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In clinical practice, differentiating Bipolar Disorder (BD) from unipolar depression is challenging due to the depressive symptoms, which are the core presentations of both disorders. Patients with BD are often misdiagnosed during depressive episodes resulting in a delay in proper treatment and a poor management of their condition.
The aim of the present study is to discriminate between unipolar depression and BD using a panel of RNA edited blood biomarkers.
Depressed patients were classified according to clinical scores in MADRS and IDSC-30 depression scales. After blood collection and RNA extraction, we used whole-transcriptome sequencing to identify differential A-to-I editing events, and Targeted Next Generation Sequencing to validate those biomarkers.
We discovered 646 variants differentially edited between depressed patients and control in a discovery cohort of 57 participants. After using stringent criteria and biological pathway analysis, 6 biomarker candidates were singled out and tested in a validation cohort of 160 patients suffering from unipolar depression and 95 BD patients in a depressive episode, which allowed a differential diagnosis of BD with an AUC of 0.935 and high specificity (Sp=84.6%) and sensitivity (Se=90.9%).
We have shown that a combination of 6 blood RNA editing-related biomarkers allows to discriminate unipolar and bipolar depression This 6 BMKs panel may be crucial to improve BD diagnosis and orientate the treatment therefore addressing the needs of millions of patients suffering from misdiagnosis and incorrect treatment for their diseases. This will change the game for the management of patients.
Concerns have emerged regarding infection transmission during flexible nasoendoscopy.
Information was gathered prospectively on flexible nasoendoscopy procedures performed between March and June 2020. Patients and healthcare workers were followed up to assess for coronavirus disease 2019 development. One-sided 97.5 per cent Poisson confidence intervals were calculated for upper limits of risk where zero events were observed.
A total of 286 patients were recruited. The most common indication for flexible nasoendoscopy was investigation of ‘red flag’ symptoms (67 per cent). Forty-seven patients (16 per cent, 95 per cent confidence interval = 13–21 per cent) had suspicious findings on flexible nasoendoscopy requiring further investigation. Twenty patients (7.1 per cent, 95 per cent confidence interval = 4.4–11 per cent) had new cancer diagnoses. Zero coronavirus disease 2019 infections were recorded in the 273 patients. No. 27 endoscopists (the doctors and nurses who carried out the procedures) were followed up.The risk of developing coronavirus disease 2019 after flexible nasoendoscopy was determined to be 0–1.3 per cent.
The risk of coronavirus disease 2019 transmission associated with performing flexible nasoendoscopy in asymptomatic patients, while using appropriate personal protective equipment, is very low. Additional data are required to confirm these findings in the setting of further disease surges.
The radiocarbon (14C) calibration curve so far contains annually resolved data only for a short period of time. With accelerator mass spectrometry (AMS) matching the precision of decay counting, it is now possible to efficiently produce large datasets of annual resolution for calibration purposes using small amounts of wood. The radiocarbon intercomparison on single-year tree-ring samples presented here is the first to investigate specifically possible offsets between AMS laboratories at high precision. The results show that AMS laboratories are capable of measuring samples of Holocene age with an accuracy and precision that is comparable or even goes beyond what is possible with decay counting, even though they require a thousand times less wood. It also shows that not all AMS laboratories always produce results that are consistent with their stated uncertainties. The long-term benefits of studies of this kind are more accurate radiocarbon measurements with, in the future, better quantified uncertainties.
The diagnostic value of exploratory tympanotomy in sudden sensorineural hearing loss remains controversial. This study and review were performed to identify the incidence of perilymphatic fistula in patients with sudden sensorineural hearing loss. The effectiveness of tympanotomy for sealing of the cochlear windows in cases with perilymphatic fistula was evaluated.
A search in common databases was performed. Overall, 5034 studies were retrieved. Further, a retrospective analysis on 90 patients was performed.
Eight publications dealing with tympanotomy in patients with sudden sensorineural hearing loss were identified. In 90 patients diagnosed with sudden sensorineural hearing loss and undergoing exploratory tympanotomy, 10 patients (11 per cent) were identified with a perilymphatic fistula, and this corresponds to the results obtained from our review (13.6 per cent).
There was no significant improvement after exploratory tympanotomy and sealing of the membranes for patients with a definite perilymphatic fistula.
