Supportive care in the acute phase of Stevens-Johnson syndrome and toxic epidermal necrolysis: an international, multidisciplinary Delphi-based consensus.

BACKGROUND: Supportive care is the cornerstone of management of adult and paediatric Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). However, consensus on the modalities of supportive care is lacking. OBJECTIVES: Our aim in this international multicentric Delphi exercise was to establish a multidisciplinary expert consensus to standardize recommendations regarding supportive care in the acute phase of SJS/TEN. METHODS: Participants were sent a survey via the online tool SurveyMonkey, consisting of 103 statements organized into 11 topics: multidisciplinary team composition, suspect drug management, infection prevention, fluid resuscitation and prevention of hypothermia, nutritional support, pain and psychological distress management, management of acute respiratory failure, local skincare, ophthalmological management, management of other mucosa, and additional measures. Participants evaluated the level of appropriateness of each statement on a scale of 1 (extremely inappropriate) to 9 (extremely appropriate). The results were analysed according to the RAND/UCLA Appropriateness Method. RESULTS: Forty-five participants from 13 countries (on three continents) participated. After the first round, a consensus was obtained for 82.5% of the 103 initially proposed statements. After the second round, a final consensus was obtained for 102 statements. CONCLUSIONS: We have reached an international Delphi-based consensus on best supportive care practice for SJS/TEN. Our expert consensus should help guide physicians in treating patients with SJS/TEN and thereby improve short-term prognosis and the risk of sequelae.

Stabilization of cyclic processes by slowly varying forcing.

We introduce a new mathematical framework for the qualitative analysis of dynamical stability, designed particularly for finite-time processes subject to slow-timescale external influences. In particular, our approach is to treat finite-time dynamical systems in terms of a slow-fast formalism in which the slow time only exists in a bounded interval, and consider stability in the singular limit. Applying this to one-dimensional phase dynamics, we provide stability definitions somewhat analogous to the classical infinite-time definitions associated with Aleksandr Lyapunov. With this, we mathematically formalize and generalize a phase-stabilization phenomenon previously described in the physics literature for which the classical stability definitions are inapplicable and instead our new framework is required.

Retinal Vasculitis and Intraocular Inflammation after Intravitreal Injection of Brolucizumab.

PURPOSE: To evaluate features and outcomes of eyes with retinal vasculitis and intraocular inflammation (IOI) after intravitreal injection (IVI) of brolucizumab 6 mg/0.05 ml for treatment of neovascular age-related macular degeneration. DESIGN: Retrospective case series. PARTICIPANTS: Fifteen eyes from 12 patients identified from 10 United States centers. METHODS: Review of patient demographics, ophthalmologic examination results, and retinal imaging findings. MAIN OUTCOME MEASURES: Baseline and follow-up visual acuity (VA), prior anti-vascular endothelial growth factor (VEGF) injections, clinical presentation, retinal findings, fluorescein angiography results, and treatment strategies. RESULTS: The number of previous anti-VEGF IVIs ranged between 2 and 80 in the affected eye before switching to brolucizumab. Retinal vasculitis and IOI were diagnosed at a mean of 30 days after brolucizumab IVI. Mean VA before brolucizumab IVI was 0.426 logarithm of the minimum angle of resolution (logMAR; Snellen equivalent, 20/53) and VA at diagnosis of retinal vasculitis was 0.981 logMAR (Snellen equivalent, 20/191; range, 20/25-20/1600; P = 0.008). All affected eyes showed IOI with variable combinations of focal or elongated segmental sheathing and discontinuity of small and large retinal arteries, sclerotic arteries, regions of vascular nonperfusion, cotton-wool spots, Kyrieleis plaques, irregular venous caliber with dilated and sclerotic segments, perivenular hemorrhages, and foci of phlebitis. Fluorescein angiography revealed delayed retinal arterial filling, retinal vascular nonperfusion, and variable dye leakage from affected vessels and the optic nerve. Systemic evaluation for embolic causes was unrevealing in 2 patients, and 3 patients showed negative laboratory assessment for uveitis. Treatment consisted of various combinations of corticosteroids (systemic, intravitreal, and topical), and 2 eyes underwent vitrectomy without improvement in vision. After a mean follow-up of 25 days, mean VA was 0.833 logMAR (Snellen equivalent, 20/136), which was reduced compared with baseline (P = 0.033). CONCLUSIONS: Retinal vasculitis and IOI after brolucizumab IVI are characterized by variable occlusion of large or small retinal arteries, or both, and perivenular abnormalities. It may span from peripheral vasculitis to occlusion of large retinal arteries around the optic nerve or macula with severe vision loss. A high index of suspicion is required because vitreous cells may obscure visualization of retinal details.

