Double faecal immunochemical testing in patients with symptoms suspicious of colorectal cancer.

BACKGROUND: Faecal immunochemical test (FIT)-directed pathways based on a single test have been implemented for symptomatic patients. However, with a single test, the sensitivity is 87 per cent at 10 µg haemoglobin (Hb) per g faeces. This aims of this study were to define the diagnostic performance of a single FIT, compared with double FIT in symptomatic populations. METHODS: Two sequential prospective patient cohorts referred with symptoms from primary care were studied. Patients in cohort 1 were sent a single FIT, and those in cohort 2 received two tests in succession before investigation. All patients were investigated, regardless of having a positive or negative test (threshold 10 µg Hb per g). RESULTS: In cohort 1, 2260 patients completed one FIT and investigation. The sensitivity of single FIT was 84.1 (95 per cent c.i. 73.3 to 91.8) per cent for colorectal cancer and 67.4 (61.0 to 73.4) per cent for significant bowel pathology. In cohort 2, 3426 patients completed at least one FIT, and 2637 completed both FITs and investigation. The sensitivity of double FIT was 96.6 (90.4 to 99.3) per cent for colorectal cancer and 83.0 (77.4 to 87.8) per cent for significant bowel pathology. The second FIT resulted in a 50.0 per cent reduction in cancers missed by the first FIT, and 30.0 per cent for significant bowel pathology. Correlation between faecal Hb level was only modest (rs = 0.58), and 16.8 per cent of double tests were discordant, 11.4 per cent in patients with colorectal cancer and 18.3 per cent in those with significant bowel pathology. CONCLUSION: FIT in patients with high-risk symptoms twice in succession reduces missed significant colorectal pathology and has an acceptable workload impact.

Mirror Instabilities in the Inner Magnetosphere and Their Potential for Localized ULF Wave Generation.

Results from the NASA Van Allen Probes mission indicate extensive observations of mirror/drift-mirror (M/D-M hereafter) unstable plasma regions in the night-side inner magnetosphere. Said plasmas lie on the threshold between the kinetic and frozen-in plasma regimes and have favorable conditions for the formation of M/D-M modes and subsequent ultralow frequency (ULF) wave signatures in the surrounding plasma. We present the results of a climatological analysis of plasma-γ (anisotropy measure) and total plasma-ß (ratio of particle to magnetic field pressure) in regard to the satisfaction of instability conditions on said M/D-M modes under bi-Maxwellian distribution assumption, and ascertain the most likely region for such plasmas to occur. Our results indicate a strong preference for the premidnight sector of the night-side magnetosphere, with events ranging in time scales from half a minute (roughly 200 km in scale size) to several hours (multiple Earth radii). The statistical distribution of these plasma regions explicitly identifies the source region of "storm time Pc5 ULF waves" and suggests an alternative mechanism for their generation in the night-side inner magnetosphere.

Metformin as a radiosensitiser for pelvic malignancy: A systematic review of the literature.

BACKGROUND: The treatment of pelvic malignancies has continued to improve over recent years, with neoadjuvant radiotherapy often considered the gold standard to downstage disease. Radiosensitisers are routinely employed in an attempt to improve response of cancers to radiotherapy. Previous preclinical evidence has suggested a role for metformin, a commonly used drug for type 2 diabetes. METHOD: A literature search was performed for published full text articles using the PubMed, Cochrane and Scopus databases using the search criteria string 'Metformin' AND ('Radiosensitivity' OR 'radiosensitising' OR 'radiosensitising'). Additional papers were detected by scanning the references of relevant papers. Data were extracted from each study by two authors onto a dedicated proforma. The review was registered on the PROSPERO database (ID: CRD42020199066). RESULTS: A total of 242 papers were identified, 11 of which were included in this review; an additional 5 papers were obtained from reference searches. Metformin has been demonstrated to reduce cell-viability post-radiotherapy in both rectal and prostate cancer cell lines, with an enhanced effect in tumours with a p53 mutation and increased apoptosis post-radiotherapy for cervical cancer. Clinical trials demonstrate improved tumour and nodal downstaging and pCR rates for rectal cancer using metformin as a radiosensitiser. CONCLUSION: With an increasing understanding of the underlying mechanism of the effects on metformin prospective studies are required to assess the effect of routine use on cancer related outcomes. Progressive future studies may be better served by the use of predictive biomarker guided treatment to enable identification of the appropriate cohort to target.

The Nutritional Intake of Patients with Organic Acidaemias on Enteral Tube Feeding: Can We Do Better?

