The risk of recurrent small-for-gestational-age infants at term is dependent on the number of previously affected births.

BACKGROUND: Small-for-gestational-age infants are at a substantially increased risk of perinatal complications, but the risk of recurrent small-for-gestational-age is not well known, particularly because there are many demographic and obstetrical factors that interact and modify this risk. We investigated the relationship between previous small-for-gestational-age births and the risk of recurrence at term in a large Australian cohort. OBJECTIVE: We aimed to identify key demographic and obstetrical variables that influence the risk of recurrence of a small-for-gestational-age infant at term. The primary outcome measure was the odds of recurrence of small-for-gestational-age in subsequent pregnancies up to a maximum of 4 consecutive term births. STUDY DESIGN: This was a retrospective analysis of women who had more than 1 consecutive nonanomalous, singleton, term live births between July 1997 and September 2018 at the Mater Mother's Hospital in Brisbane, Australia. Women with multiple pregnancy, preterm birth, or major congenital malformations were excluded. Small-for-gestational-age was defined as birthweight at the <10th centile. We calculated the odds of recurrence depending on the number of previous small-for-gestational-age infants and if only the preceding infant was small-for-gestational-age. The study population was dichotomized into small-for-gestational-age and non-small-for-gestational-age for each consecutive pregnancy. Univariate analyses compared baseline demographic and obstetrical characteristics followed by logistic regression modeling to determine the odds of recurrence in the second, third, and fourth pregnancies. RESULTS: The final study comprised 24,819 women. The proportion of women who had a small-for-gestational-age infant in their first pregnancy was 9.4%, whereas the proportion of women who had a small-for-gestational-age infant in their second, third, and fourth pregnancies after the birth of a previous small-for-gestational-age infant were 20.5% (479 of 2338), 24.6% (63 of 256), and 30.4% (14 of 46), respectively. Regardless of parity, the odds of recurrence increased if the preceding infant was small-for-gestational-age. The odds of recurrence increased markedly if there was more than 1 previous small-for-gestational-age infant. In women with 3 previous small-for-gestational-age infants, the adjusted odds of another small-for-gestational-age infant were 66.00 (95% confidence interval, 11.35-383.76). Maternal age, body mass index, ethnicity, and smoking were significant risk factors for recurrent small-for-gestational-age. However, maternal diabetes mellitus or hypertension, either in a previous or current pregnancy, did not influence the risk of recurrence. CONCLUSION: The risk of recurrence in a subsequent pregnancy increased if there was a previous small-for-gestational-age birth. Women with consecutive small-for-gestational-age infants were at the highest risk of recurrence. Our results highlight that women with a previous small-for-gestational-age infant are at a substantial risk of another small infant and need to be counseled and monitored appropriately.

An Open-Label Pilot Study Testing the Feasibility of Assessing Total Symptom Burden in Trials of Cannabinoid Medications in Palliative Care.

Background: There is considerable interest in the use of cannabinoids for symptom control in palliative care, but there is little high-quality evidence to guide clinical practice. Objectives: Assess the feasibility of using global symptom burden measures to assess response to medicinal cannabis, to determine median tolerated doses of cannabidiol (CBD) and tetrahydrocannabinol (THC), and to document adverse events (AEs). Design: Prospective two-arm open-label pilot trial of escalating doses of CBD and THC oil. Setting/Subjects: Participants had advanced cancer and cancer-related symptoms in a palliative and supportive care service in an Australian cancer center. Measurements: The main outcome measures were the number of participants screened and randomized over the time frame, the number of participants completing days 14 and 28 and providing total symptom distress scores (TSDSs) (measured using the Edmonton Symptom Assessment Scale), and the change from baseline of the TSDS at day 14. Results: Of the 21 participants enrolled (CBD, n = 16; THC, n = 5), 18 (86%) completed the primary outcome measure at day 14 and 8 completed at day 28. The median maximum tolerated doses were CBD, 300 mg/day (range 100-600 mg); THC, 10 mg/day (range 5-30 mg). Nine of 21 patients (43%) met the definition of response (≥6 point reduction in TSDS). Drowsiness was the most common AE. Conclusions: Trials of medicinal cannabis in advanced cancer patients undergoing palliative care are feasible. The doses of THC and CBD used in this study were generally well tolerated and the outcome measure of total symptom distress is promising as a measure of overall symptom benefit. Trial registration: ACTRN12618001205224.