Background: Since January 1, 2016 2358 people have died from opioid poisoning in Alberta. Buprenorphine/naloxone (bup/nal) is the recommended first line treatment for opioid use disorder (OUD) and this treatment can be initiated in emergency departments and urgent care centres (EDs). Aim Statement: This project aims to spread a quality improvement intervention to all 107 adult EDs in Alberta by March 31, 2020. The intervention supports clinicians to initiate bup/nal for eligible individuals and provide rapid referrals to OUD treatment clinics. Measures & Design: Local ED teams were identified (administrators, clinical nurse educators, physicians and, where available, pharmacists and social workers). Local teams were supported by a provincial project team (project manager, consultant, and five physician leads) through a multi-faceted implementation process using provincial order sets, clinician education products, and patient-facing information. We used administrative ED and pharmacy data to track the number of visits where bup/nal was given in ED, and whether discharged patients continued to fill any opioid agonist treatment (OAT) prescription 30 days after their index ED visit. OUD clinics reported the number of referrals received from EDs and the number attending their first appointment. Patient safety event reports were tracked to identify any unintended negative impacts. Evaluation/Results: We report data from May 15, 2018 (program start) to September 31, 2019. Forty-nine EDs (46% of 107) implemented the program and 22 (45% of 49) reported evaluation data. There were 5385 opioid-related visits to reporting ED sites after program adoption. Bup/nal was given during 832 ED visits (663 unique patients): 7 visits in the 1st quarter the program operated, 55 in the 2nd, 74 in the 3rd, 143 in the 4th, 294 in the 5th, and 255 in the 6th. Among 505 unique discharged patients with 30 day follow up data available 319 (63%) continued to fill any OAT prescription after receiving bup/nal in ED. 16 (70%) of 23 community clinics provided data. EDs referred patients to these clinics 440 times, and 236 referrals (54%) attended their first follow-up appointment. Available data may under-report program impact. 5 patient safety events have been reported, with no harm or minimal harm to the patient. Discussion/Impact: Results demonstrate effective spread and uptake of a standardized provincial ED based early medical intervention program for patients who live with OUD.
Growing evidence suggests that soluble amyloid-beta (Abeta) peptides play a pivotal role in Alzheimer’s disease(AD) pathogenesis by mediating synaptotoxic effects particularly at early disease stages.
We quantified the effects of different order Abeta assemblies on spontaneous firing dynamics ofneuronal networks cultured on multielectrode arrays ('neurochips”) as a read-out. We used naturally secreted, stable and conformationally highly homogenous Abeta monomers, dimers, and a mixture of different low-noligomers, derived from permanently transfected cell lines.
Abeta dimers promoted a dose-dependent suppression of overall activity and network synchrony and altered the burst structure already in the low picomolar dose range. By contrast, Abeta monomers exhibited no effect on overall activity, but only a slight effect on burst structure and a moderate effect on network synchrony. A yet different response pattern was seen for a mixture of various low-n Abeta oligomers. Thus, multiparametric assessment of electrical activity changes on neurochips revealed characteristic signatures of the network response for the different Abeta assemblies. Since alterations of Network function likely occur in initial disease stages, these results confirm the pivotal role of Abeta dimers in early AD pathogenesis.
Neurochip recordings of toxic dimeric Abeta species may serve as a valuable diagnostic read-out in early AD and may also be applicable for future testing of drugs, antibodies, or small molecules aiming at Abeta dimers.
Microelectrode arrays (MEAs) with cultured neuronal networks are highly suitable to quantify neuroactive activity and neurotoxicity of applied substances.
Multiparametric characterization of functional alterations of in vitro-neuronal network activity by different typical and atypical antipsychotics.
To identify differential effects of antipsychotics on spontaneous neuronal network activity as a functional readout.
Cultured networks of dissociated cortical cells of postpartal mice coupled to MEAs were exposed to increasing doses of aripiprazole, clozapine, haloperidol, olanzapine, raclopride, and risperidone.
We found a concentration-dependent inhibition of firing patterns for all substances except olanzapine. All other substances mediated a concomitant irreversible suppression of burst and spike rates, a decrease of the burst duration and the number of spikes in bursts as well as dose-dependent network desynchronization (decrease of Cohen's kappa). The comparison of the different antipsychotics with regard to their half-maximal effective dose values (EC-50) for inhibiting the spike rate yielded an increasing order of EC50 values, i.e. a declining order of toxic potency, of aripiprazole (8.77 μM) < clozapine (9.36 μM) < haloperidol (9.77 μM) < risperidone (15.9 μM) < raclopride (22.7 μM). No significant correlations were identified between EC50 values of the distinct antipsychotics and their binding affinity to the dopamine D(2), the serotonin 5-HT(1A), 5-HT(2A), 5-HT(2C), and the M(1) and M(2) muscarinic acetylcholine receptors.
