The importance of significant event analysis

Significant event analysis (SEA) is a structured quality improvement activity that is well established in general practice. Participation in SEA prompts primary care teams to reflect on their clinical reasoning, to highlight exemplary care, and to identify any potential improvements in both practice and wider healthcare systems. This article provides an overview of the SEA process and the events surrounding a SEA meeting. Cancer care examples are used to demonstrate how SEA can be used to enhance team-based learning and improve future patient care

Studies of Higgs Boson Signals Leading to Multi-Photon Final States with The ATLAS Detector

The efficient identification of photons is a crucial aspect in the search for the Higgs boson at ATLAS. With the high luminosity and collision energies provided by the Large Hadron Collider, rejection of backgrounds to photons is of key importance. It is often not feasible to fully simulate background processes that require large numbers of events, due to processing time and disk space constraints. The standard fast simulation program, ATLFAST-I, is able to simulate events ∼1000 times faster than the full simulation program but does not always provide enough detailed information to make accurate background estimates. To bridge the gap, a set of photon reconstruction efficiency parameterisations, for converted and unconverted photons, have been derived from full simulation events and subsequently applied to ATLFAST-I photons. Photon reconstruction efficiencies for isolated photons from fully simulated and ATLFAST-I, plus parameterisations, events are seen to agree within statistical error. A study into a newly proposed Two Higgs Doublet Model channel, gg → H → hh → γγγγ, where the light Higgs (h) boson is fermiophobic, has been investigated. The channel is of particular interest as it exploits the large production cross-section of a heavy Higgs (H) boson via gluon-fusion at the LHC in conjunction with the enhanced branching ratio of a light fermiophobic Higgs (h) boson to a pair of photons. This channel is characterised by a distinct signature of four high pT photons in the final state. Samples of signal events have been generated across the (mh,mH) parameter space along with the dominant backgrounds. An event selection has been developed with the search performed at generator-level. In addition, the search was also performed with simulated ATLFAST-I events utilising the above photon reconstruction efficiency parameterisations. For both analyses, the expected upper limit on the cross-section at 95% confidence level is determined and exclusion regions of the (mh,mH) parameter space are defined for integrated luminosities of 1 f b−1 and 10 f b−1 in seven fermiophobic model benchmarks

Learning from new colorectal cancers: a qualitative synthesis of significant event reports

Background Colorectal cancer is the second leading cause of cancer-related mortality in the United Kingdom and a significant contributor to morbidity and mortality worldwide. Early diagnosis provides opportunities for intervention and improved survival. Significant Event Analysis (SEA) is a well-established quality improvement method for learning from new cancer diagnoses. Aim This study aimed to provide additional insights into diagnostic processes for colorectal cancer and to identify areas for improvement in patient care pathways. Design & setting 53 general practices across Pennine Lancashire, England, submitted one or more SEA reports as part of an incentivised scheme. Method A standardised data collection form was used to collate learning points and recommendations for improvements. 161 reports were analysed using an inductive framework analysis approach. Results There was an overarching theme of building vigilance and collaboration between and within general practices and secondary care. Four main sub-themes were also identified including education, individualised and flexible care, ownership and continuity, and communication. Conclusion These findings provide additional insights into colorectal cancer pathways from a primary care perspective. Practices should be supported in developing protocols for assessment and follow-up of patients with varying presentations. Screening and access to investigations are paramount for improving early diagnosis, however, a flexible diagnostic approach is required according to the individual circumstances of each patient

Where genotype is not predictive of phenotype: towards an understanding of the molecular basis of reduced penetrance in human inherited disease

Some individuals with a particular disease-causing mutation or genotype fail to express most if not all features of the disease in question, a phenomenon that is known as ‘reduced (or incomplete) penetrance’. Reduced penetrance is not uncommon; indeed, there are many known examples of ‘disease-causing mutations’ that fail to cause disease in at least a proportion of the individuals who carry them. Reduced penetrance may therefore explain not only why genetic diseases are occasionally transmitted through unaffected parents, but also why healthy individuals can harbour quite large numbers of potentially disadvantageous variants in their genomes without suffering any obvious ill effects. Reduced penetrance can be a function of the specific mutation(s) involved or of allele dosage. It may also result from differential allelic expression, copy number variation or the modulating influence of additional genetic variants in cis or in trans. The penetrance of some pathogenic genotypes is known to be age- and/or sex-dependent. Variable penetrance may also reflect the action of unlinked modifier genes, epigenetic changes or environmental factors. At least in some cases, complete penetrance appears to require the presence of one or more genetic variants at other loci. In this review, we summarize the evidence for reduced penetrance being a widespread phenomenon in human genetics and explore some of the molecular mechanisms that may help to explain this enigmatic characteristic of human inherited disease