Screening for adverse perinatal outcomes: uterine artery Doppler, cerebroplacental ratio and estimated fetal weight in low-risk women at term.

OBJECTIVE: To stratify apparently low-risk pregnant women into those who are at risk of adverse perinatal outcomes. Appropriate stratification would allow targeted prenatal and intrapartum management. METHODS: This prospective, observational study included normotensive women with appropriately grown, non-anomalous, singleton pregnancies. Participants underwent fortnightly ultrasounds from 36 weeks' gestation and intrapartum and neonatal outcomes were recorded. The association between uterine artery pulsatility index (UtA-PI), the cerebroplacental ratio (CPR) and estimated fetal weight (EFW) were explored along with their screening performance for CS-IFC and CNM. RESULTS: The final cohort included 429 women. As continuous variables, UtA-PI and the CPR were not correlated (rho = -0.05, p = .33). UtA-PI >95th centile and the CPR <10th centile were predictive of CS-IFC and CNM, with the highest sensitivity achieved by their combination (33.3%, 95% CI 11.6-55.1) for a false positive rate (FPR) of 15.8% (12.3-19.3). For CNM, the highest sensitivity (28.4%, 95% CI 18.6-38.2) and corresponding FPR (17.0%, 95% CI 13.0-20.9) was achieved by combining UtA-PI 95th centile, the CPR 10th centile and EFW 10th centile. EFW was the weakest of the three predictors. CONCLUSION: In this population, UtA-PI 95th centile and the CPR 10th centile have modest screening performance for CS-IFC and CNM.

A Potential Link between the C5a Receptor 1 and the ß1-Adrenoreceptor in the Mouse Heart.

PURPOSE: Inflammation may contribute to the pathogenesis of specific cardiovascular diseases, but it is uncertain if mediators released during the inflammatory process will affect the continued efficacy of drugs used to treat clinical signs of the cardiac disease. We investigated the role of the complement 5a receptor 1 (C5aR1/CD88) in the cardiac response to inflammation or atenolol, and the effect of C5aR1 deletion in control of baseline heart rate in an anesthetized mouse model. METHODS: An initial study showed that PMX53, an antagonist of C5aR1 in normal C57BL6/J (wild type, WT) mice reduced heart rate (HR) and appeared to have a protective effect on the heart following induced sepsis. C5aR1 knockout (CD88-/-) mice had a lower HR than wild type mice, even during sham surgery. A model to assess heart rate variability (HRV) in anesthetized mice was developed to assess the effects of inhibiting the ß1-adrenoreceptor (ß1-AR) in a randomized crossover study design. RESULTS: HR and LF Norm were constitutively lower and SDNN and HF Norm constitutively higher in the CD88-/- compared with WT mice (P< 0.001 for all outcomes). Administration of atenolol (2.5 mg/kg) reduced the HR and increased HRV (P< 0.05, respectively) in the wild type but not in the CD88-/- mice. There was no shift of the sympathovagal balance post-atenolol in either strains of mice (P> 0.05), except for the reduced LF/HF (Lower frequency/High frequency) ratio (P< 0.05) at 60 min post-atenolol, suggesting increased parasympathetic tone of the heart due to the effect of atenolol administration. The HR of the WT mice were lower post atenolol compared to the CD88-/- mice (P = 0.001) but the HRV of CD88-/- mice were significantly increased (P< 0.05), compared with WT mice. CONCLUSION: Knockout of the C5aR1 attenuated the effect of ß1-AR in the heart, suggesting an association between the ß1-AR and C5aR1, although further investigation is required to determine if this is a direct or causal association.

Acceptability and compliance of atenolol tablet, compounded paste and compounded suspension prescribed to healthy cats*.