In MEAs, a dose-dependent neurotoxic effect of typical and atypical antipsychotics alike occurred at supratherapeutic doses via a yet unknown mechanism that did not involve actions on major receptor targets of these compounds.
Disclosure of interest
The authors have not supplied their declaration of competing interest.
From 2007 to 2010, the largest reported Q-fever epidemic occurred in the Netherlands with 4026 notified laboratory-confirmed cases. During the course of the epidemic, health-seeking behaviour changed and awareness among health professionals increased. Changes in laboratory workflows were implemented. The aim of this study was to analyse how these changes instigated adjustments of notification criteria and how these adjustments affected the monitoring and interpretation of the epidemic. We used the articles on laboratory procedures related to the epidemic and a description of the changes that were made to the notification criteria. We compared the output of a regional laboratory with notifications to the regional Public Health Service and the national register of infectious diseases. We compared the international notification criteria for acute Q-fever. Screening with ELISA IgM phase II and PCR was added to the diagnostic workflow. In the course of the epidemic, serology often revealed a positive IgG/IgM result although cases were not infected recently. With increasing background seroprevalence, the presence of IgM antibodies can only be suggestive for acute Q-fever and has to be confirmed either by seroconversion of IgG or a positive PCR result. Differences in sero-epidemiology make it unlikely that full harmonisation of notification criteria between countries is feasible.
Background: Buprenorphine/naloxone (bup/nal) is a partial opioid agonist/antagonist and recommended first line treatment for opioid use disorder (OUD). Emergency departments (EDs) are a key point of contact with the healthcare system for patients living with OUD. Aim Statement: We implemented a multi-disciplinary quality improvement project to screen patients for OUD, initiate bup/nal for eligible individuals, and provide rapid next business day walk-in referrals to addiction clinics in the community. Measures & Design: From May to September 2018, our team worked with three ED sites and three addiction clinics to pilot the program. Implementation involved alignment with regulatory requirements, physician education, coordination with pharmacy to ensure in-ED medication access, and nurse education. The project is supported by a full-time project manager, data analyst, operations leaders, physician champions, provincial pharmacy, and the Emergency Strategic Clinical Network leadership team. For our pilot, our evaluation objective was to determine the degree to which our initiation and referral pathway was being utilized. We used administrative data to track the number of patients given bup/nal in ED, their demographics and whether they continued to fill bup/nal prescriptions 30 days after their ED visit. Addiction clinics reported both the number of patients referred to them and the number of patients attending their referral. Evaluation/Results: Administrative data shows 568 opioid-related visits to ED pilot sites during the pilot phase. Bup/nal was given to 60 unique patients in the ED during 66 unique visits. There were 32 (53%) male patients and 28 (47%) female patients. Median patient age was 34 (range: 21 to 79). ED visits where bup/nal was given had a median length of stay of 6 hours 57 minutes (IQR: 6 hours 20 minutes) and Canadian Triage Acuity Scores as follows: Level 1 – 1 (2%), Level 2 – 21 (32%), Level 3 – 32 (48%), Level 4 – 11 (17%), Level 5 – 1 (2%). 51 (77%) of these visits led to discharge. 24 (47%) discharged patients given bup/nal in ED continued to fill bup/nal prescriptions 30 days after their index ED visit. EDs also referred 37 patients with OUD to the 3 community clinics, and 16 of those individuals (43%) attended their first follow-up appointment. Discussion/Impact: Our pilot project demonstrates that with dedicated resources and broad institutional support, ED patients with OUD can be appropriately initiated on bup/nal and referred to community care.
We derive a mathematical model for the drawing of a two-dimensional thin sheet of viscous fluid in the direction of gravity. If the gravitational field is sufficiently strong, then a portion of the sheet experiences a compressive stress and is thus unstable to transverse buckling. We analyse the dependence of the instability and the subsequent evolution on the process parameters, and the mutual coupling between the weakly nonlinear buckling and the stress profile in the sheet. Over long time scales, the sheet centreline ultimately adopts a universal profile, with the bulk of the sheet under tension and a single large bulge caused by a small compressive region near the bottom, and we derive a canonical inner problem that describes this behaviour. The large-time analysis involves a logarithmic asymptotic expansion, and we devise a hybrid asymptotic–numerical scheme that effectively sums the logarithmic series.