High-level semi-synthetic production of the potent antimalarial artemisinin.

In 2010 there were more than 200 million cases of malaria, and at least 655,000 deaths. The World Health Organization has recommended artemisinin-based combination therapies (ACTs) for the treatment of uncomplicated malaria caused by the parasite Plasmodium falciparum. Artemisinin is a sesquiterpene endoperoxide with potent antimalarial properties, produced by the plant Artemisia annua. However, the supply of plant-derived artemisinin is unstable, resulting in shortages and price fluctuations, complicating production planning by ACT manufacturers. A stable source of affordable artemisinin is required. Here we use synthetic biology to develop strains of Saccharomyces cerevisiae (baker's yeast) for high-yielding biological production of artemisinic acid, a precursor of artemisinin. Previous attempts to produce commercially relevant concentrations of artemisinic acid were unsuccessful, allowing production of only 1.6 grams per litre of artemisinic acid. Here we demonstrate the complete biosynthetic pathway, including the discovery of a plant dehydrogenase and a second cytochrome that provide an efficient biosynthetic route to artemisinic acid, with fermentation titres of 25 grams per litre of artemisinic acid. Furthermore, we have developed a practical, efficient and scalable chemical process for the conversion of artemisinic acid to artemisinin using a chemical source of singlet oxygen, thus avoiding the need for specialized photochemical equipment. The strains and processes described here form the basis of a viable industrial process for the production of semi-synthetic artemisinin to stabilize the supply of artemisinin for derivatization into active pharmaceutical ingredients (for example, artesunate) for incorporation into ACTs. Because all intellectual property rights have been provided free of charge, this technology has the potential to increase provision of first-line antimalarial treatments to the developing world at a reduced average annual price.

Obesity-induced changes in lipid mediators persist after weight loss.

BACKGROUND: Obesity induces significant changes in lipid mediators, however, the extent to which these changes persist after weight loss has not been investigated. SUBJECTS/METHODS: We fed C57BL6 mice a high-fat diet to generate obesity and then switched the diet to a lower-fat diet to induce weight loss. We performed a comprehensive metabolic profiling of lipid mediators including oxylipins, endocannabinoids, sphingosines and ceramides in key metabolic tissues (including adipose, liver, muscle and hypothalamus) and plasma. RESULTS: We found that changes induced by obesity were largely reversible in most metabolic tissues but the adipose tissue retained a persistent obese metabolic signature. Prostaglandin signaling was perturbed in the obese state and lasting increases in PGD2, and downstream metabolites 15-deoxy PGJ2 and delta-12-PGJ2 were observed after weight loss. Furthermore expression of the enzyme responsible for PGD2 synthesis (hematopoietic prostaglandin D synthase, HPGDS) was increased in obese adipose tissues and remained high after weight loss. We found that inhibition of HPGDS over the course of 5 days resulted in decreased food intake in mice. Increased HPGDS expression was also observed in human adipose tissues obtained from obese compared with lean individuals. We then measured circulating levels of PGD2 in obese patients before and after weight loss and found that while elevated relative to lean subjects, levels of this metabolite did not decrease after significant weight loss. CONCLUSIONS: These results suggest that lasting changes in lipid mediators induced by obesity, still present after weight loss, may play a role in the biological drive to regain weight.

Generating Rasch-based activity of daily living measures from the Spinal Cord Injury Longitudinal Aging Study.

