General practitioner referrals to paediatric specialist outpatient clinics: Referral goals and parental influence

© 2018 Royal New Zealand College of General Practitioners. Introduction: Previous research on general practitioner (GP) referrals in adult populations demonstrated that patient pressure influenced referral practice. No research has been conducted to investigate how involvement of a parent influences paediatric referrals. Aim: To investigate whether GPs who report parental influence on their decision to refer paediatric patients differ in their referral patterns from GPs who do not report parental influence. Method: A mail survey of 400 GPs who had referred at least two children to paediatric specialist outpatient clinics during 2014 was distributed. Results: The response rate was 67% (n = 254). For initial referrals, 27% of GPs stated that parental request frequently or almost always influenced their referral decision. For returning referrals, 63% of GPs experienced parental influence to renew a referral because a paediatrician wanted a child to return; 49% of GPs experienced influence to renew a referral because a parent wanted to continue care with a paediatrician. Experiencing parental influence was associated with increased likelihood for frequent referrals in order for a paediatrician to take over management of a child's condition. Discussion: GPs who frequently refer with a goal for a paediatrician to take over management of a child's condition also report that parental request almost always influences their decision to refer

INDIGO : better geomagnetic observatories where we need them

The INDIGO project aims to improve the global coverage of digital observatories by deploying digital magnetometer systems in: i) Observatories where existing analog recording equipment is in need of upgrading. ii) Newly established digital observatories. iii) Existing digital observatories for the purpose of quality control and redundancy. In implementing the project and selecting suitable sites, special attention is paid to parts of the Earth devoid of magnetic observatories, increasing the reliability and long-term operation of existing observatories and cost-effective use of local resources. The Poster reviews the current status of the project. We examine the different steps and initiatives taken since the initiation of INDIGO in 2004 and assess their effectiveness in achieving progress towards our aims of improving global coverage and enhanced data quality

A multi-exon deletion within WWOX is associated with a 46,XY disorder of sex development

Disorders of sex development (DSD) are congenital conditions where chromosomal, gonad or genital development is atypical. In a significant proportion of 46,XY DSD cases it is not possible to identify a causative mutation, making genetic counseling difficult and potentially hindering optimal treatment. Here, we describe the analysis of a 46,XY DSD patient that presented at birth with ambiguous genitalia. Histological analysis of the surgically removed gonads showed bilateral undifferentiated gonadal tissue and immature testis, both containing malignant germ cells. We screened genomic DNA from this patient for deletions and duplications using an Illumina whole-genome SNP microarray. This analysis revealed a heterozygous deletion within the WWOX gene on chromosome 16, removing exons 6-8. Analysis of parental DNA showed that the deletion was inherited from the mother. cDNA analysis confirmed that the deletion maintained the reading frame, with exon 5 being spliced directly onto exon 9. This deletion is the first description of a germline rearrangement affecting the coding sequence of WWOX in humans. Previously described Wwox knockout mouse models showed gonadal abnormalities, supporting a role for WWOX in human gonad development

Diving efficiency at depth and pre-breeding foraging effort increase with haemoglobin levels in gentoo penguins

Individual differences in oxygen storage and carrying capacity have been associated with fitness-related traits and, for air-breathing aquatic animals, to diving ability and foraging success. In winter, many seabirds must replenish the energy reserves they have depleted during the breeding period. Thus, winter foraging efficiency can influence their upcoming breeding behaviour. Using gentoo penguins Pygoscelis papua as a study species, we investigated (1) if inter-individual variation in diving efficiency (proportion of time spent at the bottom) is associated with indices of oxygen storage and carrying capacity (haemoglobin, haematocrit, body mass), and (2) if measures of pre-breeding foraging effort (mean trip duration, total time at sea, and vertical distance travelled) are associated with these oxygen indices and breeding status. Haemoglobin was positively correlated with diving efficiency, particularly for deeper dives, and only penguins with high haemoglobin levels frequently dove to depths ≥140 m. Such differences could affect resource access. However, because reaching deep offshore waters likely requires travelling more than foraging nearshore, vertical distance travelled during pre-breeding increased with haemoglobin levels. The relationship with haematocrit was non-linear, suggesting that commonly used analyses may be inappropriate for this index. We found that early-laying penguins spent less time at sea prior to nesting than non-breeding penguins, suggesting that more efficient foragers lay earlier. Given that diving efficiency at depth is linked to aerobic capacity, anthropogenic activities taking place in either nearshore or offshore waters (e.g. shallow-water fisheries, offshore oil rigs) may have differing impacts on individuals. Further understanding these links could help the conservation of diving species

