Variation in hospital caesarean rates among nulliparae at term is unexplained and unrelated to maternal or neonatal outcome: a population based cohort study

OBJECTIVE To explore variation in hospital caesarean rates for nulliparous women; determine whether casemix, labour and delivery, and hospital factors explain the variation and examine the association between hospital caesarean rates and outcomes. DESIGN Population-based cohort study. SETTING New South Wales, 2009-2010. POPULATION Nulliparous women with singleton cephalic live births at term. METHODS Random effects multilevel logistic regression models using linked hospital discharge and birth data. MAIN OUTCOME MEASURES Prelabour, and intrapartum caesarean rates following spontaneous labour or labour induction; maternal and neonatal severe morbidity rates. RESULTS Of 67,239 nulliparous women, 4,902 (7.3%) had prelabour caesareans, 39,049 (58.1%) had spontaneous labour and 23,288 (34.6%) had induction of labour. Overall, there were 18,875 (28.1%) caesareans, with labour inductions twice as likely to end in an intrapartum caesarean than spontaneous labour (34.0% versus 15.5%). Variation in caesarean rates for term nulliparae 3 After adjusting for casemix, labour and delivery, and hospital factors, the overall variation in caesarean rates decreased by 78% for prelabour caesareans; for intrapartum caesarean by 52% following spontaneous labour and by 9% following labour induction. However, adjusting for labour and delivery practices increased the unexplained variation in intrapartum caesareans. The rates of severe maternal and neonatal morbidity were not significantly different across caesarean rate quintile groups, except for women in spontaneous labour, where the hospitals in the lowest caesarean quintile had the lowest neonatal morbidity rate. CONCLUSIONS Differences in clinical practice were substantial contributors to variations in intrapartum caesarean rates. Strategies aiming at lowering the caesarean rate should not adversely affect maternal or neonatal outcome.National Health and Medical Research Council Centre for Research Excellence Grant (1001066) and the New South Wales Population Health and Health Services Research Support Program. NHMRC Senior Research Fellowship (APP1021025)

WHAT FACTORS CONTRIBUTE TO HOSPITAL VARIATION IN OBSTETRIC TRANSFUSION RATES?

Background & Objectives: To explore variation in red blood cell transfusion rates between hospitals, and the extent to which this can be explained. A secondary objective was to assess whether hospital transfusion rates are associated with maternal morbidity. Materials & Methods: Linked hospital discharge and birth data were used to identify births (N=279,145) in hospitals with at least 10 deliveries per annum between 2008-2010 in New South Wales, Australia. To investigate transfusion rates, a series of random effects multilevel logistic regression models were fitted, progressively adjusting for maternal, obstetric and hospital factors. Correlations between hospital transfusion and maternal, neonatal morbidity and readmission rates were assessed. Results: Overall, the transfusion rate was 1.4% (hospital range 0.6 to 2.9) across 89 hospitals. Adjusting for maternal casemix, reduced the variation between hospitals by 26%. Adjustment for obstetric interventions further reduced variation by 8% and a further 39% after adjustment for hospital type. At a hospital level, high transfusion rates were moderately correlated with maternal morbidity (0.56, p=0.01) and low Apgar scores (0.54, p=0.002), but not with readmission rates (0.18, p=0.28). Conclusion: Both casemix and practice differences contributed to the variation in transfusion rates between hospitals. The relationship between outcomes and transfusion rates was variable, however low transfusion rates were not associated with worse outcomes.Partnership Grant from the Australian National Health and Medical Research Council NHMRC (#1027262), the Australian Red Cross and the NSW Clinical Excellence Commission, NHMRC Senior Research Fellowship (#1021025). ARC Future Fellowship (#120100069)

WHAT FACTORS CONTRIBUTE TO HOSPITAL VARIATION IN OBSTETRIC TRANSFUSION RATES?