BACKGROUND: Detailed nutritional intake data on children with organic acidaemias (OA) (propionic acidaemia (PA), vitamin B12 nonresponsive methylmalonic acidaemia (MMA) and isovaleric acidaemia (IVA)) remains unreported. Aim and subjects: A review of the longitudinal nutritional intake of 14 children with organic acidaemias (PA n = 8; MMA n = 5; IVA n = 1) dependent on enteral tube feeding (≥90% of energy requirements) from a single treatment centre. METHODS: Nutritional intake (energy, protein, precursor-free L-amino acids, vitamins and minerals), anthropometry and nutritional biochemistry data were collated from diagnosis to current age. RESULTS: The median energy intake was only 72% (63-137) of the estimated average DH (1991) requirement (EAR), decreasing significantly by 40% between 6 months and 5 years (p < 0.05). Total protein intake met WHO/FAO/UNU (2007) safe intake levels with median (range) precursor-free L-amino acids providing 21% (14-28) of total protein intake. Median mineral intake for sodium was 57% (20-97%), potassium 64% (27-125%) and magnesium 72% (22-116%) and was consistently < RNI for all age points. Fibre median intake was 4 g/day (0-11 g), and fluid intake provided 80% (60-100%) of the requirements for age. Linear growth was poor, and children were overweight for their height (1-10 years: z score median weight +0.6, height -1.2). Nutritional markers consistently indicated that plasma valine concentrations were < target reference ranges in PA and MMA. Iron deficiency anaemia was common in MMA/PA, and in PA, 50% of plasma zinc concentrations were < reference range. CONCLUSION: In MMA/PA, energy intake decreases over time, weight gain accelerates, but linear height is poor. There are many nutrient deficiencies which may affect short- and long-term outcome of patients with organic acidaemias. The quality of long-term diet in these conditions deserves more attention.

An impenetrable barrier to ultrarelativistic electrons in the Van Allen radiation belts.

Early observations indicated that the Earth's Van Allen radiation belts could be separated into an inner zone dominated by high-energy protons and an outer zone dominated by high-energy electrons. Subsequent studies showed that electrons of moderate energy (less than about one megaelectronvolt) often populate both zones, with a deep 'slot' region largely devoid of particles between them. There is a region of dense cold plasma around the Earth known as the plasmasphere, the outer boundary of which is called the plasmapause. The two-belt radiation structure was explained as arising from strong electron interactions with plasmaspheric hiss just inside the plasmapause boundary, with the inner edge of the outer radiation zone corresponding to the minimum plasmapause location. Recent observations have revealed unexpected radiation belt morphology, especially at ultrarelativistic kinetic energies (more than five megaelectronvolts). Here we analyse an extended data set that reveals an exceedingly sharp inner boundary for the ultrarelativistic electrons. Additional, concurrently measured data reveal that this barrier to inward electron radial transport does not arise because of a physical boundary within the Earth's intrinsic magnetic field, and that inward radial diffusion is unlikely to be inhibited by scattering by electromagnetic transmitter wave fields. Rather, we suggest that exceptionally slow natural inward radial diffusion combined with weak, but persistent, wave-particle pitch angle scattering deep inside the Earth's plasmasphere can combine to create an almost impenetrable barrier through which the most energetic Van Allen belt electrons cannot migrate.

Sustainable energy at the 100 W level for scientific sites on the Antarctic Plateau: lessons learned from the Polar Experiment Network for Geospace Upper atmosphere Investigations-Automatic Geophysical Observatory project.

The need to provide power to unmanned instrumentation over the course of an entire year on the Antarctic plateau presents a large number of engineering and logistical challenges. Designs formulated in ideal laboratory environments often fail in the Antarctic due to the harsh operating conditions, and field experience is necessary to achieve year-round operation in the 100 W power range. In this paper we present our current power design for the Automatic Geophysical Observatories; a design based on over two decades of experience on the ice and allows for relatively continuous operation at the aforementioned power level. We also discuss our various implementation methods, both failures and successes, in an effort assist other unmanned deployments on the ice.

Continuous aerobic phenol degradation by defined mixed immobilized culture in packed bed reactors.

A defined mixed culture of Pseudomonas putida, Commamonas testosteroni and Candida tropicalis was immobilized by adsorption on polyurethane foam, cocoa-fibers, expanded slate and sintered glass. Packed bed reactors were used for long-term continuous phenol biodegradations. Loading experiments were done to study the impact of the following parameters: (1) hydraulic retention time, (2) dissolved oxygen concentration, and (3) elimination of the oxygen limitation. After the acclimation period (approximately 10 d), the loading test with the individual packings showed the following maximum degradation rates: sintered glass 34, polyurethane foam 12, expanded slate 11.5, and cocoa-fibers 7.7 kg m(-3) d(-1). All these values were reached at a removal efficiency >99 % and with oxygen in excess. Under these conditions, the pH of the diluted unbuffered medium in the reactor effluent was 3.2-4.0 and no incompletely oxidized metabolic intermediates were found. The free cell concentration in the effluent increased after the phenol overloading time period.