Bioactive growth hormone in older men and women: Its relationship to immune markers and healthspan

Objective: The consequences of age-related decline in the somatotropic axis of humans are complex and remain largely unresolved. We tested the hypothesis that hGH measurements of plasma by bioassay vs immunoassay from samples obtained from free-living, elderly individuals would reveal a dichotomy in GH activities that are correlated with the functional status of the donors, i.e. their healthspan. Design: Forty-one men and women of advanced age (men: N=16, age, 80.5±6.5years; height, 173.1±6.9cm; body mass, 81.8±13.0kg) and (women: N=25, age, 80.7±7.2years; height, 157.7±6.0cm; body mass, 68.8±17kg), were recruited for a cross-sectional study. Participants filled out PROMIS (Patient-Reported Outcomes Measurement Information System, U. S. Department of Health and Human Services) scales, undertook physical performance tests and had fasted blood samples obtained at rest for measurement of hormonal and immunology biomarkers. Results: When measured by the well-established rat tibial line GH bioassay, one half of the plasma samples (n=20) contained bioassayable GH (bGH), but the other half (n=21) failed to mount increases in tibial plate width above saline injected controls. This difference did not correlate with the age, sex or physical functionality of the plasma donor. It also did not correlate with hGH concentrations measured by immunoassay. In those cases in which bGH was detected, various hierarchical regression models predicted that GHRH, c-peptide, VEGF, NPY, IL-4 and T-regulatory lymphocytes were associated with the difference and predicted bGH. Conclusion: Results from this study suggest that the actions of bGH at the cellular level may be modified by other factors and that this may explain the lack of correlations observed in this study

An investigation of the clinical impact and therapeutic relevance of a DNA damage immune response (DDIR) signature in patients with advanced gastroesophageal adenocarcinoma

Background: An improved understanding of which gastroesophageal adenocarcinoma (GOA) patients respond to both chemotherapy and immune checkpoint inhibitors (ICI) is needed. We investigated the predictive role and underlying biology of a 44-gene DNA damage immune response (DDIR) signature in patients with advanced GOA.Materials and methods: Transcriptional profiling was carried out on pretreatment tissue from 252 GOA patients treated with platinum-based chemotherapy (three dose levels) within the randomized phase III GO2 trial. Cross-validation was carried out in two independent GOA cohorts with transcriptional profiling, immune cell immunohistochemistry and epidermal growth factor receptor (EGFR) fluorescent in situ hybridization (FISH) (n = 430).Results: In the GO2 trial, DDIR-positive tumours had a greater radiological response (51.7% versus 28.5%, P = 0.022) and improved overall survival in a dose-dependent manner (P = 0.028). DDIR positivity was associated with a pretreatment inflamed tumour microenvironment (TME) and increased expression of biomarkers associated with ICI response such as CD274 (programmed death-ligand 1, PD-L1) and a microsatellite instability RNA signature. Consensus pathway analysis identified EGFR as a potential key determinant of the DDIR signature. EGFR amplification was associated with DDIR negativity and an immune cold TME.Conclusions: Our results indicate the importance of the GOA TME in chemotherapy response, its relationship to DNA damage repair and EGFR as a targetable driver of an immune cold TME. Chemotherapy-sensitive inflamed GOAs could benefit from ICI delivered in combination with standard chemotherapy. Combining EGFR inhibitors and ICIs warrants further investigation in patients with EGFR-amplified tumours