Background & Objectives: To explore variation in red blood cell transfusion rates between hospitals, and the extent to which this can be explained. A secondary objective was to assess whether hospital transfusion rates are associated with maternal morbidity. Materials & Methods: Linked hospital discharge and birth data were used to identify births (N=279,145) in hospitals with at least 10 deliveries per annum between 2008-2010 in New South Wales, Australia. To investigate transfusion rates, a series of random effects multilevel logistic regression models were fitted, progressively adjusting for maternal, obstetric and hospital factors. Correlations between hospital transfusion and maternal, neonatal morbidity and readmission rates were assessed. Results: Overall, the transfusion rate was 1.4% (hospital range 0.6 to 2.9) across 89 hospitals. Adjusting for maternal casemix, reduced the variation between hospitals by 26%. Adjustment for obstetric interventions further reduced variation by 8% and a further 39% after adjustment for hospital type. At a hospital level, high transfusion rates were moderately correlated with maternal morbidity (0.56, p=0.01) and low Apgar scores (0.54, p=0.002), but not with readmission rates (0.18, p=0.28). Conclusion: Both casemix and practice differences contributed to the variation in transfusion rates between hospitals. The relationship between outcomes and transfusion rates was variable, however low transfusion rates were not associated with worse outcomes.Partnership Grant from the Australian National Health and Medical Research Council NHMRC (#1027262), the Australian Red Cross and the NSW Clinical Excellence Commission, NHMRC Senior Research Fellowship (#1021025). ARC Future Fellowship (#120100069)

Biallelic CPAMD8 Variants Are a Frequent Cause of Childhood and Juvenile Open-Angle Glaucoma

© 2020 by the American Academy of Ophthalmology. This is an open access article under the CC BY-NC-ND licensePurpose Developmental abnormalities of the ocular anterior segment in some cases can lead to ocular hypertension and glaucoma. CPAMD8 is a gene of unknown function recently associated with ocular anterior segment dysgenesis, myopia, and ectopia lentis. We sought to assess the contribution of biallelic CPAMD8 variants to childhood and juvenile open-angle glaucoma. Design Retrospective, multicenter case series. Participants A total of 268 probands and their relatives with a diagnosis of childhood or juvenile open-angle glaucoma. Purpose Developmental abnormalities of the ocular anterior segment in some cases can lead to ocular hypertension and glaucoma. CPAMD8 is a gene of unknown function recently associated with ocular anterior segment dysgenesis, myopia, and ectopia lentis. We sought to assess the contribution of biallelic CPAMD8 variants to childhood and juvenile open-angle glaucoma. Methods Patients underwent a comprehensive ophthalmic assessment, with DNA from patients and their relatives subjected to genome, exome, or capillary sequencing. CPAMD8 RNA expression analysis was performed on tissues dissected from cadaveric human eyes. Main Outcome Measures Diagnostic yield within a cohort of childhood and juvenile open-angle glaucoma, prevalence and risk of ophthalmic phenotypes, and relative expression of CPAMD8 in the human eye. Results We identified rare (allele frequency < 4×10−5) biallelic CPAMD8 variants in 5.7% (5/88) of probands with childhood glaucoma and 2.1% (2/96) of probands with juvenile open-angle glaucoma. When including family members, we identified 11 individuals with biallelic variants in CPAMD8 from 7 unrelated families. Nine of these individuals were diagnosed with glaucoma (9/11, 81.8%), with a mean age at diagnosis of 9.22±14.89 years, and all individuals with glaucoma required 1 or more incisional procedures to control high intraocular pressure. Iris abnormalities were observed in 9 of 11 individuals, cataract was observed in 8 of 11 individuals (72.7%), and retinal detachment was observed in 3 of 11 individuals (27.3%). CPAMD8 expression was highest in neural crest–derived tissues of the adult anterior segment, suggesting that CPAMD8 variation may cause malformation or obstruction of key drainage structures. Conclusions Biallelic CPAMD8 variation was associated with a highly heterogeneous phenotype and in our cohorts was the second most common inherited cause of childhood glaucoma after CYP1B1 and juvenile open-angle glaucoma after MYOC. CPAMD8 sequencing should be considered in the investigation of both childhood and juvenile open-angle glaucoma, particularly when associated with iris abnormalities, cataract, or retinal detachment

