Factors influencing parent satisfaction in a children's emergency department: Prospective questionnaire-based study

Objective: To identify the factors considered by parents to be most important in determining overall satisfaction with care in a children's emergency department, and to assess whether these factors are influenced by the child's age and triage category. Design: A prospective questionnaire-based study of parents attending a paediatric emergency department with their child. Setting: Bristol Royal Hospital for Children, Bristol, UK. Participants: The parent or next of kin adult accompanying a child to the emergency department during the study period. Outcome measures: The primary outcome measure was the response to the questionnaire. The secondary outcome analysed responses according to the child's age and triage category. Results: During the sampling period questionnaires were distributed to the parent or accompanying adult of 247 children, of which 225 (91%) were completed. The most important factors were: a clear explanation of the child's diagnosis and treatment plan; the ability of a parent to stay with their child at all times; rapid and adequate pain relief; and staff attitude. These factors significantly outranked waiting times and other process issues. The age and triage category of the child did not influence these preferences. Conclusion: Despite recent emphasis on waiting times and emergency department throughput in the UK, parents still value the clinical interaction above process issues when their child visits an emergency department. Current efforts to reduce the time spent by children in an emergency department must not undermine the core service values that are most appreciated by parents, and which will lead to the greatest satisfaction

Dressings and topical agents for arterial leg ulcers

Background: It is estimated that up to 1% of people in high-income countries suffer from a leg ulcer at some time in their life. The majority of leg ulcers are associated with circulation problems; poor blood return in the veins causes venous ulcers (around 70% of ulcers) and poor blood supply to the legs causes arterial ulcers (around 22% of ulcers). Treatment of arterial leg ulcers is directed towards correcting poor arterial blood supply, for example by correcting arterial blockages (either surgically or pharmaceutically). If the blood supply has been restored, these arterial ulcers can heal following principles of good wound-care. Dressings and topical agents make up a part of good wound-care for arterial ulcers, but there are many products available, and it is unclear what impact these have on ulcer healing. This is the third update of a review first published in 2003. Objectives: To determine whether topical agents and wound dressings affect healing in arterial ulcers. To compare healing rates and patient-centred outcomes between wound dressings and topical agents. Search methods: The Cochrane Vascular Information Specialist searched the Cochrane Vascular Specialised Register, Cochrane Central Register of Controlled Trials, MEDLINE, Embase, Cumulative Index to Nursing and Allied Health Literature and Allied and Complementary Medicine databases, the World Health Organization International Clinical Trials Registry Platform and ClinicalTrials.gov trials register to 28 January 2019. Selection criteria: Randomised controlled trials (RCTs), or controlled clinical trials (CCTs) evaluating dressings and topical agents in the treatment of arterial leg ulcers were eligible for inclusion. We included participants with arterial leg ulcers irrespective of method of diagnosis. Trials that included participants with mixed arterio-venous disease and diabetes were eligible for inclusion if they presented results separately for the different groups. All wound dressings and topical agents were eligible for inclusion in this review. We excluded trials which did not report on at least one of the primary outcomes (time to healing, proportion completely healed, or change in ulcer area). Data collection and analysis: Two review authors independently extracted information on the participants' characteristics, the interventions, and outcomes using a standardised data extraction form. Review authors resolved any disagreements through discussion. We presented the data narratively due to differences in the included trials. We used GRADE to assess the certainty of the evidence. Main results: Two trials met the inclusion criteria. One compared 2% ketanserin ointment in polyethylene glycol (PEG) with PEG alone, used twice a day by 40 participants with arterial leg ulcers, for eight weeks or until healing, whichever was sooner. One compared topical application of blood-derived concentrated growth factor (CGF) with standard dressing (polyurethane film or foam); both applied weekly for six weeks by 61 participants with non-healing ulcers (venous, diabetic arterial, neuropathic, traumatic, or vasculitic). Both trials were small, reported results inadequately, and were of low methodological quality. Short follow-up times (six and eight weeks) meant it would be difficult to capture sufficient healing events to allow us to make comparisons between treatments. One trial demonstrated accelerated wound healing in the ketanserin group compared with the control group. In the trial that compared CGF with standard dressings, the number of participants with diabetic arterial ulcers were only reported in the CGF group (9/31), and the number of participants with diabetic arterial ulcers and their data were not reported separately for the standard dressing group. In the CGF group, 66.6% (6/9) of diabetic arterial ulcers showed more than a 50% decrease in ulcer size compared to 6.7% (2/30) of non-healing ulcers treated with standard dressing. We assessed this as very-low certainty evidence due to the small number of studies and arterial ulcer participants, inadequate reporting of methodology and data, and short follow-up period. Only one trial reported side effects (complications), stating that no participant experienced these during follow-up (six weeks, low-certainty evidence). It should also be noted that ketanserin is not licensed in all countries for use in humans. Neither study reported time to ulcer healing, patient satisfaction or quality of life. Authors' conclusions: There is insufficient evidence to determine whether the choice of topical agent or dressing affects the healing of arterial leg ulcers

Analysis of exome data for 4293 trios suggests GPI-anchor biogenesis defects are a rare cause of developmental disorders.

