We present a new single-pulse pipeline for the PALFA survey to efficiently identify single radio pulses from pulsars, rotating radio transients (RRATs), and fast radio bursts (FRBs). We conducted a ...sensitivity analysis of this new pipeline in which many single pulses were injected into PALFA data and run through the pipeline. We find that for single pulse widths <5 ms, the sensitivity of our new pipeline is at most a factor of ∼2 less sensitive than theoretically predicted. For pulse widths >10 ms, as the DM decreases, the degradation in sensitivity gets worse and can increase up to a factor of ∼4.5. Using this pipeline, we have discovered seven pulsars and two RRATs, and identified three candidate RRATs and one candidate FRB. The confirmed pulsars and RRATs have DMs ranging from 133 to 386 pc cm−3 and flux densities ranging from 20 to 160 mJy. The pulsar periods range from 0.4 to 2.1 s. We report on candidate FRB 141113, which is likely astrophysical and extragalactic, having DM 400 pc cm−3, which is over the Galactic maximum along this line of sight by ∼100-200 pc cm−3. We consider implications for the FRB population and show via simulations that if FRB 141113 is real and extragalactic, the slope of the distribution of integral source counts as a function of flux density (N(>S) ∝ S− ) is 1.4 0.5 (95% confidence range). However, this conclusion is dependent on assumptions that require verification.
•Road user classes are identified based on repeated trip behaviour.•The spatial similarity of trips is measured using Sequence Alignment.•Time of day clusters are estimated for individual travellers ...making sufficient trips.•The method is applied to one year of Bluetooth data from a town in England.
Analysing the repeated trip behaviour of travellers, including trip frequency and intrapersonal variability, can provide insights into traveller needs, flexibility and knowledge of the network, as well as inputs for models including learning and/or behaviour change. Data from emerging data sources provide new opportunities to examine repeated trip making on the road network. Point-to-point sensor data, for example from Bluetooth detectors, is collected using fixed detectors installed next to roads which can record unique identifiers of passing vehicles or travellers which can then be matched across space and time. Such data is used in this research to segment road users based on their repeated trip making behaviour, as has been done in public transportation research using smart card data to understand different categories of users. Rather than deciding on traveller segmentation based on a priori assumptions, the method provides a data driven approach to cluster together travellers who have similar trip regularity and variability between days. Measures which account for the strengths and weaknesses of point-to-point sensor data are presented for (a) spatial variability, using Sequence Alignment, and (b) time of day variability, using Model Based Clustering. The proposed method is also applied to one year of data from 23 fixed Bluetooth detectors in a town in northwest England. The data consists of almost 7.5 million trips made by over 300,000 travellers. Applying the proposed methods allows three traveller user classes to be identified: infrequent, frequent, and very frequent. Interestingly, the spatial and time of day variability characteristics of each user class are distinct and are not linearly correlated with trip frequency. The frequent travellers are observed 1–5 times per week on average and make up 57% of the trips recorded during the year. Focusing on these frequent travellers, it is shown that these can be further separated into those with high spatial and time of day variability and those with low spatial and time of day variability. Understanding the distribution of travellers and trips across these user classes, as well as the repeated trip characteristics of each user class, can inform further data collection and the development of policies targeting the needs of specific travellers.
Binge alcohol consumption in adolescents is increasing, and studies in animal models show that adolescence is a period of high vulnerability to brain insults. The purpose of the present study was to ...determine the deleterious effects of binge alcohol on hippocampal neurogenesis in adolescent nonhuman primates. Heavy binge alcohol consumption over 11 mo dramatically and persistently decreased hippocampal proliferation and neurogenesis. Combinatorial analysis revealed distinct, actively dividing hippocampal neural progenitor cell types in the subgranular zone of the dentate gyrus that were in transition from stem-like radial glia-like cells (type 1) to immature transiently amplifying neuroblasts (type 2a, type 2b, and type 3), suggesting the evolutionary conservation of milestones of neuronal development in macaque monkeys. Alcohol significantly decreased the number of actively dividing type 1, 2a, and 2b cell types without significantly altering the early neuronal type 3 cells, suggesting that alcohol interferes with the division and migration of hippocampal preneuronal progenitors. Furthermore, the lasting alcohol-induced reduction in hippocampal neurogenesis paralleled an increase in neural degeneration mediated by nonapoptotic pathways. Altogether, these results demonstrate that the hippocampal neurogenic niche during adolescence is highly vulnerable to alcohol and that alcohol decreases neuronal turnover in adolescent nonhuman primate hippocampus by altering the ongoing process of neuronal development. This lasting effect, observed 2 mo after alcohol discontinuation, may underlie the deficits in hippocampus-associated cognitive tasks that are observed in alcoholics.