Detection of microchromosomal aberrations in refractory epilepsy: a pilot study

ABSTRACT -Seizures often occur in patients with microchromosomal aberrations responsible for moderate to severe intellectual disability. We hypothesised that epilepsy alone could be caused by microdeletions or microduplications, which might also relate to epilepsy refractory to medication. Chromosomes from 20 subjects with epilepsy and repeated failure of antiepileptic medication were examined using molecular methods. Firstly, the 41 subtelomeric regions were scanned using fluorescence in situ hybridization and multiplex ligationdependent probe amplification. Secondly, a genome-wide scan was carried out using oligonucleotide-array comparative genome hybridisation on two platforms: Nimblegen and Agilent. Two aberrations (2/20) were identified: a recurrent microdeletion at 15q13.3 previously characterised in patients with seizures that generally respond to medication, and a novel 1.15 Mb microchromosomal duplication at 10q21.2 also present in the unaffected mother. We conclude that gene content of microchromosomal aberrations is not a major cause of refractory seizures, but that microchromosomal anomalies are found in an appreciable fraction of such cases

Short GRB Host Galaxies I: Photometric and Spectroscopic Catalogs, Host Associations, and Galactocentric Offsets

We present a comprehensive optical and near-infrared census of the fields of 90 short gamma-ray bursts (GRBs) discovered in 2005-2021, constituting all short GRBs for which host galaxy associations are feasible ($\approx$ 60% of the total Swift short GRB population). We contribute 245 new multi-band imaging observations across 49 distinct GRBs and 25 spectra of their host galaxies. Supplemented by literature and archival survey data, the catalog contains 335 photometric and 40 spectroscopic data sets. The photometric catalog reaches $3\sigma$ depths of $\gtrsim 24-27$ mag and $\gtrsim 23-26$ mag for the optical and near-infrared bands, respectively. We identify host galaxies for 84 bursts, in which the most robust associations make up 54% (49/90) of events, while only a small fraction, 6.7%, have inconclusive host associations. Based on new spectroscopy, we determine 17 host spectroscopic redshifts with a range of $z\approx 0.15-1.6$ and find that $\approx$ 25-44% of Swift short GRBs originate from $z>1$. We also present the galactocentric offset catalog for 83 short GRBs. Taking into account the large range of individual measurement uncertainties, we find a median of projected offset of $\approx 7.9$ kpc, for which the bursts with the most robust associations have a smaller median of $\approx 4.9$ kpc. Our catalog captures more high-redshift and low-luminosity hosts, and more highly-offset bursts than previously found, thereby diversifying the population of known short GRB hosts and properties. In terms of locations and host luminosities, the populations of short GRBs with and without detectable extended emission are statistically indistinguishable. This suggests that they arise from the same progenitors, or from multiple progenitors which form and evolve in similar environments. All of the data products are available on the BRIGHT website.Comment: 53 pages, 9 figures, 6 tables, submitte

Rare copy number variation in cerebral palsy

As per publisher: published online 22 May 2013Recent studies have established the role of rare copy number variants (CNVs) in several neurological disorders but the contribution of rare CNVs to cerebral palsy (CP) is not known. Fifty Caucasian families having children with CP were studied using two microarray designs. Potentially pathogenic, rare (<1% population frequency) CNVs were identified, and their frequency determined, by comparing the CNVs found in cases with 8329 adult controls with no known neurological disorders. Ten of the 50 cases (20%) had rare CNVs of potential relevance to CP; there were a total of 14 CNVs, which were observed in <0.1% (<8/8329) of the control population. Eight inherited from an unaffected mother: a 751-kb deletion including FSCB, a 1.5-Mb duplication of 7q21.13, a 534-kb duplication of 15q11.2, a 446-kb duplication including CTNND2, a 219-kb duplication including MCPH1, a 169-kb duplication of 22q13.33, a 64-kb duplication of MC2R, and a 135-bp exonic deletion of SLC06A1. Three inherited from an unaffected father: a 386-kb deletion of 12p12.2-p12.1, a 234-kb duplication of 10q26.13, and a 4-kb exonic deletion of COPS3. The inheritance was unknown for three CNVs: a 157-bp exonic deletion of ACOX1, a 693-kb duplication of 17q25.3, and a 265-kb duplication of DAAM1. This is the first systematic study of CNVs in CP, and although it did not identify de novo mutations, has shown inherited, rare CNVs involving potentially pathogenic genes and pathways requiring further investigation.Gai McMichael, Santhosh Girirajan, Andres Moreno-De-Luca, Jozef Gecz, Chloe Shard, Lam Son Nguyen, Jillian Nicholl, Catherine Gibson, Eric Haan, Evan Eichler, Christa Lese Martin and Alastair MacLenna