This study was designed to evaluate the cats' acceptance and compliance of the owners and cats towards an extemporaneously prepared palatable compounded atenolol (paste and suspension) formulation in comparison to the commercially obtained tablet, in a randomised, cross-over study design.The three formulations were prescribed twice daily for 6 days to 13 healthy privately-owned cats of 13 different owners, with varying levels of experience in medicating cats. Daily compliance was evaluated via an owner-completed diary, completed after each dose administered. Owner's experience and preference of the formulation was evaluated via questionnaires given prior to, at the end of each treatment protocol, and upon completion of the study. Although compounded suspension was association with fewest missed doses, the majority of cat owners expressed a preference for the divided tablet. Atenolol tablets, compounded paste and suspension acceptance and compliance were comparable. Further work is now required to assess the amount and stability of the active ingredient and the robustness of the paste and suspension formulations prior to any bioavailability comparisons between the formulations.

Pulmonary function and long-term follow-up of children with tracheobronchomalacia.

BACKGROUND: Primary tracheobronchomalacia (TBM) is a disease of the large airways. Long-term follow-up studies of TBM patients have not been reported. This study was undertaken to further elicit the natural history of this condition and the presence of concomitant reactive airways disease through clinical profiling and pulmonary function testing. METHODS: Twenty-one children diagnosed with TBM by bronchoscopy between 1998 and 2001 in Queensland were recruited in 2008. Parents completed a questionnaire detailing their child's respiratory symptoms over the previous 12 months. Children then undertook pulmonary function and flow-volume loop classification. Mannitol bronchial provocation testing or post-bronchodilator spirometry was performed to assess for the confounding presence of reactive airways disease. RESULTS: Data from 19 children (12 males) were able to be analyzed. The median age was 9.4 (range 7.6-14.3) years. 15 parents indicated their child's symptoms were unresolved. The mean FEV(1) was 81% predicted with 7 <80% predicted. This was significantly lower than the percent predicted population mean (P = 0.0005). Mean FEV(1) /FVC, FEF(25-75) , and PEF were also significantly reduced (P = < 0.0001). Four participants had a classical TBM flow-volume loop on analysis. One of 15 (6.7%) participants recorded a positive test for reactive airways disease. CONCLUSIONS: Clinical symptom profiles and pulmonary function indicate persistent functional mechanical abnormalities of the large and small airways in TBM patients, and the absence of reactive airways disease.

Transcriptional basis for hepatic fibrosis in cystic fibrosis-associated liver disease.

OBJECTIVES: Liver disease contributes to significant morbidity and mortality in cystic fibrosis (CF). Although all patients with CF express the defective CF transmembrane conductance regulator in cholangiocytes, many develop asymptomatic fibrosing liver disease. Only some develop cirrhosis, with pathogenesis remaining enigmatic. Available noninvasive diagnostic tools do not identify patients at risk before development of advanced fibrosis. We conducted a pilot study to identify genes associated with hepatic injury and fibrosis on liver biopsy that may help elucidate determinants of CF-associated liver disease (CFLD). METHODS: Liver tissue from children with CFLD with various stages of hepatic fibrosis was compared with pediatric controls using cDNA array analysis. Differential expression of genes of interest was then assessed relative to pediatric control liver and non-CF cholestatic disease control liver from patients with biliary atresia, using both real-time reverse transcription-polymerase chain reaction and immunohistochemistry. RESULTS: cDNA array demonstrated differential expression of numerous genes associated with hepatic fibrogenesis including collagens, matrix metalloproteinases, and chemokines in CFLD versus normal controls, particularly decreased expression in tissue remodeling genes including plasminogen activator inhibitor-1 (PAI-1, up to 25-fold) and tissue inhibitor of metalloproteinase-1 (TIMP-1); this was validated by real-time reverse transcription-polymerase chain reaction (PAI-1, P = 0.004; TIMP-1, P = 0.019). No significant decrease in PAI-1 or TIMP-1 mRNA was observed in biliary atresia versus normal control. Immunohistochemistry confirmed the decreased expression of hepatic PAI-1 and TIMP-1 protein in CFLD versus both normal and biliary atresia disease controls. CONCLUSIONS: The coordinated differential expression of these genes associated with liver fibrosis provides evidence for a transcriptional basis for the pathogenesis of CFLD and provides avenues for further study. Clarifying the pathogenesis of CFLD will facilitate techniques for early, precirrhotic detection and targeted interventions.

Importance of hepatic fibrosis in cystic fibrosis and the predictive value of liver biopsy.