Over 150 different proteins attach to the plasma membrane using glycosylphosphatidylinositol (GPI) anchors. Mutations in 18 genes that encode components of GPI-anchor biogenesis result in a phenotypic spectrum that includes learning disability, epilepsy, microcephaly, congenital malformations and mild dysmorphic features. To determine the incidence of GPI-anchor defects, we analysed the exome data from 4293 parent-child trios recruited to the Deciphering Developmental Disorders (DDD) study. All probands recruited had a neurodevelopmental disorder. We searched for variants in 31 genes linked to GPI-anchor biogenesis and detected rare biallelic variants in PGAP3, PIGN, PIGT (n=2), PIGO and PIGL, providing a likely diagnosis for six families. In five families, the variants were in a compound heterozygous configuration while in a consanguineous Afghani kindred, a homozygous c.709G>C; p.(E237Q) variant in PIGT was identified within 10-12 Mb of autozygosity. Validation and segregation analysis was performed using Sanger sequencing. Across the six families, five siblings were available for testing and in all cases variants co-segregated consistent with them being causative. In four families, abnormal alkaline phosphatase results were observed in the direction expected. FACS analysis of knockout HEK293 cells that had been transfected with wild-type or mutant cDNA constructs demonstrated that the variants in PIGN, PIGT and PIGO all led to reduced activity. Splicing assays, performed using leucocyte RNA, showed that a c.336-2A>G variant in PIGL resulted in exon skipping and p.D113fs*2. Our results strengthen recently reported disease associations, suggest that defective GPI-anchor biogenesis may explain ~0.15% of individuals with developmental disorders and highlight the benefits of data sharing

Evaluating an early social communication intervention for young children with Down Syndrome: a feasibility study (ASCEND)

This feasibility study aims to estimate the parameters to inform a future randomised controlled trial to test whether an early social communication intervention is effective in improving language skills in young children with Down Syndrome. In a two-arm randomised controlled trial (RCT), with 1:1 randomisation stratified by trial site, children were allocated to receive either the intervention plus standard NHS speech and language therapy, or standard NHS speech and language therapy only. In the intervention arm, parents/guardians received brief training videos on the parent-based intervention, a manual to follow with their child, a bag of toys and parent diaries. The intervention lasted 10 weeks. Twenty children with Down Syndrome, aged between 11 and 36 months were recruited into the trial and 19 were randomised. The dataset contains the baseline, post-treatment and 6 month follow-up data from 9 participants receiving the intervention (in addition to standard NHS speech and language therapy) and 10 control participants receiving standard NHS speech and language therapy only

Use of genome sequencing to hunt for cryptic second-hit variants: analysis of 31 cases recruited to the 100 000 Genomes Project.

Peer reviewed: TrueAcknowledgements: We thank the families involved in this study and the clinicians for providing information about the respective first-hit variants. This work was made possible through access to the data and findings generated by the 100 000 Genomes Project.Funder: NIHR Oxford Biomedical Research Centre; FundRef: http://dx.doi.org/10.13039/501100013373Funder: Cancer Research UK; FundRef: http://dx.doi.org/10.13039/501100000289BACKGROUND: Current clinical testing methods used to uncover the genetic basis of rare disease have inherent limitations, which can lead to causative pathogenic variants being missed. Within the rare disease arm of the 100 000 Genomes Project (100kGP), families were recruited under the clinical indication 'single autosomal recessive mutation in rare disease'. These participants presented with strong clinical suspicion for a specific autosomal recessive disorder, but only one suspected pathogenic variant had been identified through standard-of-care testing. Whole genome sequencing (WGS) aimed to identify cryptic 'second-hit' variants. METHODS: To investigate the 31 families with available data that remained unsolved following formal review within the 100kGP, SVRare was used to aggregate structural variants present in <1% of 100kGP participants. Small variants were assessed using population allele frequency data and SpliceAI. Literature searches and publicly available online tools were used for further annotation of pathogenicity. RESULTS: Using these strategies, 8/31 cases were solved, increasing the overall diagnostic yield of this cohort from 10/41 (24.4%) to 18/41 (43.9%). Exemplar cases include a patient with cystic fibrosis harbouring a novel exonic LINE1 insertion in CFTR and a patient with generalised arterial calcification of infancy with complex interlinked duplications involving exons 2-6 of ENPP1. Although ambiguous by short-read WGS, the ENPP1 variant structure was resolved using optical genome mapping and RNA analysis. CONCLUSION: Systematic examination of cryptic variants across a multi-disease cohort successfully identifies additional pathogenic variants. WGS data analysis in autosomal recessive rare disease should consider complex structural and small intronic variants as potentially pathogenic second hits

