Yield of clinically reportable genetic variants in unselected cerebral palsy by whole genome sequencing.

Cerebral palsy (CP) is the most common cause of childhood physical disability, with incidence between 1/500 and 1/700 births in the developed world. Despite increasing evidence for a major contribution of genetics to CP aetiology, genetic testing is currently not performed systematically. We assessed the diagnostic rate of genome sequencing (GS) in a clinically unselected cohort of 150 singleton CP patients, with CP confirmed at >4 years of age. Clinical grade GS was performed on the proband and variants were filtered, and classified according to American College of Medical Genetics and Genomics-Association for Molecular Pathology (ACMG-AMP) guidelines. Variants classified as pathogenic or likely pathogenic (P/LP) were further assessed for their contribution to CP. In total, 24.7% of individuals carried a P/LP variant(s) causing or increasing risk of CP, with 4.7% resolved by copy number variant analysis and 20% carrying single nucleotide or indel variants. A further 34.7% carried one or more rare, high impact variants of uncertain significance (VUS) in variation intolerant genes. Variants were identified in a heterogeneous group of genes, including genes associated with hereditary spastic paraplegia, clotting and thrombophilic disorders, small vessel disease, and other neurodevelopmental disorders. Approximately 1/2 of individuals were classified as likely to benefit from changed clinical management as a result of genetic findings. In addition, no significant association between genetic findings and clinical factors was detectable in this cohort, suggesting that systematic sequencing of CP will be required to avoid missed diagnoses.

Targeted resequencing identifies genes with recurrent variation in cerebral palsy.

A growing body of evidence points to a considerable and heterogeneous genetic aetiology of cerebral palsy (CP). To identify recurrently variant CP genes, we designed a custom gene panel of 112 candidate genes. We tested 366 clinically unselected singleton cases with CP, including 271 cases not previously examined using next-generation sequencing technologies. Overall, 5.2% of the naïve cases (14/271) harboured a genetic variant of clinical significance in a known disease gene, with a further 4.8% of individuals (13/271) having a variant in a candidate gene classified as intolerant to variation. In the aggregate cohort of individuals from this study and our previous genomic investigations, six recurrently hit genes contributed at least 4% of disease burden to CP: COL4A1, TUBA1A, AGAP1, L1CAM, MAOB and KIF1A. Significance of Rare VAriants (SORVA) burden analysis identified four genes with a genome-wide significant burden of variants, AGAP1, ERLIN1, ZDHHC9 and PROC, of which we functionally assessed AGAP1 using a zebrafish model. Our investigations reinforce that CP is a heterogeneous neurodevelopmental disorder with known as well as novel genetic determinants.

Prognostic value of B-type natriuretic peptide in surgical palliation of children with single-ventricle congenital heart disease.

The objective of this prospective study was to assess the prognostic role of perioperative B-type natriuretic peptide (BNP) levels in infants and children with single-ventricle congenital heart disease undergoing Norwood, bidirectional cavopulmonary anastomosis (BCPA), or Fontan operation. BNP levels were measured at baseline, after cardiopulmonary bypass, 6 to 12 hours after surgery, and then daily until indwelling vascular catheters were removed. Outcome measures included length of mechanical ventilation, inotropic support, and hospital stay. Twenty subjects underwent 23 surgical procedures (13 Norwood, 5 BCPA, and 5 Fontan). BNP levels were significantly higher in patients undergoing a Norwood procedure compared with a BCPA or Fontan procedure (p < 0.01). BNP levels measured 6 to 12 hours after surgery were predictive of duration of hospitalization (p = 0.005) and inotropic support (p = 0.01). An increase in BNP level within 48 hours of extubation was observed in 92% of patients undergoing a Norwood procedure. Early postoperative BNP levels correlate significantly with the ensuing duration of inotropic support and length of hospitalization. An increase in BNP after extubation may be reflective of the degree of underlying cardiopulmonary instability. Further investigation is necessary to define this important relation.

Attitudes and barriers to incident reporting: a collaborative hospital study.