Jaswal & Akhtar provide several quotes ostensibly from people with autism but obtained via the discredited techniques of Facilitated Communication and the Rapid Prompting Method, and they do not acknowledge the use of these techniques. As a result, their argument is substantially less convincing than they assert, and the article lacks transparency.
A total of eight ileal and caecal cannulated Yorkshire barrows were used to determine the interactions of dietary fibre (DF) and lipid types on apparent digestibility of DM and fatty acids (FA) and FA flows in gastrointestinal segments. Pigs were offered four diets that contained either pectin or cellulose with or without beef tallow or maize oil in two Youden square designs (n 6). Each period lasted 15 d. Faeces, ileal and caecal contents were collected to determine apparent ileal digestibility (AID), apparent caecal digestibility and apparent total tract digestibility (ATTD) of dietary components. The interactions between DF and lipid types influenced (P <0·05) the digestibility of DM and FA flows. The addition of maize oil decreased (P <0·05) AID of DM in pectin diets, and the addition of beef tallow depressed (P <0·001) ATTD of DM in cellulose diets. Dietary supplementation with beef tallow decreased (P <0·05) the AID of FA in pectin-containing diets but had no effects in cellulose-containing diets. Dietary supplementation with beef tallow increased (P <0·05) AID of SFA and PUFA and the flow of ileal oleic, vaccenic, linolenic and eicosadienoic acids and reduced the flow of faecal lauric, docosatetraenoic and docosapentaenoic acids in pectin- and cellulose-containing diets. In conclusion, the interaction between DF type and lipid saturation modulates digestibility of DM and lipids and FA flows but differs for soluble and insoluble fibre sources, SFA and unsaturated fatty acids and varies in different gastrointestinal segments.
Measurements in the infrared wavelength domain allow direct assessment of the physical state and energy balance of cool matter in space, enabling the detailed study of the processes that govern the formation and evolution of stars and planetary systems in galaxies over cosmic time. Previous infrared missions revealed a great deal about the obscured Universe, but were hampered by limited sensitivity.
SPICA takes the next step in infrared observational capability by combining a large 2.5-meter diameter telescope, cooled to below 8 K, with instruments employing ultra-sensitive detectors. A combination of passive cooling and mechanical coolers will be used to cool both the telescope and the instruments. With mechanical coolers the mission lifetime is not limited by the supply of cryogen. With the combination of low telescope background and instruments with state-of-the-art detectors SPICA provides a huge advance on the capabilities of previous missions.
SPICA instruments offer spectral resolving power ranging from R ~50 through 11 000 in the 17–230 μm domain and R ~28.000 spectroscopy between 12 and 18 μm. SPICA will provide efficient 30–37 μm broad band mapping, and small field spectroscopic and polarimetric imaging at 100, 200 and 350 μm. SPICA will provide infrared spectroscopy with an unprecedented sensitivity of ~5 × 10−20 W m−2 (5σ/1 h)—over two orders of magnitude improvement over what earlier missions. This exceptional performance leap, will open entirely new domains in infrared astronomy; galaxy evolution and metal production over cosmic time, dust formation and evolution from very early epochs onwards, the formation history of planetary systems.
Effective integrated weed management in agricultural landscapes depends on the ability to identify and manage processes that drive weed dynamics. The current study reports the effects of grazing management and crop rotation strategies on the seedbank and emerged weed flora in an integrated crop-livestock system (ICLS) experiment during a 12-year period under no-tillage in sub-tropical southern Brazil. During winter, Italian ryegrass cover crops were grazed by sheep: grazing management treatments included two stocking methods (continuous and rotational) and two forage allowances (10 and 20 kg of herbage dry matter available per 100 kg animal live weight). During summer, the crop rotation treatments involved either soybean-maize or soybean-soybean in succession with winter-grazed cover crops. The treatments were part of a factorial randomized complete block design. Treatment effects were evaluated on the weed seedbank and emerged weed flora populations during winter-grazed cover crop and summer crop growth as well as during the harvest phase. The current results demonstrate that crop rotation and grazing management exhibited interactive effects on the determination of weed outcomes in an ICLS. However, overall, compared with moderate forage allowance, high forage allowance during the winter-grazed cover crop caused lower emerged weed flora in subsequent crops (20% reduction during crop growth and 90% reduction at crop harvest) and 48% reduction in seedbank size. High forage allowance promoted more residue from winter-grazed cover crop biomass, which remained during the summer crop phases and probably resulted in a physical barrier to weed emergence.