STUDY DESIGN: Retrospective Longitudinal Study. OBJECTIVES: (1) To determine whether the Spinal Cord Injury Activities of Daily Living (SCI_ADL) measure shows adequate item-level and precision psychometrics; (2) to investigate whether the SCI_ADL measure effectively detects ADL changes across time; (3) to describe self-care task(s) participants can and cannot do across time. SETTING: Two Midwestern hospitals and 1 Southeastern specialty hospital in 1993. METHODS: All participants were adults with traumatic SCI of at least 1-year duration at enrollment. We used 20-year (1993-2013) retrospective longitudinal data and categorized participants into three injury levels: C1-C4 (cervical; n=50), C5-C8 (n=126) and T1-S5 (thoracic, lumbar and sacral; n=168). We first examined psychometrics of the SCI_ADL with factor and Rasch analyses; then we investigated longitudinal change of SCI_ADL scores at three time points over 20 years (1993, 2003 and 2013) using generalized linear mixed modeling and post hoc analyses. RESULTS: The SCI_ADL measure demonstrated unidimensionality, person strata of 2.9, high Cronbach's α (0.93) and fair person reliability (0.76). T1-S5 had the highest measures, following C5-C8 and C1-C4 at three time points (P<0.05). The C1-C4 and T1-S5 groups showed significant decreases from 2003 to 2013; however, none of the three groups showed significant differences from 1993 to 2003 (P<0.05). CONCLUSIONS: The SCI_ADL measure could detect longitudinal ADL changes of the population with SCI across time. The C1-C4 group decreased the most in ADLs, indicating higher need of long-term services and rehabilitation.

Post-Carotid Endarterectomy Hypertension. Part 1: Association with Pre-operative Clinical, Imaging, and Physiological Parameters.

OBJECTIVE/BACKGROUND: Post-endarterectomy hypertension (PEH) is a well recognised, but poorly understood, phenomenon after carotid endarterectomy (CEA) that is associated with post-operative intracranial haemorrhage, hyperperfusion syndrome, and cardiac complications. The aim of the current study was to identify pre-operative clinical, imaging, and physiological parameters associated with PEH. METHODS: In total, 106 CEA patients undergoing CEA under general anaesthesia underwent pre-operative evaluation of 24 hour ambulatory arterial blood pressure (BP), baroreceptor sensitivity, cerebral autoregulation, and transcranial Doppler measurement of cerebral blood flow velocity (CBFv) and pulsatility index. Patients who met pre-existing criteria for treating PEH after CEA (systolic BP [SBP] > 170 mmHg without symptoms or SBP > 160 mmHg with headache/seizure/neurological deficit) were treated according to a previously established protocol. RESULTS: In total, 40/106 patients (38%) required treatment for PEH at some stage following CEA (26 in theatre recovery [25%], 27 while on the vascular surgical ward [25%]), while seven (7%) had SBP surges > 200 mmHg back on the ward. Patients requiring treatment for PEH had a significantly higher pre-operative SBP (144 ± 11 mmHg vs. 135 ± 13 mmHg; p < .001) and evidence of pre-existing impairment of baroreceptor sensitivity (3.4 ± 1.7 ms/mmHg vs. 5.3 ± 2.8 ms/mmHg; p = .02). However, PEH was not associated with any other pre-operative clinical features, CBFv, or impaired cerebral haemodynamics. Paradoxically, autoregulation was better preserved in patients with PEH. All four cases of hyperperfusion associated symptoms were preceded by PEH. Length of hospital stay was significantly increased in patients with PEH (p < .001). CONCLUSION: In this study, where all patients underwent CEA under general anaesthesia, PEH was associated with poorly controlled pre-operative BP and impaired baroreceptor sensitivity, but not with other peripheral or central haemodynamic parameters, including impaired cerebral autoregulation.

The natural course of spinal cord injury: changes over 40 years among those with exceptional survival.

OBJECTIVES: To identify 40-year longitudinal changes in health, activity, employment, life satisfaction and self-rated adjustment after spinal cord injury. STUDY DESIGN: Longitudinal, mailed self-report. METHODS: Participants were identified from outpatient records of a Midwestern USA university hospital in 1973. Follow-ups were conducted in 1984 and approximate 10-year intervals thereafter. A total of 49 participants completed each of the five assessments. Data were reviewed and analyzed by research team members and a research associate with experience in biostatistics at a medical university in Southeastern USA. Life Situation Questionnaire included the following: (1) demographic and injury characteristics, (2) educational status and employment, (3) community participation, (4) life satisfaction, (5) adjustment, and (6) recent medical history. RESULTS: Proportion of individuals with 10+ non-routine physician visits increased from consistently <10% to >40% during the 40 years. Proportion who spent a week or more in hospital increased from a low of 10% at 20-year follow-up to 43% at 40-year follow-up. Percentage employed and average hours employed initially improved over time but decreased substantially during the last two times of measurement. Satisfaction with health, sex life and social life declined over time, whereas satisfaction with employment improved initially and was maintained over time. Self-rated current adjustment remained stable, whereas predicted future adjustment declined steadily over 40 years. CONCLUSIONS: Age-related declines were apparent for need of physician visits and hospitalizations, with notable declines in satisfaction with sex life, social life and health. However, not all indices declined over time. Participants appeared to maintain stability when rating their own adjustment.