Exposure to nerve agents, pyridostigmine bromide (PB), pesticides, and oil-well fires during the 1991 Gulf War (GW) are major contributors to the etiology of Gulf War Illness (GWI). Since the ...apolipoprotein E (APOE) ε4 allele is associated with the risk of cognitive decline with age, particularly in the presence of environmental exposures, and cognitive impairment is one of the most common symptoms experienced by veterans with GWI, we examined whether the ε4 allele was associated with GWI.
Using a case-control design, we obtained data on APOE genotypes, demographics, and self-reported GW exposures and symptoms that were deposited in the Boston Biorepository and Integrative Network (BBRAIN) for veterans diagnosed with GWI (n = 220) and healthy GW control veterans (n = 131). Diagnosis of GWI was performed using the Kansas and/or Center for Disease Control (CDC) criteria.
Age- and sex-adjusted analyses showed a significantly higher odds ratio for meeting the GWI case criteria in the presence of the ε4 allele (Odds ratio OR = 1.84, 95% confidence interval CI = 1.07-3.15, p ≤ 0.05) and with two copies of the ε4 allele (OR = 1.99, 95% CI 1.23-3.21, p ≤ 0.01). Combined exposure to pesticides and PB pills (OR = 4.10 2.12-7.91, p ≤ 0.05) as well as chemical alarms and PB pills (OR = 3.30 1.56-6.97 p ≤ 0.05) during the war were also associated with a higher odds ratio for meeting GWI case criteria. There was also an interaction between the ε4 allele and exposure to oil well fires (OR = 2.46, 95% CI 1.07-5.62, p ≤ 0.05) among those who met the GWI case criteria.
These findings suggest that the presence of the ε4 allele was associated with meeting the GWI case criteria. Gulf War veterans who reported exposure to oil well fires and have an ε4 allele were more likely to meet GWI case criteria. Long-term surveillance of veterans with GWI, particularly those with oil well fire exposure, is required to better assess the future risk of cognitive decline among this vulnerable population.
Ten percent of people may experience pain under the heel (plantar heel pain) at some time. Injections, insoles, heel pads, strapping and surgery have been common forms of treatment offered. The ...absolute and relative effectiveness of these interventions are poorly understood.
The objective of this review was to identify and evaluate the evidence for effectiveness of treatments for plantar heel pain.
We searched the Cochrane Musculoskeletal Injuries Group specialised register (September 2002), the Cochrane Central Register of Controlled Trials Register (The Cochrane Library issue 3, 2002), MEDLINE (1966 to September 2002), EMBASE (1988 to September 2002) and reference lists of articles and dissertations. Four podiatry journals were handsearched to 1998. We contacted all UK schools of podiatry to identify dissertations on the management of heel pain, and investigators in the field to identify unpublished data or research in progress. No language restrictions were applied.
Randomised and quasi-randomised trials of interventions for plantar heel pain in adults.
Two reviewers independently evaluated randomised controlled trials for inclusion, extracted data and assessed trial quality. Additional information was obtained by direct contact with investigators. No poolable data were identified. Where measures of variance were available we have calculated the weighted mean differences based on visual analogue scale (VAS) scores.
Nineteen randomised trials involving 1626 participants were included. Trial quality was generally poor, and pooling of data was not conducted. All trials measured heel pain as the primary outcome. Seven trials evaluated interventions against placebo/dummy or no treatment. There was limited evidence for the effectiveness of topical corticosteroid administered by iontophoresis, i.e using an electric current, in reducing pain. There was some evidence for the effectiveness of injected corticosteroid providing temporary relief of pain. There was conflicting evidence for the effectiveness of low energy extracorporeal shock wave therapy in reducing night pain, resting pain and pressure pain in the short term (6 and 12 weeks) and therefore its effectiveness remains equivocal. In individuals with chronic pain (longer than six months), there was limited evidence for the effectiveness of dorsiflexion night splints in reducing pain. There was no evidence to support the effectiveness of therapeutic ultrasound, low-intensity laser therapy, exposure to an electron generating device or insoles with magnetic foil. No randomised trials evaluating surgery, or radiotherapy against a randomly allocated control population were identified. There was limited evidence for the superiority of corticosteroid injections over orthotic devices.