Heavy element production in a compact object merger observed by JWST

The mergers of binary compact objects such as neutron stars and black holes are of central interest to several areas of astrophysics, including as the progenitors of gamma-ray bursts (GRBs) 1, sources of high-frequency gravitational waves (GWs) 2 and likely production sites for heavy-element nucleosynthesis by means of rapid neutron capture (the r-process) 3. Here we present observations of the exceptionally bright GRB 230307A. We show that GRB 230307A belongs to the class of long-duration GRBs associated with compact object mergers 4–6 and contains a kilonova similar to AT2017gfo, associated with the GW merger GW170817 (refs. 7–12). We obtained James Webb Space Telescope (JWST) mid-infrared imaging and spectroscopy 29 and 61 days after the burst. The spectroscopy shows an emission line at 2.15 microns, which we interpret as tellurium (atomic mass A = 130) and a very red source, emitting most of its light in the mid-infrared owing to the production of lanthanides. These observations demonstrate that nucleosynthesis in GRBs can create r-process elements across a broad atomic mass range and play a central role in heavy-element nucleosynthesis across the Universe

Detection of DNA copy number imbalance using array CGH.

The association of constitutional chromosome imbalance in patients with intellectual disability with or without related dysmorphism and malformations is well established. The resolution of conventional cytogenetic examination is limited to imbalances of 5-10Mb. Patients with characteristic phenotypes which allude to a specific microdeletion or duplication syndrome may be investigated using locus specific fluorescent in situ hybridisation (FISH). Subtelomere FISH, a recently new improvement for cytogenetics screening, detects subtelomeric rearrangements in around 6% of patients with idiopathic disability. However it is evident that for these patients, most do not have a recurrent pattern of dysmorphism or malformations suggesting imbalance in a particular chromosome region. Array CGH has the potential to detect chromosome imbalances beyond that of current technology allowing the whole genome can be screened in a single hybridisation at a resolution limited only by the genomic distance between the arrayed target clones. The aim of this study was to develop a custom whole genome array and utilize this array to screen a number of diverse patient groups. Rather than immediately begin with the development of a whole genome array a smaller pilot study was initiated, in so enabling the efficacy of the methodology to be tested. A small clinical/ subtelomere array was designed and constructed to screen for cytogenetic imbalances within the first 5Mb of each chromosome end (excluding acrocentric chromosomes) together with the number of known clinically significant regions. This clinical/subtelomere array (chapter 3), was ulilised to map the extent of deletion and/or duplication in patients with previously determined subtelomere abnormalities. This was followed with the screening of a small group of patients with idiopathic intellectual disability (chapter 4). Novel Copy number changes were identified together with a number of changes determined to be non-pathogenic variants. The methodology used in the utilization of this array could determine copy changes in patients, however it became clearly evident that the effective resolution was compromised when a number of clones were shown to map to other sites of the genome or cross hybridise to multiple sites. With this knowledge the next stage of the project, a whole genome array, primarily constructed from a FISH validated clone set, reduced the possibility of mapping discrepancies. These FISH mapped clones did not give a even genomic coverage. All clones from this set were mapped using Ensembl resources. Any identified gaps (greater than 1Mb) were covered using clones from a second clone set (32K), giving a resolution of ~0.2-1Mb. Three diverse groups of patients were screened using the whole genome array. Using a novel scoring system which evaluated degree of intellectual disability/developmental delay, dysmorphism, presence of malformations and the presence of an apparently balanced cytogenetic rearrangement, twenty five patients with idiopathic disability were assessed. Four novel copy number changes were determined of which three were determined likely to contribute to the phenotype of the patient. The fourth patient is under investigation. Chapter 6 saw the application of the whole genome array to a second patient group; medically terminated pregnancies, in utero fetal deaths or newborn infants with one or more facial dysmorphism or fetal malformation. One potentially pathogenic copy number change was ascertained from this study. The third patient group, those with retractable epilepsy (chapter 7) showed two copy number changes both of which will require further follow up and investigation, including screening with a higher density array platform. The screening of more than seventy varied patients has shown the efficacy of these two custom platforms, to detect previously undetermined copy number changes.Thesis (Ph.D.) -- University of Adelaide, School of Paediatrics and Reproductive Health, 201