Consideration of non-Poisson distributions for lidar applications.

Poisson statistics are traditionally used to estimate the mean and standard deviation of the mean in time-range realizations of received photon counts from stationary processes in incoherent-detection lidar systems. However, this approach must be modified if the process under study is measurably nonstationary to account for any additional (and potentially unanticipated) variability. We demonstrate that the modified approach produces a different form for the estimated standard deviation of the mean for lidar return counts, which can also be applied to binning of higher-order data products. This modified technique also serves to determine optimum time-range integrations, diagnose system stability, and constrain operational modes.

IVF performance of women who have fluctuating early follicular FSH levels.

OBJECTIVES: The aim was to evaluate whether women who have early follicular follicle-stimulating hormone (FSH) levels > 12 mIU/ml have reduced response to follicular stimulation for in vitro fertilization (IVF) in a following month, in spite of normal FSH levels. MATERIAL AND METHODS: In a 3-year period from January 1996 to December 1998, 303 women aged 38 years and above and/or who had previously responded poorly to superovulation for IVF gave blood samples for FSH, luteinizing hormone (LH), and estradiol (E2) on day 2 of menstruation before commencing treatment. RESULTS: In 117 (38.6%) of these women, FSH levels were > 12 mIU/ml (range 12-114 mIU/ml). Sixty-six of these women gave a further 130 blood samples for FSH measurement in the following months. Seventy-eight (60.0%) of the tests showed raised FSH value > 12 mIU/ml. Thirty women whose repeat FSH levels were < 12 mIU/ml underwent 41 IVF cycles (group 1). Sixty-three other women, older than 38 and/or who had a poor response to superovulation previously and whose FSH levels were < 12 mIU/ml, served as the control group (group II). There were no differences in the responses to superovulation and delivery rates between the two groups (14.6% vs. 12.7%). CONCLUSIONS: Women whose early follicular phase FSH levels were raised > 12 mIU/ml had an increased risk (> 50%) that in subsequent cycles levels would remain raised, and it was not possible to predict which individuals would have favorable FSH levels. If the cycle day 2 FSH level returns to a "normal" level of < 12 mIU/ml, women aged 40 and above had substantial cycle cancellation rates (43%), but patients who achieved the stage of embryo transfer had a good chance of conceiving, regardless of their age.

Recombinant factor IX secreted by transduced human keratinocytes is biologically active.

We have been investigating the use of human keratinocytes as potential target cells for gene therapy for haemophilia B, with the aim of curing haemophilia by means of a factor IX secreting skin graft. Previous studies indicated that keratinocytes might be suitable cells, although a potential problem was that the recombinant factor IX secreted by transduced keratinocytes was found to be only 40% biologically active. We now report, using an alternative assay to test for activity, that the secreted factor IX appears to be almost fully active.

Towards gene therapy for haemophilia B using primary human keratinocytes.

Haemophilia B might be permanently cured by gene therapy--the introduction of a correct copy of the factor IX gene into the somatic cells of a patient. Here, we have introduced a recombinant human factor IX cDNA into primary human keratinocytes by means of a defective retroviral vector. In tissue culture, transduced keratinocytes were found to secrete biologically active factor IX and after transplantation of these cells into nude mice, human factor IX was detected in the bloodstream in small quantities for one week. This is the first demonstration of a therapeutic protein reaching the bloodstream from transduced primary keratinocytes. This may have implications for the treatment of haemophilia B and other disorders.

Subcutaneous injection of factor IX for the treatment of haemophilia B.

Haemophilia B patients are normally treated, either prophylactically or in response to bleeding episodes, by frequent intravenous injections of factor IX purified from blood donors. Here we show in model animal experiments that purified human factor IX, when injected subcutaneously, is rapidly (in 3-11 h) and reasonably efficiently (30-40% of an equivalent intravenous dose) transported at least partly by the lymphatic drainage of the skin into the bloodstream, mostly in a biologically active form. This suggests that patients could be treated prophylactically by subcutaneous rather than intravenous injection, where the short delay in raising plasma factor IX to haemostatic levels would be clinically acceptable. More generally, our studies emphasize that the subcutaneous route of injection should be useful for other therapeutic proteins, including other clotting factors, which have to be delivered to the bloodstream, as long as their half-life is at least a few hours allowing time for transport into the general circulation.