Frequent travelers and rate of spread of epidemics

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Evaluation of the Arabin cervical pessary for prevention of preterm birth in women with a twin pregnancy and short cervix (STOPPIT-2):An open-label randomised trial and updated meta-analysis

BackgroundPreterm-labour-associated preterm birth is a common cause of perinatal mortality and morbidity in twin pregnancy. We aimed to test the hypothesis that the Arabin pessary would reduce preterm-labour-associated preterm birth by 40% or greater in women with a twin pregnancy and a short cervix.Methods and findingsWe conducted an open-label randomised controlled trial in 57 hospital antenatal clinics in the UK and Europe. From 1 April 2015 to 14 February 2019, 2,228 women with a twin pregnancy underwent cervical length screening between 18 weeks 0 days and 20 weeks 6 days of gestation. In total, 503 women with cervical length ≤ 35 mm were randomly assigned to pessary in addition to standard care (n = 250, mean age 32.4 years, mean cervical length 29 mm, with pessary inserted in 230 women [92.0%]) or standard care alone (n = 253, mean age 32.7 years, mean cervical length 30 mm). The pessary was inserted before 21 completed weeks of gestation and removed at between 35 and 36 weeks or before birth if earlier. The primary obstetric outcome, spontaneous onset of labour and birth before 34 weeks 0 days of gestation, was present in 46/250 (18.4%) in the pessary group compared to 52/253 (20.6%) following standard care alone (adjusted odds ratio [aOR] 0.87 [95% CI 0.55-1.38], p = 0.54). The primary neonatal outcome-a composite of any of stillbirth, neonatal death, periventricular leukomalacia, early respiratory morbidity, intraventricular haemorrhage, necrotising enterocolitis, or proven sepsis, from birth to 28 days after the expected date of delivery-was present in 67/500 infants (13.4%) in the pessary group compared to 76/506 (15.0%) following standard care alone (aOR 0.86 [95% CI 0.54-1.36], p = 0.50). The positive and negative likelihood ratios of a short cervix (≤35 mm) to predict preterm birth before 34 weeks were 2.14 and 0.83, respectively. A meta-analysis of data from existing publications (4 studies, 313 women) and from STOPPIT-2 indicated that a cervical pessary does not reduce preterm birth before 34 weeks in women with a short cervix (risk ratio 0.74 [95% CI 0.50-1.11], p = 0.15). No women died in either arm of the study; 4.4% of babies in the Arabin pessary group and 5.5% of babies in the standard treatment group died in utero or in the neonatal period (p = 0.53). Study limitations include lack of power to exclude a smaller than 40% reduction in preterm labour associated preterm birth, and to be conclusive about subgroup analyses.ConclusionsThese results led us to reject our hypothesis that the Arabin pessary would reduce the risk of the primary outcome by 40%. Smaller treatment effects cannot be ruled out.Trial registrationISRCTN Registry ISRCTN 02235181. ClinicalTrials.gov NCT02235181

EBV T-cell immunotherapy generated by peptide selection has enhanced effector functionality compared to LCL stimulation

Adoptive immunotherapy with Epstein–Barr virus (EBV)-specific T cells is an effective treatment for relapsed or refractory EBV-induced post-transplant lymphoproliferative disorders (PTLD) with overall survival rates of up to 69%. EBV-specific T cells have been conventionally made by repeated stimulation with EBV-transformed lymphoblastoid cell lines (LCL), which act as antigen-presenting cells. However, this process is expensive, takes many months, and has practical risks associated with live virus. We have developed a peptide-based, virus-free, serum-free closed system to manufacture a bank of virus-specific T cells (VST) for clinical use. We compared these with standard LCL-derived VST using comprehensive characterization and potency assays to determine differences that might influence clinical benefits. Multi-parameter flow cytometry revealed that peptide-derived VST had an expanded central memory population and less exhaustion marker expression than LCL-derived VST. A quantitative HLA-matched allogeneic cytotoxicity assay demonstrated similar specific killing of EBV-infected targets, though peptide-derived EBV T cells had a significantly higher expression of antiviral cytokines and degranulation markers after antigen recall. High-throughput T cell receptor-beta (TCRβ) sequencing demonstrated oligoclonal repertoires, with more matches to known EBV-binding complementary determining region 3 (CDR3) sequences in peptide-derived EBV T cells. Peptide-derived products showed broader and enhanced specificities to EBV nuclear antigens (EBNAs) in both CD8 and CD4 compartments, which may improve the targeting of highly expressed latency antigens in PTLD. Importantly, peptide-based isolation and expansion allows rapid manufacture and significantly increased product yield over conventional LCL-based approaches.</p

