An investigation of minimisation criteria

Minimisation can be used within treatment trials to ensure that prognostic factors are evenly distributed between treatment groups. The technique is relatively straightforward to apply but does require running tallies of patient recruitments to be made and some simple calculations to be performed prior to each allocation. As computing facilities have become more widely available, minimisation has become a more feasible option for many. Although the technique has increased in popularity, the mode of application is often poorly reported and the choice of input parameters not justified in any logical way

Variations in the detection of anorectal anomalies at birth amongst European cities

Aim: The diagnosis of anorectal malformations (ARM) is made at birth by perineal examination of the newborn, yet small series reported late diagnosis in almost 13%. No large series to date have looked into the magnitude of missed ARM cases in the neonatal period across Europe. This study aimed to define the rate of missed ARM at birth across four UK and EU centers. Methods: All ARM cases treated at two UK tertiary centers in the past 15 years were compared to two tertiary European centers. Demographic and relevant clinical data were collected. Late diagnosis was defined as any diagnosis made after discharge from the birth unit. Factors associated with late diagnosis were explored with descriptive statistics. Results: Across the four centers (117/1350, 8.7%) were sent home from the birth unit without recognizing the anorectal anomaly. Missed cases showed a slight female predominance (1.3:1), and the majority (113/117, 96.5%) were of the low anomaly with a fistula to the perineum. The rate of missed ARM cases was significantly higher in the UK centers combined (74/415, 17.8%) compared to those in the EU (43/935, 4.6%), (p<0.00001), and this was independent of individual center and year of birth. Conclusion: Significant variation exist between the UK and other European countries in the detection of ARM at birth. We recommend raising the awareness of accurate perineal examination at time of newborn physical examination. We feel this highlights an urgent need for a national initiative to assess and address the timely diagnosis of ARM in the UK

The CACCC-binding protein KLF3/BKLF represses a subset of KLF1/EKLF target genes and is required for proper erythroid maturation in vivo

The CACCC-box binding protein erythroid Kruppel-like factor (EKLF/KLF1) is a master regulator that directs the expression of many important erythroid genes. We have previously shown that EKLF drives transcription of the gene for a second KLF, basic Kruppel-like factor, or KLF3. We have now tested the in vivo role of KLF3 in erythroid cells by examining Klf3 knockout mice. KLF3-deficient adults exhibit a mild compensated anemia, including enlarged spleens, increased red pulp, and a higher percentage of erythroid progenitors, together with elevated reticulocytes and abnormal erythrocytes in the peripheral blood. Impaired erythroid maturation is also observed in the fetal liver. We have found that KLF3 levels rise as erythroid cells mature to become TER119(+). Consistent with this, microarray analysis of both TER119(-) and TER119(+) erythroid populations revealed that KLF3 is most critical at the later stages of erythroid maturation and is indeed primarily a transcriptional repressor. Notably, many of the genes repressed by KLF3 are also known to be activated by EKLF. However, the majority of these are not currently recognized as erythroid-cell-specific genes. These results reveal the molecular and physiological function of KLF3, defining it as a feedback repressor that counters the activity of EKLF at selected target genes to achieve normal erythropoiesis

Oral anticoagulants for primary prevention, treatment and secondary prevention of venous thromboembolic disease, and for prevention of stroke in atrial fibrillation:systematic review, network meta-analysis and cost-effectiveness analysis