We performed a new series of measurements on samples that were part of early measurements on radiocarbon (14C) dating made in 1948–1949. Our results show generally good agreement to the data published in 1949–1951, despite vast changes in technology, with only two exceptions where there was a discrepancy in the original studies. Our new measurements give calibrated ages that overlap with the known ages. We dated several samples at four different laboratories, and so we were also able to make a small intercomparison at the same time. In addition, new measurements on samples from other Egyptian materials used by Libby and co-workers were made at UC Irvine. Samples of tree rings used in the original studies (from Broken Flute Cave and Centennial Stump) were obtained from the University of Arizona Laboratory of Tree-Ring Research archive and remeasured. New data were compared to the original studies and other records.
Recent evidence shows that the serotonin 2A receptor (5-hydroxytryptamine2A receptor, 5-HT2AR) is critically involved in the formation of visual hallucinations and cognitive impairments in lysergic acid diethylamide (LSD)-induced states and neuropsychiatric diseases. However, the interaction between 5-HT2AR activation, cognitive impairments and visual hallucinations is still poorly understood. This study explored the effect of 5-HT2AR activation on response inhibition neural networks in healthy subjects by using LSD and further tested whether brain activation during response inhibition under LSD exposure was related to LSD-induced visual hallucinations.
In a double-blind, randomized, placebo-controlled, cross-over study, LSD (100 µg) and placebo were administered to 18 healthy subjects. Response inhibition was assessed using a functional magnetic resonance imaging Go/No-Go task. LSD-induced visual hallucinations were measured using the 5 Dimensions of Altered States of Consciousness (5D-ASC) questionnaire.
Relative to placebo, LSD administration impaired inhibitory performance and reduced brain activation in the right middle temporal gyrus, superior/middle/inferior frontal gyrus and anterior cingulate cortex and in the left superior frontal and postcentral gyrus and cerebellum. Parahippocampal activation during response inhibition was differently related to inhibitory performance after placebo and LSD administration. Finally, activation in the left superior frontal gyrus under LSD exposure was negatively related to LSD-induced cognitive impairments and visual imagery.
Our findings show that 5-HT2AR activation by LSD leads to a hippocampal–prefrontal cortex-mediated breakdown of inhibitory processing, which might subsequently promote the formation of LSD-induced visual imageries. These findings help to better understand the neuropsychopharmacological mechanisms of visual hallucinations in LSD-induced states and neuropsychiatric disorders.
Introduction: Point-of-care ultrasound (POCUS) has been suggested as an initial investigation in the management of renal colic. Our objectives were: 1) to determine the accuracy of POCUS for the diagnosis of nephrolithiasis, and 2) to assess its prognostic value in the management of renal colic (PROSPERO: 42016035331). Methods: An electronic database search of MEDLINE, EMBASE, and PubMed was conducted utilizing subject headings, keywords, and synonyms that address our research question. Bibliographies of included studies and narrative reviews were manually examined. Studies of adult emergency department patients with renal colic symptoms were included. Any degree of hydronephrosis was considered a positive POCUS finding. Accepted criterion standards were CT evidence of renal stone or hydronephrosis, direct stone visualization, or surgical findings. Screening of abstracts, quality assessment with the QUADAS-2 instrument, and data extraction were performed by two reviewers, with discrepancies resolved by conference with a third reviewer.Test performance was assessed by pooled sensitivity and specificity, calculated likelihood ratios, and a summary receiver operator curve (SROC). The secondary outcome of prognostic value was reported as a narrative summary. Results: The electronic search yielded 627 unique titles. After relevance screening, 25 papers underwent full-text review, and 8 articles met all inclusion criteria. Of these, 5 high-quality studies (N=1773) were included in the meta-analysis for diagnostic accuracy, and three yielded data on prognostic value. The pooled results for sensitivity and specificity were 70.2% (95% CI=67.1% to 73.2%) and 75.4% (95% CI=72.5% to 78.2%), respectively. The calculated positive and negative likelihood ratios were 2.85 and 0.39. The SROC generated did not show evidence of a threshold effect.Three studies examining prognostic value noted a higher likelihood of a large stone or surgical intervention with positive POCUS findings. The largest randomized trial showed lower cumulative radiation exposure and no increase in adverse events in those who received POCUS investigation as the initial renal colic investigation. Conclusion: Point-of-care ultrasound is of modest accuracy for the diagnosis of nephrolithiasis. While positive POCUS findings are associated with larger stones and greater likelihood for intervention, the clinical importance of this is unclear.