UNLABELLED: Cystic fibrosis liver disease (CFLD), which results from progressive hepatobiliary fibrosis, is an important cause of morbidity and mortality, but it is difficult to identify before portal hypertension (PHT) ensues. Clinical signs, serum alanine aminotransferase (ALT) levels, and ultrasound (US) are widely applied, but their value in predicting the presence of cirrhosis, the development of PHT, or adverse outcomes is undetermined. The potential gold standard, liver biopsy, is not standard practice and, notwithstanding sampling error considerations, has not been systematically evaluated. Forty patients with cystic fibrosis (median age = 10.6 years) with abnormal clinical, biochemical, and US findings were subjected to dual-pass percutaneous liver biopsy. Clinical outcomes were recorded over 12 years of follow-up (median = 9.5 years for survivors). Logistic regression and receiver operating characteristic analyses were applied to predict hepatic fibrosis (which was assessed by fibrosis staging and quantitative immunohistochemistry) and the occurrence of PHT. PHT occurred in 17 of 40 patients (42%), including 6 of 7 (17%) who died during follow-up. Clinical examination, serum ALT levels, and US findings failed to predict either the presence of liver fibrosis or the development of PHT. Fibrosis staging on liver biopsy, where the accuracy was improved by dual passes (P = 0.002, nonconcordance = 38%), predicted the development of PHT (P < 0.001), which occurred more frequently and at a younger age in those with severe fibrosis. CONCLUSION: Clinical modalities currently employed to evaluate suspected CFLD help to identify a cohort of children at risk for liver disease and adverse outcomes but do not predict an individual's risk of liver fibrosis or PHT development. Liver fibrosis on biopsy predicts the development of clinically significant liver disease. Dual passes help to address sampling concerns. Liver biopsy has a relevant role in the management of patients with suspected CFLD and deserves more widespread application.

Comparison of ultrasound and biopsy findings in children with cystic fibrosis related liver disease.

BACKGROUND: The objective of our study was to determine if hepatic ultrasound findings in paediatric patients with cystic fibrosis and suspected liver disease are related to histopathological results derived from liver biopsies. METHODS: A retrospective analysis of ultrasound and liver biopsy findings using published criteria was performed in 30 children with cystic fibrosis suspected as having liver disease on clinical, biochemical and ultrasonographic criteria. The results were correlated and assessed for intra- and interobserver agreement. RESULTS: A significant association was found for the prediction of fibrosis or cirrhosis on the basis of ultrasound (p=0.03). There was no significant association between normal or indeterminate ultrasound and histology results. A high intra- and interobserver variability was found in sonographic assessment of the hepatic echostructure. CONCLUSIONS: The diagnosis of early liver disease in cystic fibrosis cannot reliably be made on the basis of ultrasound alone. A normal ultrasound does not preclude significant liver fibrosis in cystic fibrosis. An abnormal US that suggests cirrhosis predicts the presence of moderate to severe liver disease.

Genotype-phenotype associations in patients with severe hyperinsulinism of infancy.

In hyperinsulinism of infancy (HI), unregulated insulin secretion causes hypoglycemia. Pancreatectomy may be required in severe cases, most of which result from a defect in the beta-cell KATP channel, encoded by ABCC8 and KCNJ11. Pancreatic histology may be classified as diffuse or focal disease (the latter associated with single paternal ABCC8 mutations), indicated by the presence of islet cell nuclear enlargement in areas of diffuse abnormality. We investigated genotype-phenotype associations in a heterogeneous Australian cohort. ABCC8 and KCNJ11 genes were sequenced and case histology was reviewed in 21 infants who had pancreatectomy. Ninety-eight control DNA samples were tested by single nucleotide polymorphism analysis. Eighteen ABCC8 mutations were identified, 10 novel. Eleven patients (4 compound heterozygote, 4 single mutation, 3 no mutation detected) had diffuse hyperinsulinism. Nine patients had focal hyperinsulinism (6 single paternal mutation, 2 single mutation of undetermined parental origin, 1 none found) with absence of islet cell nuclear enlargement outside the focal area, although centroacinar cell proliferation and/or nesidiodysplasia was present in 7 cases. Regeneration after near-total pancreatectomy was documented in 4 patients, with aggregates of endocrine tissue observed at subsequent operations in 3. Although the absence of enlarged islet cell nuclei is a useful discriminant of focal hyperinsulinism associated with a paternal ABCC8 mutation, further research is needed to understand the pathophysiology of other histological abnormalities in patients with HI, which may have implications for mechanisms of ductal and islet cell proliferation. Previous surgery should be taken into account when interpreting pancreatic histology.