Although there is limited evidence for the effectiveness of local corticosteroid therapy, the effectiveness of other frequently employed treatments in altering the clinical course of plantar heel pain has not been established in randomised controlled trials. At the moment there is limited evidence upon which to base clinical practice. Treatments that are used to reduce heel pain seem to bring only marginal gains over no treatment and control therapies such as stretching exercises. Steroid injections are a popular method of treating the condition but only seem to be useful in the short term and only to a small degree. Orthoses should be cautiously prescribed for those patients who stand for long periods; there is limited evidence that stretching exercises and heel pads are associated with better outcomes than custom made orthoses in people who stand for more than eight hours per day. Well designed and conducted randomised trials are required.
Transport across the blood-brain barrier (BBB) is an important mediator of beta-amyloid (Aβ) accumulation in the brain and a contributing factor in the pathogenesis of Alzheimer's disease (AD). One ...of the receptors responsible for the transport of Aβ in the BBB is the low density lipoprotein receptor-related protein 1 (LRP1). LRP1 is susceptible to proteolytic shedding at the cell surface, which prevents endocytic transport of ligands. Previously, we reported a strong inverse correlation between LRP1 shedding in the brain and Aβ transit across the BBB. Several proteases contribute to the ectodomain shedding of LRP1 including the α-secretase, a desintegrin and metalloproteinase domain containing protein 10 (ADAM10).
The role of ADAM10 in the shedding of LRP1 and Aβ BBB clearance was assessed through pharmacological inhibition of ADAM10 in an in vitro model of the BBB and through the use of ADAM10 endothelial specific knock-out mice. In addition, an acute treatment paradigm with an ADAM10 inhibitor was also tested in an AD mouse model to assess the effect of ADAM10 inhibition on LRP1 shedding and Aβbrain accumulation.
In the current studies, inhibition of ADAM10 reduced LRP1 shedding in brain endothelial cultures and increased Aβ42 transit across an in vitro model of the BBB. Similarly, transgenic ADAM10 endothelial knockout mice displayed lower LRP1 shedding in the brain and significantly enhanced Aβ clearance across the BBB compared to wild-type animals. Acute treatment with the ADAM10-selective inhibitor GI254023X in an AD mouse model substantially reduced brain LRP1 shedding and increased Aβ40 levels in the plasma, indicating enhanced Aβ transit from the brain to the periphery. Furthermore, both soluble and insoluble Aβ40 and Aβ42 brain levels were decreased following GI254023X treatment, but these effects lacked statistical significance.
These studies demonstrate a role for ADAM10 in the ectodomain shedding of LRP1 in the brain and the clearance of Aβ across the BBB, which may provide a novel strategy for attenuating Aβ accumulation in the AD brain.
To investigate the role of multiparametric magnetic resonance (MR) imaging in the evaluation of response to platinum-based neoadjuvant chemotherapy in advanced ovarian cancer and to compare imaging ...parameters between primary ovarian mass and metastatic disease.
Evaluable patients suspected of having advanced ovarian carcinoma were enrolled in a prospective protocol-driven study. Research ethics committee approval and written informed consent were obtained. Multiparametric MR imaging (diffusion-weighted MR imaging, dynamic contrast material-enhanced DCE MR imaging, and hydrogen 1 MR spectroscopy) was performed with a 3.0-T wholebody MR imaging system. Three marker lesions-primary ovarian mass, omental cake, and peritoneal deposit-were outlined by a radiologist on apparent diffusion coefficient (ADC) and vascular signal fraction (VSF) maps and on DCE MR images. Comparisons of mean ADC, mean VSF, DCE MR imaging parameters, and choline concentration between responders and nonresponders were based on Response Evaluation Criteria in Solid Tumors and CA-125 criteria.
Twenty-two patients were evaluable. The mean ADC for peritoneal metastases was lower than that for ovarian (P = .015) and omental (P = .006) sites. There were no differences in pretreatment DCE MR imaging parameters between tumor sites. After treatment, responders showed a significantly larger increase in ADC (P = .021) and fractional volume of the extravascular extracellular space (v(e)) (P = .025) of ovarian lesions compared with nonresponders, but there was no change in ADC at other sites. Pre- and posttreatment values of choline concentration of ovarian lesions were lower in responders (P = .025) than in nonresponders (P = .010).