Almost nothing is known about the potential negative effects of Internet-based psychological treatments for depression. This study aims at investigating deterioration and its moderators within randomized trials on Internet-based guided self-help for adult depression, using an individual patient data meta-analyses (IPDMA) approach.
Studies were identified through systematic searches (PubMed, PsycINFO, EMBASE, Cochrane Library). Deterioration in participants was defined as a significant symptom increase according to the reliable change index (i.e. 7.68 points in the CES-D; 7.63 points in the BDI). Two-step IPDMA procedures, with a random-effects model were used to pool data.
A total of 18 studies (21 comparisons, 2079 participants) contributed data to the analysis. The risk for a reliable deterioration from baseline to post-treatment was significantly lower in the intervention v. control conditions (3.36 v. 7.60; relative risk 0.47, 95% confidence interval 0.29–0.75). Education moderated effects on deterioration, with patients with low education displaying a higher risk for deterioration than patients with higher education. Deterioration rates for patients with low education did not differ statistically significantly between intervention and control groups. The benefit–risk ratio for patients with low education indicated that 9.38 patients achieve a treatment response for each patient experiencing a symptom deterioration.
Internet-based guided self-help is associated with a mean reduced risk for a symptom deterioration compared to controls. Treatment and symptom progress of patients with low education should be closely monitored, as some patients might face an increased risk for symptom deterioration. Future studies should examine predictors of deterioration in patients with low education.
Background: Accurate prediction of length of stay (LOS) following elective lumbar fusion may help optimize the utilization of resources and may assist with physician and patient expectations. Methods: Outcomes were collected prospectively among patients undergoing elective lumbar fusion. Prolonged LOS was defined as ≥5 days. The influence of baseline and peri-operative characteristics on the odds of prolonged LOS was assessed by a multivariate logistic regression model. Results: 150 patients underwent elective lumbar fusion surgery. Patient characteristics were as follows: average age was 61.9, average pre-operative back pain measured by the visual analogue scale was 54.3, and 36.5% of patients were identified as having severe disability, defined by an Oswestry disability index over 40. The average LOS was 4.9 days, with 28% having a prolonged LOS. Majority of patients had one level fused (69.7%). The odds of prolonged LOS were increased by severe disability (odds ratio [OR] 3.58, p<0.005), levels fused (OR 2.52, p<0.005), greater than 70 years of age (OR 3.81, p<0.005), and any treatment related adverse event (OR 4.32, p <0.02). There was no significant influence of prolonged surgery (p=0.3) or pre-operative back pain (p=0.23) on LOS. Conclusions: Prolonged length of stay was significantly influenced by severe disability, levels fused, age > 70, and any adverse events.
Thin glass sheets may be manufactured using a two-part process in which a sheet is first cast and then subsequently reheated and drawn to a required thickness. The latter redrawing process typically results in a sheet with non-uniform thickness and with smaller width than the cast glass block. Experiments suggest that the loss of width can be minimized and the non-uniformities can be essentially confined to thickening at the sheet edges if the heater zone through which the glass is drawn is made very short. We present a three-dimensional mathematical model for the redraw process and consider the limits in which (i) the heater zone is short compared with the sheet width, and (ii) the sheet thickness is small compared with both of these length scales. We show that, in the majority of the sheet, the properties vary only in the direction of drawing and the sheet motion is one-dimensional, with two-dimensional behaviour and the corresponding thick edges confined to boundary layers at the sheet extremities. We present numerical solutions to this boundary-layer problem and demonstrate good agreement with experiment, as well as with numerical solutions to the full three-dimensional problem. We show that the final thickness at the sheet edge scales with the inverse square root of the draw ratio, and explore the effect of tapering of the ends to identify a shape for the initial preform that results in a uniform rectangular final product.