current consensus in diagnosis, classification and treatment of mastocytosis and in vitro and in vivo studies looking at mast cell behavior in response to drugs commonly used during anesthesia. DISCUSSION: The literature search revealed that general anesthesia has precipitated life threatening complications in adult patients with systemic mastocytosis (SM) but no such complications have been described in children with mastocytosis. Our own experience with children with mastocytosis is of uneventful anesthesia. Advances in the understanding of the genetic basis of mastocytosis suggest that pediatric cutaneous mastocytosis (CM) and SM are different entities. SM in children is extremely rare and is associated with elevated baseline serum tryptase. There are few reports of anesthesia in this group. CONCLUSION: The risks for most pediatric patients are overstated by mastocytosis websites. Most pediatric patients with CM do not appear to be at risk of widespread mast cell degranulation during anesthesia but because of the small number of cases reported, the risk cannot be ascertained with confidence. Children with SM and a high baseline serum tryptase (marker of mast cell burden) may merit extra precautions but experience in this subgroup is even more limited. Drugs which cause minimal histamine release can be selected from the range of drugs available in most pediatric centers without compromise to technique.

A model for decision support in signal triage.

Spontaneous reporting of suspected adverse drug reactions (ADRs) has long been a cornerstone of pharmacovigilance. With the increasingly large volume of ADRs, regulatory agencies, scientific/academic organizations and marketing authorization holders have applied statistical tools to assist in signal detection by identifying disproportionate reporting relationships in spontaneous reporting databases. These tools have generated large numbers of signals defined as drug-ADR reporting associations that meet specified statistical criteria. The challenge is to identify which signals are most likely to be medically important and therefore warrant priority for further investigation. Decisions related to signal triage are often complex and are based on a combination of clinical, epidemiological, pharmacological and regulatory criteria. There are no specific regulations, guidelines or standards that provide an objective basis for these decisions. This paper describes preliminary work to identify and quantify the specific factors that contribute to a decision to prioritize a specific drug-ADR combination for further in-depth review. We applied a tool from the discipline of decision analysis to systematically assess the important attributes of spontaneously reported ADRs. A model was created that integrates these assessments and produces rankings for the signals generated from quantitative signalling methods. Although more research is necessary to evaluate the performance of this model fully, preliminary results suggest that the use of formal decision analysis approaches to support signal triage can provide potential benefit and will help meet an important need.

Pilot evaluation of an instrument to measure quality of life in British children with inflammatory bowel disease.

The IMPACT questionnaire was developed in Canada to measure quality of life in children with inflammatory bowel disease (IBD). In the present study, 20 children with IBD completed 2 versions of the IMPACT questionnaire with a Likert scale or visual analog scale (VAS), 5 of whom expressed problems with language or phrasing. Difficult words included "restrictions," "moderate," "diarrhea," "school break," and the abbreviation "IBD." Fifteen children preferred the Likert scale to the VAS (chi = 20, P < 0.01). Rewording the difficult words and using a Likert scale should facilitate completion of the IMPACT questionnaire in the United Kingdom. Further validation is needed to ensure that the instrument is reliable and valid.