Copy Number Variation in Patients with Disorders of Sex Development Due to 46,XY Gonadal Dysgenesis

Disorders of sex development (DSD), ranging in severity from mild genital abnormalities to complete sex reversal, represent a major concern for patients and their families. DSD are often due to disruption of the genetic programs that regulate gonad development. Although some genes have been identified in these developmental pathways, the causative mutations have not been identified in more than 50% 46,XY DSD cases. We used the Affymetrix Genome-Wide Human SNP Array 6.0 to analyse copy number variation in 23 individuals with unexplained 46,XY DSD due to gonadal dysgenesis (GD). Here we describe three discrete changes in copy number that are the likely cause of the GD. Firstly, we identified a large duplication on the X chromosome that included DAX1 (NR0B1). Secondly, we identified a rearrangement that appears to affect a novel gonad-specific regulatory region in a known testis gene, SOX9. Surprisingly this patient lacked any signs of campomelic dysplasia, suggesting that the deletion affected expression of SOX9 only in the gonad. Functional analysis of potential SRY binding sites within this deleted region identified five putative enhancers, suggesting that sequences additional to the known SRY-binding TES enhancer influence human testis-specific SOX9 expression. Thirdly, we identified a small deletion immediately downstream of GATA4, supporting a role for GATA4 in gonad development in humans. These CNV analyses give new insights into the pathways involved in human gonad development and dysfunction, and suggest that rearrangements of non-coding sequences disturbing gene regulation may account for significant proportion of DSD cases

Recommendations for effective documentation in regional anesthesia: an expert panel Delphi consensus project

Background and objectives: Documentation is important for quality improvement, education, and research. There is currently a lack of recommendations regarding key aspects of documentation in regional anesthesia. The aim of this study was to establish recommendations for documentation in regional anesthesia. Methods: Following the formation of the executive committee and a directed literature review, a long list of potential documentation components was created. A modified Delphi process was then employed to achieve consensus amongst a group of international experts in regional anesthesia. This consisted of 2 rounds of anonymous electronic voting and a final virtual round table discussion with live polling on items not yet excluded or accepted from previous rounds. Progression or exclusion of potential components through the rounds was based on the achievement of strong consensus. Strong consensus was defined as ≥75% agreement and weak consensus as 50%-74% agreement. Results: Seventy-seven collaborators participated in both rounds 1 and 2, while 50 collaborators took part in round 3. In total, experts voted on 83 items and achieved a strong consensus on 51 items, weak consensus on 3 and rejected 29. Conclusion: By means of a modified Delphi process, we have established expert consensus on documentation in regional anesthesia

Dimethyl fumarate in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial

Dimethyl fumarate (DMF) inhibits inflammasome-mediated inflammation and has been proposed as a treatment for patients hospitalised with COVID-19. This randomised, controlled, open-label platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), is assessing multiple treatments in patients hospitalised for COVID-19 (NCT04381936, ISRCTN50189673). In this assessment of DMF performed at 27 UK hospitals, adults were randomly allocated (1:1) to either usual standard of care alone or usual standard of care plus DMF. The primary outcome was clinical status on day 5 measured on a seven-point ordinal scale. Secondary outcomes were time to sustained improvement in clinical status, time to discharge, day 5 peripheral blood oxygenation, day 5 C-reactive protein, and improvement in day 10 clinical status. Between 2 March 2021 and 18 November 2021, 713 patients were enroled in the DMF evaluation, of whom 356 were randomly allocated to receive usual care plus DMF, and 357 to usual care alone. 95% of patients received corticosteroids as part of routine care. There was no evidence of a beneficial effect of DMF on clinical status at day 5 (common odds ratio of unfavourable outcome 1.12; 95% CI 0.86-1.47; p = 0.40). There was no significant effect of DMF on any secondary outcome