Dietary DHA reduces downstream endocannabinoid and inflammatory gene expression and epididymal fat mass while improving aspects of glucose use in muscle in C57BL/6J mice.

OBJECTIVES: Endocannabinoid system (ECS) overactivation is associated with increased adiposity and likely contributes to type 2 diabetes risk. Elevated tissue cannabinoid receptor 1 (CB1) and circulating endocannabinoids (ECs) derived from the n-6 polyunsaturated acid (PUFA) arachidonic acid (AA) occur in obese and diabetic patients. Here we investigate whether the n-3 PUFA docosahexaenoic acid (DHA) in the diet can reduce ECS overactivation (that is, action of ligands, receptors and enzymes of EC synthesis and degradation) to influence glycemic control. This study targets the ECS tonal regulation of circulating glucose uptake by skeletal muscle as its primary end point. DESIGN: Male C57BL/6J mice were fed a semipurified diet containing DHA or the control lipid. Serum, skeletal muscle, epididymal fat pads and liver were collected after 62 and 118 days of feeding. Metabolites, genes and gene products associated with the ECS, glucose uptake and metabolism and inflammatory status were measured. RESULTS: Dietary DHA enrichment reduced epididymal fat pad mass and increased ECS-related genes, whereas it reduced downstream ECS activation markers, indicating that ECS activation was diminished. The mRNA of glucose-related genes and proteins elevated in mice fed the DHA diet with increases in DHA-derived and reductions in AA-derived EC and EC-like compounds. In addition, DHA feeding reduced plasma levels of various inflammatory cytokines, 5-lipoxygenase-dependent inflammatory mediators and the vasoconstrictive 20-HETE. CONCLUSIONS: This study provides evidence that DHA feeding altered ECS gene expression to reduce CB1 activation and reduce fat accretion. Furthermore, the DHA diet led to higher expression of genes associated with glucose use by muscle in mice, and reduced those associated with systemic inflammatory status.

Myelin-associated glycoprotein gene mutation causes Pelizaeus-Merzbacher disease-like disorder.

Pelizaeus-Merzbacher disease is an X-linked hypomyelinating leukodystrophy caused by mutations or rearrangements in PLP1. It presents in infancy with nystagmus, jerky head movements, hypotonia and developmental delay evolving into spastic tetraplegia with optic atrophy and variable movement disorders. A clinically similar phenotype caused by recessive mutations in GJC2 is known as Pelizaeus-Merzbacher-like disease. Both genes encode proteins associated with myelin. We describe three siblings of a consanguineous family manifesting the typical infantile-onset Pelizaeus-Merzbacher disease-like phenotype slowly evolving into a form of complicated hereditary spastic paraplegia with mental retardation, dysarthria, optic atrophy and peripheral neuropathy in adulthood. Magnetic resonance imaging and spectroscopy were consistent with a demyelinating leukodystrophy. Using genetic linkage and exome sequencing, we identified a homozygous missense c.399C>G; p.S133R mutation in MAG. This gene, previously associated with hereditary spastic paraplegia, encodes myelin-associated glycoprotein, which is involved in myelin maintenance and glia-axon interaction. This mutation is predicted to destabilize the protein and affect its tertiary structure. Examination of the sural nerve biopsy sample obtained in childhood in the oldest sibling revealed complete absence of myelin-associated glycoprotein accompanied by ill-formed onion-bulb structures and a relatively thin myelin sheath of the affected axons. Immunofluorescence, cell surface labelling, biochemical analysis and mass spectrometry-based proteomics studies in a variety of cell types demonstrated a devastating effect of the mutation on post-translational processing, steady state expression and subcellular localization of myelin-associated glycoprotein. In contrast to the wild-type protein, the p.S133R mutant was retained in the endoplasmic reticulum and was subjected to endoplasmic reticulum-associated protein degradation by the proteasome. Our findings identify involvement of myelin-associated glycoprotein in this family with a disorder affecting the central and peripheral nervous system, and suggest that loss of the protein function is responsible for the unique clinical phenotype.