The Arabin pessary to prevent preterm birth in women with a twin pregnancy and a short cervix:the STOPPIT 2 RCT

Background: Preterm birth is common in twins and accounts for significant mortality and morbidity. There are no effective preventative treatments. Some studies have suggested that, in twin pregnancy complicated by a short cervix, the Arabin pessary, which fits around the cervix and can be inserted as an outpatient procedure, reduces preterm birth and prevents neonatal morbidity. Objective: STOPPIT 2 aimed to evaluate the clinical utility of the Arabin cervical pessary in preventing preterm birth in women with a twin pregnancy and a short cervix. Design: STOPPIT 2 was a pragmatic, open label, multicentre randomised controlled trial with two treatment group – the Arabin pessary plus standard care (intervention) and standard care alone (control). Participants were initially recruited into the screening phase of the study, when cervical length was measured. Women with a measured cervical length of ≤ 35 mm were then recruited into the treatment phase of the study. An economic evaluation considered cost-effectiveness and a qualitative substudy explored the experiences of participants and clinicians. Setting: Antenatal clinics in the UK and elsewhere in Europe. Participants: Women with twin pregnancy at < 21 weeks’ gestation with known chorionicity and gestation established by scan at ≤ 16 weeks’ gestation. Interventions: Ultrasound scan to establish cervical length. Women with a cervical length of ≤ 35 mm at 18+ 0–20+ 6 weeks’ gestation were randomised to standard care or Arabin pessary plus standard care. Randomisation was performed by computer and accessed through a web-based browser. Main outcome measures: Obstetric – all births before 34+ 0 weeks’ gestation following the spontaneous onset of labour; and neonatal – composite of adverse outcomes, including stillbirth or neonatal death, periventricular leukomalacia, early respiratory morbidity, intraventricular haemorrhage, necrotising enterocolitis or proven sepsis, all measured up to 28 days after the expected date of delivery. Results: A total of 2228 participants were recruited to the screening phase, of whom 2170 received a scan and 503 were randomised: 250 to Arabin pessary and 253 to standard care alone. The rate of the primary obstetric outcome was 18.4% (46/250) in the intervention group and 20.6% (52/253) in the control group (adjusted odds ratio 0.87, 95% confidence interval 0.55 to 1.38; p = 0.54). The rate of the primary neonatal outcome was 13.4% (67/500) and 15.0% (76/506) in the intervention group and control group, respectively (adjusted odds ratio 0.86, 95% confidence interval 0.54 to 1.36; p = 0.52). The pessary was largely well tolerated and clinicians found insertion and removal ‘easy’ or ‘fairly easy’ in the majority of instances. The simple costs analysis showed that pessary treatment is no more costly than standard care. Limitations: There was the possibility of a type II error around smaller than anticipated benefit. Conclusions: In this study, the Arabin pessary did not reduce preterm birth or adverse neonatal outcomes in women with a twin pregnancy and a short cervix. The pessary either is ineffective at reducing preterm birth or has an effect size of < 0.4. Future work: Women with twin pregnancy remain at risk of preterm birth; work is required to find treatments for this. Trial registration: Current Controlled Trials ISRCTN98835694 and ClinicalTrials.gov NCT02235181. Funding: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 25, No. 44. See the NIHR Journals Library website for further project information

The Moon Zoo citizen science project: preliminary results for the Apollo 17 landing site

Moon Zoo is a citizen science project that utilises internet crowd-sourcing techniques. Moon Zoo users are asked to review high spatial resolution images from the Lunar Reconnaissance Orbiter Camera (LROC), onboard NASA’s LRO spacecraft, and perform characterisation such as measuring impact crater sizes and identify morphological ‘features of interest’. The tasks are designed to address issues in lunar science and to aid future exploration of the Moon. We have tested various methodologies and parameters therein to interrogate and reduce the Moon Zoo crater location and size dataset against a validated expert survey. We chose the Apollo 17 region as a test area since it offers a broad range of cratered terrains, including secondary-rich areas, older maria, and uplands. The assessment involved parallel testing in three key areas: (1) filtering of data to remove problematic mark-ups; (2) clustering methods of multiple notations per crater; and (3) derivation of alternative crater degradation indices, based on the statistical variability of multiple notations and the smoothness of local image structures. We compared different combinations of methods and parameters and assessed correlations between resulting crater summaries and the expert census. We derived the optimal data reduction steps and settings of the existing Moon Zoo crater data to agree with the expert census. Further, the regolith depth and crater degradation states derived from the data are also found to be in broad agreement with other estimates for the Apollo 17 region. Our study supports the validity of this citizen science project but also recommends improvements in key elements of the data acquisition planning and production