Fotografia del carrer Constantinopla quan el porter l'està regant , 1944

Objective: Capecitabine is an oral 5-fluorouracil (5-FU) pro-drug commonly used to treat colorectal carcinoma and other tumours. About 35% of patients experience dose-limiting toxicity. The few proven genetic biomarkers of 5-FU toxicity are rare variants and polymorphisms, respectively, at candidate loci dihydropyrimidine dehydrogenase (DPYD) and thymidylate synthase (TYMS). Design: We investigated 1456 polymorphisms and rare coding variants near 25 candidate 5-FU pathway genes in 968 UK patients from the QUASAR2 clinical trial. Results: We identified the first common DPYD polymorphisms to be consistently associated with capecitabine toxicity, rs12132152 (toxicity allele frequency (TAF)=0.031, OR=3.83, p=4.31×10−6) and rs12022243 (TAF=0.196, OR=1.69, p=2.55×10−5). rs12132152 was particularly strongly associated with hand-foot syndrome (OR=6.1, p=3.6×10−8). The rs12132152 and rs12022243 associations were independent of each other and of previously reported DPYD toxicity variants. Next-generation sequencing additionally identified rare DPYD variant p.Ala551Thr in one patient with severe toxicity. Using functional predictions and published data, we assigned p.Ala551Thr as causal for toxicity. We found that polymorphism rs2612091, which lies within an intron of ENOSF1, was also associated with capecitabine toxicity (TAF=0.532, OR=1.59, p=5.28×10−6). ENSOF1 is adjacent to TYMS and there is a poorly characterised regulatory interaction between the two genes/proteins. Unexpectedly, rs2612091 fully explained the previously reported associations between capecitabine toxicity and the supposedly functional TYMS variants, 5′VNTR 2R/3R and 3′UTR 6 bp ins-del. rs2612091 genotypes were, moreover, consistently associated with ENOSF1 mRNA levels, but not with TYMS expression. Conclusions: DPYD harbours rare and common capecitabine toxicity variants. The toxicity polymorphism in the TYMS region may actually act through ENOSF1.Dan Rosmarin, Claire Palles, Alistair Pagnamenta, Kulvinder Kaur, Guillermo Pita, Miguel Martin ... et al

The impact of inversions across 33,924 families with rare disease from a national genome sequencing project

Detection of structural variants (SVs) is currently biased toward those that alter copy number. The relative contribution of inversions toward genetic disease is unclear. In this study, we analyzed genome sequencing data for 33,924 families with rare disease from the 100,000 Genomes Project. From a database hosting &gt;500 million SVs, we focused on 351 genes where haploinsufficiency is a confirmed disease mechanism and identified 47 ultra-rare rearrangements that included an inversion (24 bp to 36.4 Mb, 20/47 de novo). Validation utilized a number of orthogonal approaches, including retrospective exome analysis. RNA-seq data supported the respective diagnoses for six participants. Phenotypic blending was apparent in four probands. Diagnostic odysseys were a common theme (&gt;50 years for one individual), and targeted analysis for the specific gene had already been performed for 30% of these individuals but with no findings. We provide formal confirmation of a European founder origin for an intragenic MSH2 inversion. For two individuals with complex SVs involving the MECP2 mutational hotspot, ambiguous SV structures were resolved using long-read sequencing, influencing clinical interpretation. A de novo inversion of HOXD11-13 was uncovered in a family with Kantaputra-type mesomelic dysplasia. Lastly, a complex translocation disrupting APC and involving nine rearranged segments confirmed a clinical diagnosis for three family members and resolved a conundrum for a sibling with a single polyp. Overall, inversions play a small but notable role in rare disease, likely explaining the etiology in around 1/750 families across heterogeneous clinical cohorts.</p

The impact of inversions across 33,924 families with rare disease from a national genome sequencing project

Detection of structural variants (SVs) is currently biased towards those that alter copy number. The relative contribution of inversions towards genetic disease is unclear. In this study, we analysed genome sequencing data for 33,924 families with rare-disease, from the 100,000 Genomes Project. From a database hosting &gt;500 million SVs, we focussed on 351 genes where haploinsufficiency is a confirmed disease mechanism and identified 47 ultra-rare rearrangements that included an inversion (24bp to 36.4Mb, 20/47 de novo). Validation utilised a number of orthogonal approaches, including retrospective exome analysis. RNAseq data supported the respective diagnoses for 6 participants. Phenotypic blending was apparent in 4 probands. Diagnostic odysseys were a common theme (&gt;50 years for one individual) and targeted analysis for the specific gene had already been performed for 30% of these individuals but with no findings. We provide formal confirmation of a European founder origin for an intragenic MSH2 inversion. For two individuals with complex SVs involving the MECP2 mutational hotspot, ambiguous SV structures were resolved using long-read sequencing, influencing clinical interpretation. A de novo inversion of HOXD11-13 was uncovered in a family with Kantaputra-type mesomelic dysplasia. Lastly, a complex translocation disrupting APC and involving 9 rearranged segments, confirmed a clinical diagnosis for 3 family members and resolved a conundrum for a sibling with a single polyp. Overall, inversions play a small but notable role in rare-disease, likely explaining the aetiology in around 1/750 families across heterogeneous clinical cohorts