The significant differences in baseline ADCs among primary ovarian cancer, omental cake, and peritoneal deposits indicate that diffusivity profiles may be tumor-site dependent, suggesting biologic heterogeneity of disease. ADC and v(e) parameters correlated with the cytotoxic effects of platinum-based therapy and may be useful response markers, while choline concentration predicted but did not reflect response.
Aims
To estimate the rate at which people with diabetes and a low risk of foot ulceration change diabetic foot ulceration risk status over time, and to estimate the rate of ulceration, amputation and ...death among this population.
Methods
We conducted an observational study of 10 421 people with diabetes attending foot screening in an outpatient setting in NHS Fife, UK, using routinely collected data from a national diabetes register, NHS SCI Diabetes. We estimated the proportion of people who changed risk status and the cumulative incidence of ulceration, amputation and death, respectively, among people with diabetes at low risk of diabetic foot ulceration at 2‐year follow‐up.
Results
At 2‐year follow‐up, 5.1% (95% CI 4.7, 5.6) of people with diabetes classified as low risk at their first visit had progressed to moderate risk. The cumulative incidence of ulceration, amputation and death was 0.4% (95% CI 0.3, 0.6), 0.1% (95% CI 0.1, 0.2) and 3.4% (95% CI 3.1, 3.8), respectively.
Conclusions
At 2‐year follow‐up, 5% of people at low risk of diabetic foot ulceration changed clinical risk status and <1% of people experienced foot ulceration or amputation. These findings provide information which will help to inform the current debate regarding optimal foot screening intervals.
What's new?
People with diabetes are at increased risk of foot ulceration. However, there is no evidence regarding the rate at which people at low risk of diabetic foot ulceration change risk status over time.
This study found that people with diabetes who are at a low risk of foot ulceration do not readily change ulceration risk status over time (5% at 2 years). The cumulative incidence of ulceration and amputation, respectively, at 2 years was <1%.
This has implications for current guidelines on the frequency of foot screening in the UK.
The Pulsar Arecibo L-Band Feed Array (PALFA) survey, the most sensitive blind search for radio pulsars yet conducted, is ongoing at the Arecibo Observatory in Puerto Rico. The vast majority of the ...180 pulsars discovered by PALFA have spin periods shorter than 2 s. Pulsar surveys may miss long-period radio pulsars owing to the summing of a finite number of harmonic components in conventional Fourier analyses (typically ∼16), or as a result of the strong effect of red noise at low modulation frequencies. We address this reduction in sensitivity by using a time-domain search technique: the fast-folding algorithm (FFA). We designed a program that implements an FFA-based search in the PALFA processing pipeline and tested the efficiency of the algorithm by performing tests under both ideal, white-noise conditions, as well as with real PALFA observational data. In the two scenarios, we show that the time-domain algorithm has the ability to outperform the FFT-based periodicity search implemented in the survey. We perform simulations to compare the previously reported PALFA sensitivity with that obtained using our new FFA implementation. These simulations show that for a pulsar having a pulse duty cycle of roughly 3%, the performance of our FFA pipeline exceeds that of our FFT pipeline for pulses with dispersion measure 40 pc cm−3 and for periods as short as ∼500 ms, and that the survey sensitivity is improved by at least a factor of two for periods 6 s. Early results from the implementation of the algorithm in PALFA, including discoveries, are also presented in this paper.
Clinical guidelines recommend that all patients with diabetes should be screened annually to establish their risk of foot ulceration. The aim of this systematic review was to quantify the predictive ...value of diagnostic tests, physical signs and elements from the patient's history in relation to diabetic foot ulcers. Observational studies were identified from: electronic databases (MEDLINE, EMBASE and CINAHL); bibliographies of studies meeting the inclusion criteria; review articles and clinical guidelines; direct contact with authors. Published reports of cohort and case-control studies were considered for inclusion. Pooled estimates were calculated from absolute numbers as weighted mean differences, standard mean differences or odds ratios. Adjusted odds ratios from published reports were also extracted. We identified five case-control and 11 cohort studies. The incidence of foot ulcers ranged from 8% to 17% in the cohort studies, with varying lengths of follow-up. Diagnostic tests and physical signs that detect peripheral neuropathy (biothesiometry, monofilaments and absent ankle reflexes), and those that detect excessive plantar pressure (peak plantar pressure and joint deformity) were all significantly associated with future diabetic foot ulceration. However, there was a paucity of evidence concerning the predictive value of symptoms and signs. Further research is needed to establish the independent factors associated with diabetic foot ulceration, particularly elements from a patient's history and physical examination.
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