BACKGROUND: Warfarin is effective for stroke prevention in atrial fibrillation (AF), but anticoagulation is underused in clinical care. The risk of venous thromboembolic disease during hospitalisation can be reduced by low-molecular-weight heparin (LMWH): warfarin is the most frequently prescribed anticoagulant for treatment and secondary prevention of venous thromboembolism (VTE). Warfarin-related bleeding is a major reason for hospitalisation for adverse drug effects. Warfarin is cheap but therapeutic monitoring increases treatment costs. Novel oral anticoagulants (NOACs) have more rapid onset and offset of action than warfarin, and more predictable dosing requirements.OBJECTIVE: To determine the best oral anticoagulant/s for prevention of stroke in AF and for primary prevention, treatment and secondary prevention of VTE.DESIGN: Four systematic reviews, network meta-analyses (NMAs) and cost-effectiveness analyses (CEAs) of randomised controlled trials.SETTING: Hospital (VTE primary prevention and acute treatment) and primary care/anticoagulation clinics (AF and VTE secondary prevention).PARTICIPANTS: Patients eligible for anticoagulation with warfarin (stroke prevention in AF, acute treatment or secondary prevention of VTE) or LMWH (primary prevention of VTE).INTERVENTIONS: NOACs, warfarin and LMWH, together with other interventions (antiplatelet therapy, placebo) evaluated in the evidence network.MAIN OUTCOME MEASURES: Efficacy Stroke, symptomatic VTE, symptomatic deep-vein thrombosis and symptomatic pulmonary embolism. Safety Major bleeding, clinically relevant bleeding and intracranial haemorrhage. We also considered myocardial infarction and all-cause mortality and evaluated cost-effectiveness.DATA SOURCES: MEDLINE and PREMEDLINE In-Process & Other Non-Indexed Citations, EMBASE and The Cochrane Library, reference lists of published NMAs and trial registries. We searched MEDLINE and PREMEDLINE In-Process & Other Non-Indexed Citations, EMBASE and The Cochrane Library. The stroke prevention in AF review search was run on the 12 March 2014 and updated on 15 September 2014, and covered the period 2010 to September 2014. The search for the three reviews in VTE was run on the 19 March 2014, updated on 15 September 2014, and covered the period 2008 to September 2014.REVIEW METHODS: Two reviewers screened search results, extracted and checked data, and assessed risk of bias. For each outcome we conducted standard meta-analysis and NMA. We evaluated cost-effectiveness using discrete-time Markov models.RESULTS: Apixaban (Eliquis(rcledR), Bristol-Myers Squibb, USA; Pfizer, USA) [5 mg bd (twice daily)] was ranked as among the best interventions for stroke prevention in AF, and had the highest expected net benefit. Edoxaban (Lixiana(rcledR), Daiichi Sankyo, Japan) [60 mg od (once daily)] was ranked second for major bleeding and all-cause mortality. Neither the clinical effectiveness analysis nor the CEA provided strong evidence that NOACs should replace postoperative LMWH in primary prevention of VTE. For acute treatment and secondary prevention of VTE, we found little evidence that NOACs offer an efficacy advantage over warfarin, but the risk of bleeding complications was lower for some NOACs than for warfarin. For a willingness-to-pay threshold of > £5000, apixaban (5 mg bd) had the highest expected net benefit for acute treatment of VTE. Aspirin or no pharmacotherapy were likely to be the most cost-effective interventions for secondary prevention of VTE: our results suggest that it is not cost-effective to prescribe NOACs or warfarin for this indication.CONCLUSIONS: NOACs have advantages over warfarin in patients with AF, but we found no strong evidence that they should replace warfarin or LMWH in primary prevention, treatment or secondary prevention of VTE.LIMITATIONS: These relate mainly to shortfalls in the primary data: in particular, there were no head-to-head comparisons between different NOAC drugs.FUTURE WORK: Calculating the expected value of sample information to clarify whether or not it would be justifiable to fund one or more head-to-head trials.STUDY REGISTRATION: This study is registered as PROSPERO CRD42013005324, CRD42013005331 and CRD42013005330.FUNDING: The National Institute for Health Research Health Technology Assessment programme

Intensive care unit course of infants and children after cranial vault reconstruction for craniosynostosis