Pubertal development and its influences on bone mineral density in Australian children and adolescents with cystic fibrosis.

BACKGROUND: Pubertal delay is thought to contribute to suboptimal peak bone mass acquisition in young people with cystic fibrosis (CF), leading to an increased fracture incidence. This study aims to compare pubertal development in young people with CF with that of a local healthy population and assess the influence it has on areal bone mineral density (aBMD). METHODS: Tanner stage, age of menarche, bone age (BA), sex hormone levels and aBMD were examined in 85 individuals with CF (aged 5.3-18.1 years, 39 females) and 100 local controls (5.6-17.9 years, 54 females). RESULTS: Tanner stage and age of menarche were not significantly different between controls and CF. Tanner stage-adjusted mean values for follicle stimulating hormone (FSH), luteinizing hormone (LH) and testosterone (T) were lower in males with CF (FSH: P = 0.004, LH: P = 0.01 and T: P = 0.002). Bone age was delayed in adolescents with CF compared to controls (chronological age-BA: controls = 0.13 years (SE = 0.16), CF = 0.95 years (SE = 0.22), P = 0.003). Areal bone mineral density (adjusted for age, sex, height and lean tissue mass) was not significantly different between CF and controls. Moderate negative correlations were found between delayed BA and weight (r = -0.41, P < 0.001) and height (r = -0.41, P < 0.001). CONCLUSIONS: There was no evidence of clinical pubertal delay or low aBMD (adjusted for short stature and lean tissue mass) in young people with CF when compared with a local population, despite lower nutritional markers, height and weight and delayed skeletal maturation.

Vitamin A levels in patients with CF are influenced by the inflammatory response.

BACKGROUND: Serum vitamin A, normally depressed in inflammatory conditions, is frequently low in people with CF. Vitamin A is important in respiratory epithelial regeneration and repair. We hypothesised that serum vitamin A would be associated with inflammation and disease severity. METHODS: Serum vitamin A (as retinol), C-reactive protein (CRP), vitamin E, 25-hydroxy vitamin D (25OHD), 1,25-dihydroxy vitamin D (1,25(OH)(2)D), weight, and lumbar spine bone mineral density (LSBMD) were measured in 138 subjects with CF (5-56 years) and 138 control subjects (5-48 years). FEV(1), presence of CF liver disease (CFLD) and hospital admissions were recorded in those with CF. RESULTS: Serum vitamin A level was lower in CF subjects than in controls (mean, 95% CI: 1.29, 1.0-1.37 vs. 1.80, 1.7-1.87 micromol/l, p < 0.0001), and inversely correlated with CRP (r(s) = -0.37, p < 0.0001). CF subjects with low vitamin A (45%) level had poorer FEV(1), weight z-score, LSBMD z-score, and higher CRP compared with those with normal levels. In the CF group CRP, vitamin E, 1,25(OH)(2)D, presence of CFLD, admissions, and age were associated with vitamin A level. CONCLUSIONS: Serum vitamin A is negatively associated with CRP in subjects with CF, consistent with normal population studies. It is important to distinguish between low serum vitamin A associated with the inflammatory response and that due to poor nutritional stores. The role of vitamin A in CF warrants further study, in the contexts both of chronic recurrent inflammatory disease and acute pulmonary exacerbation.

Abnormalities of the PTH-vitamin D axis and bone turnover markers in children, adolescents and adults with cystic fibrosis: comparison with healthy controls.