OBJECTIVES: To assess awareness and use of the current incident reporting system and to identify factors inhibiting reporting of incidents in hospitals. DESIGN, SETTING AND PARTICIPANTS: Anonymous survey of 186 doctors and 587 nurses from diverse clinical settings in six South Australian hospitals (response rate = 70.7% and 73.6%, respectively). MAIN OUTCOME MEASURES: Knowledge and use of the current reporting system; barriers to incident reporting. RESULTS: Most doctors and nurses (98.3%) were aware that their hospital had an incident reporting system. Nurses were more likely than doctors to know how to access a report (88.3% v 43.0%; relative risk (RR) 2.05, 95% CI 1.61 to 2.63), to have ever completed a report (89.2% v 64.4%; RR 1.38, 95% CI 1.19 to 1.61), and to know what to do with the completed report (81.9% v 49.7%; RR 1.65, 95% CI 1.27 to 2.13). Staff were more likely to report incidents which are habitually reported, often witnessed, and usually associated with immediate outcomes such as patient falls and medication errors requiring corrective treatment. Near misses and incidents which occur over time such as pressure ulcers and DVT due to inadequate prophylaxis were least likely to be reported. The most frequently stated barrier to reporting for doctors and nurses was lack of feedback (57.7% and 61.8% agreeing, respectively). CONCLUSIONS: Both doctors and nurses believe they should report most incidents, but nurses do so more frequently than doctors. To improve incident reporting, especially among doctors, clarification is needed of which incidents should be reported, the process needs to be simplified, and feedback given to reporters.

Randomized controlled trial of alendronate in airways disease and low bone mineral density.

BACKGROUND: Patients with airways disease have been demonstrated to be at risk of osteoporosis, and this is likely to be multifactorial. Our aim was to identify patients with low bone mineral density (BMD) using a screening program, and then evaluate the benefit of daily alendronate. METHOD: Subjects with hip or lumbar spine baseline T-scores < - 2.5, or Z-score < - 1.0 commenced on alendronate/calcium (10 mg/600 mg day) or placebo/calcium, in a double blind randomized controlled trial. BMD by dual emission X-ray absorptiometry (lumbar vertebrae 2-4, neck of femur, total femur) was repeated after 12 months, with adverse events recorded. RESULTS: 145 subjects (74 male, 71 female, mean age 67, median FEV1 1.0 litres = 43% of predicted) were enrolled; 66 alendronate/calcium, 79 placebo/calcium with 24 and 26 withdrawals, respectively. Per protocol but not intention to treat analysis of covariance demonstrated statistically significant improvements in T and Z scores for lumbar spine bone mineral density (P = 0.035, P = 0.040), with no improvement demonstrated at the hip. CONCLUSIONS: Improvement in bone mineral density has been demonstrated at the lumbar spine, but not hip, by per protocol analysis, with daily alendronate, at 12 months.

Relationship of seminal vesicle size and measures of libido in yearling beef bulls.

Ninety-five yearling beef bulls were given routine Breeding Soundness Examinations, two libido tests and palpated rectally for internal genital disease and measurement of seminal vesicle size. Finger tips were premeasured, and then used as "glandometers". The bulls were examined at the end of a 140-day performance test. Sixteen lines of breeding were examined including 13 Hereford, 2 Angus and 1 Red Angus. Average age was 384 days and average weight was 961 lbs. Line and breed differences (P<.05) were observed for scrotal circumference, scrotal circumference score and second libido test. Similar differences were observed for SV length (P<.01), depth and volume both (P<.05). There were no significant correlations between seminal vesicle (SV) size and libido scores. There were, however, significant correlations between SV size and scrotal circumference (P<.05), BSE score (P<.01), body weight (P<.01), and semen morphology score (P<.05). Proximal droplets and midpiece abnormalities, respectively, were the most common spermatozoal abnormalities observed in semen from this group of bulls.

Evaluation of CGA 72662 as a topical spray and feed additive for controlling house flies breeding in chicken manure.

The insect growth regulator, CGA 72662 (N-cyclopropyl-1,3,5-triazine-2,4,6-triamine), was tested both as a topical spray and feed additive for controlling the house fly (Musca domestica L.) breeding in chicken manure. Dosage concentrations of .025%, .05%, and .1% were sprayed on sections of manure surface in a shallow pit egg layer operation at rates of 1.9 and 3.8 liters/10.2m2. AT 17 days posttreatment each concentration at both rats, except .025% at 1.9 liters/10.2m2, provided at least a 70% reduction of native house flies and 100% inhibition of laboratory reared house flies. CGA 72662 fed to both hens and broilers at rates of 1.5 ppm and 5 ppm provided up to 100% mortality of house flies 1 day after birds were started on treated feed to 1 day after treated feed was removed.

Control of northern fowl mite with permethrin and fenvalerate, two synthetic pyrethroid compounds.

Trials were conducted to evaluate the efficacy of permethrin and fenvalerate, two synthetic pyrethroid compounds, for the control of the northern fowl mite, Ornithonyssus sylviarum (Canestrini and Fanzago), on White Leghorn hens. Fenvalerate at .0125%, .025%, and .05% active ingredient (ai) were as effective as carbaryl at .5% ai for 56 days posttreatment. Permethrin at .01%, .025%, and .05% ai were as effective, or better than, malathion at .27% ai for 56 days posttreatment. All treatments were applied to the birds as high pressure sprays.