<p>Abstract</p> <p>Background</p> <p>Craniosynostosis (CSS) results from the premature closure of one or more cranial sutures, leading to deformed calvaria at birth. It is a common finding in children with an incidence of one in 2000 births. Surgery is required in order to release the synostotic constraint and promote normal calvaria growth. Cranial vault remodeling is the surgical approach to CSS repair at our institution and it involves excision of the frontal, parietal, and occipital bones. The purpose of this article is to describe the post-operative course of infants and children admitted to our PICU after undergoing cranial vault remodeling for primary CSS.</p> <p>Findings</p> <p>Complete data was available for analyses in only 82 patients, 44 males (M) and 38 females (F); M: F ratio was 1:1.2. Patients (pts) age in months (mo) ranged from 2 mo to 132 mo, mean 18.2 ±-24.9 mo and weights (wt) ranged from 4.7 kg to 31.4 kg, mean 10.24 ± 5.5 Kg.. Duration of surgery (DOS) ranged from 70 minutes to 573 minutes mean 331.6 ± 89.0 minutes. No significant correlation exist between duration of surgery, suture category, patient's age or use of blood products (P > 0.05). IOP blood loss was higher in older pts (P < 0.05) and it correlates with body temperature in the PICU (P < .0001). Post-op use of FFP correlated with intra-operative PRBC transfusion (P < 0.0001). More PRBC was transfused within 12 hrs-24 hrs in PICU compared to other time periods (P < 0.05). LOS in PICU was < 3 days in 68% and > 3 days in 32%. Pts with fever had prolonged LOS (P < 0. 05); re-intubation rate was 2.4% and MVD were 1.83 days. Repeat operation for poor cosmetic results occurred in 9.7% of pts.</p> <p>Conclusions</p> <p>Post-op morbidities from increased use of blood products can be minimized if cranial vault remodeling is done at a younger age in patients with primary CSS. PICU length of stay is determined in part by post-op pyrexia and it can be reduced if extensive evaluations of post-op fever are avoided.</p

Clinical factors associated with fatigue over time in paediatric oncology patients receiving chemotherapy

The purpose of this study was to investigate the relationships between clinical factors (including haemoglobin value, chemotherapeutic agents, and corticosteroid use) and changing patterns of fatigue before and for the next 10 days following the start of a new round of chemotherapy in children with cancer. A prospective longitudinal design was used to collect data from 48 paediatric oncology patients who were about to begin a new round of chemotherapy and their parents. Fatigue levels were assessed using multidomain questionnaires with three categories of patient self-report (including ‘General Fatigue', ‘Sleep/Rest Fatigue', and ‘Cognitive Fatigue') and four categories of parent proxy-report (including ‘Lack of Energy', ‘Unable to Function', ‘Altered Sleep', and ‘Altered Mood'). The findings suggest that fatigue from both patient self-report and parent proxy-report changed significantly over time. The major findings from this study are that patients have more problems with fatigue in the first few days after the start of a cycle of chemotherapy. Corticosteroid use and haemoglobin value were associated with significant increases in fatigue that were sustained for several days and reached the highest level of fatigue at day 5 for those receiving concurrent steroids. The association of chemotherapeutic agents with fatigue varied between patient self-report and parent report, but the type of chemotherapeutic agents used was not associated with most changes in fatigue

Optimisation of the RT-PCR detection of immunomagnetically enriched carcinoma cells

BACKGROUND: Immunomagnetic enrichment followed by RT-PCR (immunobead RT-PCR) is an efficient methodology to identify disseminated carcinoma cells in the blood and bone marrow. The RT-PCR assays must be both specific for the tumor cells and sufficiently sensitive to enable detection of single tumor cells. We have developed a method to test RT-PCR assays for any cancer. This has been investigated using a panel of RT-PCR markers suitable for the detection of breast cancer cells. METHODS: In the assay, a single cell line-derived tumor cell is added to 100 peripheral blood mononuclear cells (PBMNCs) after which mRNA is isolated and reverse transcribed for RT-PCR analysis. PBMNCs without added tumor cells are used as specificity controls. The previously studied markers epidermal growth factor receptor (EGFR), mammaglobin 1 (MGB1), epithelial cell adhesion molecule (EpCAM/TACSTD1), mucin 1 (MUC1), carcinoembryonic antigen (CEA) were tested. Two new epithelial-specific markers ELF3 and EphB4 were also tested. RESULTS: MUC1 was unsuitable as strong amplification was detected in 100 cell PBMNC controls. Expression of ELF3, EphB4, EpCAM, EGFR, CEA and MGB1 was found to be both specific for the tumor cell, as demonstrated by the absence of a signal in most 100 cell PBMNC controls, and sensitive enough to detect a single tumor cell in 100 PBMNCs using a single round of RT-PCR. CONCLUSIONS: ELF3, EphB4, EpCAM, EGFR, CEA and MGB1 are appropriate RT-PCR markers for use in a marker panel to detect disseminated breast cancer cells after immunomagnetic enrichment