Abnormalities of calcium and vitamin D metabolism in cystic fibrosis (CF) are well documented. We tested the hypothesis that alterations in calcium metabolism are related to vitamin D deficiency, and that bone resorption is increased relative to accretion in patients with CF. Calcitropic hormones, electrolytes, osteocalcin (OC) and bone alkaline phosphatase (BAP), (markers of bone mineralisation), urinary deoxypyridinoline [total (t) Dpd, a marker of bone resorption] and lumbar spine bone mineral density (LS BMD), expressed as a z-score, were measured in 149 (81 M) CF and 141 (61 M) control children aged 5.3-10.99 years, adolescents aged 11-17.99 years and adults aged 18-55.9 years. Data were analysed by multiple regression to adjust for age. In patients, FEV(1)% predicted and CRP (as disease severity markers), genotype and pancreatic status (PS) were recorded. The distribution of PTH differed between groups ( P<0.0001), with CF levels both below and above the control range. 25OH vitamin D (25OHD) was not different in control and CF subjects ( P=0.06). Active hormonal vitamin D (1,25(OH)(2)D) was lower in the CF group ( P<0.0001), not explained by 25OHD or disease severity, as was serum magnesium ( P<0.0001). OC was decreased in CF adults ( P=0.004), and tDpd increased in CF adolescents ( P=0.003) and adults ( P=0.03). The ratio of OC to tDpd (a measure of bone coupling) was similar in CF and control children, but decreased in CF adolescents ( P=0.04) and adults ( P=0.02), suggesting decreased overall bone accrual in CF adolescents and uncoupling of bone balance in adults. 1,25(OH)2D was weakly correlated with OC in CF children ( r=0.43, P=0.01), and with tDpd in CF and control adolescents ( r=0.33, P=0.05 and r=0.36, P=0.02, respectively); thus there was limited evidence of association of calcitropic hormones, which had an abnormal pattern in all age groups, with bone turnover. There was no association between calcitropic hormones or bone turnover markers and LS BMD z-score. Despite vitamin D sufficiency, abnormalities of calcium metabolism and bone turnover markers were still apparent and bone accretion was decreased relative to resorption in the CF adolescent and adult groups. These changes were not fully explained by disease severity or genotype, but are consistent with reports of decreased BMD and unique bone histomorphometry in older subjects with CF.

The outcome in Australian children with hyperinsulinism of infancy: early extensive surgery in severe cases lowers risk of diabetes.

AIMS: Hyperinsulinism of infancy (HI) is characterized by unregulated insulin secretion in the presence of hypoglycaemia, often resulting in brain damage. Pancreatic resection for control of hypoglycaemia is frequently resisted because of the risk of diabetes mellitus (DM). We investigated retrospectively 62 children with HI from nine Australian treatment centres born between 1972 and 1998, comparing endocrine and neurological outcome in 28 patients receiving medical therapy alone with 34 who required pancreatic resection to control their hypoglycaemia. METHODS: History, treatment and clinical course were ascertained from file audit and interview. Risk of DM (hazard ratio) attributable to age at surgery (< vs. > or = 100 days at last pancreatectomy) and extent of resection (< vs. > or = 95%) were calculated using Cox proportional hazards regression and categorical variables compared by the chi2-test. Neurological outcome (normal, mild deficit or severe deficit) was derived from the most authoritative source. RESULTS: Surgically treated patients had a greater birthweight, earlier presentation and higher plasma insulin levels. Of 18 infants < 100 days and 16 > or = 100 days of age at surgery, four (all > or = 100 days) became diabetic as an immediate consequence of surgery and five (two < 100 days and three > or = 100 days) became diabetic 7-18 years later. Surgery > or = 100 days and pancreatectomy > or = 95% were associated with development of diabetes (HR = 12.61, CI 1.53-104.07 and HR = 7.03, CI 1.43-34.58, respectively). Neurodevelopmental outcome was no different between the surgical and medical groups with 44% overall with neurological deficits. Patients euglycaemic within 35 days of the first symptom of hypoglycaemia (Group A) had a better neurodevelopmental outcome than those still hypoglycaemic > 35 days from first presentation (Group B) (P = 0.007). Prolonged hypoglycaemia in Group B was due either to delayed diagnosis or to need for repeat surgery because of continued hypoglycaemia. Within Group A, medically treated patients (who presented later with apparently milder disease) had a higher incidence of neurodevelopmental deficit (n = 15, four mild, three severe deficit) compared with surgically treated patients (n = 18, two mild, none severe deficit) (P < 0.025). CONCLUSIONS: Poor neurodevelopmental outcome remains a major problem in hyperinsulinism of infancy. Risk of diabetes mellitus with pancreatectomy varies according to age at surgery and extent of resection. Patients presenting early with severe disease have a better neurodevelopmental outcome and lower risk of diabetes if they are treated with early extensive surgery.