The structure of the hexameric atrazine chlorohydrolase AtzA.

Atrazine chlorohydrolase (AtzA) was discovered and purified in the early 1990s from soil that had been exposed to the widely used herbicide atrazine. It was subsequently found that this enzyme catalyzes the first and necessary step in the breakdown of atrazine by the soil organism Pseudomonas sp. strain ADP. Although it has taken 20 years, a crystal structure of the full hexameric form of AtzA has now been obtained. AtzA is less well adapted to its physiological role (i.e. atrazine dechlorination) than the alternative metal-dependent atrazine chlorohydrolase (TrzN), with a substrate-binding pocket that is under considerable strain and for which the substrate is a poor fit.

Effects of total and regional fat loss on plasma CRP and IL-6 in overweight and obese, older adults with knee osteoarthritis.

OBJECTIVE: To describe associations between total and regional body fat mass loss and reduction of systemic levels of inflammation (C-reactive protein (CRP) and interleukin-6 (IL-6)) in obese, older adults with osteoarthritis (OA), undergoing intentional weight loss. DESIGN: Data come from a single-blind, 18-month, randomized controlled trial in adults (age: 65.6 ± 6.2; Body mass index (BMI): 33.6 ± 3.7) with knee OA. Participants were randomized to diet-induced weight loss plus exercise (D + E; n = 150), diet-induced weight loss-only (D; n = 149), or exercise-only (E; n = 151). Total body and region-specific (abdomen and thigh) fat mass were measured at baseline and 18 months. High-sensitivity CRP and IL-6 were measured at baseline, six and 18 months. Intervention effects were assessed using mixed models and associations between inflammation and adiposity were compared using logistic and mixed linear regression models. RESULTS: Intentional total body fat mass reduction was associated with significant reductions in log-adjusted CRP (ß = 0.06 (95% CI = 0.04, 0.08) mg/L) and IL-6 (ß = 0.02 (95% CI = 0.01, 0.04) pg/mL). Loss of abdominal fat volume was also associated with reduced inflammation, independent of total body fat mass; although models containing measures of total adiposity yielded the best fit. The odds of achieving clinically desirable levels of CRP (<3.0 mg/L) and IL-6 (<2.5 pg/mL) were 3.8 (95% CI = 1.6, 8.9) and 2.2 (95% CI = 1.1, 4.6), respectively, with 5% total weight and fat mass loss. CONCLUSIONS: Achievement of clinically desirable levels of CRP and IL-6 more than double with intentional 5% loss of total body weight and fat mass. Global, rather than regional, measures of adiposity are better predictors of change in inflammatory burden. CLINICAL TRIAL REGISTRATION NUMBER: NCT00381290.

Integrative review on the non-invasive management of lower urinary tract symptoms in men following treatments for pelvic malignancies.

AIM: To develop a non-invasive management strategy for men with lower urinary tract symptoms (LUTS) after treatment for pelvic cancer, that is suitable for use in a primary healthcare context. METHODS: PubMed literature searches of LUTS management in this patient group were carried out, together with obtaining a consensus of management strategies from a panel of authors for the management of LUTS from across the UK. RESULTS: Data from 41 articles were investigated and collated. Clinical experience was sought from authors where there was no clinical evidence. The findings discussed in this paper confirm that LUTS after the cancer treatment can significantly impair men's quality of life. While many men recover from LUTS spontaneously over time, a significant proportion require long-term management. Despite the prevalence of LUTS, there is a lack of consensus on best management. This article offers a comprehensive treatment algorithm to manage patients with LUTS following pelvic cancer treatment. CONCLUSION: Based on published research literature and clinical experience, recommendations are proposed for the standardisation of management strategies employed for men with LUTS after the pelvic cancer treatment. In addition to implementing the algorithm, understanding the rationale for the type and timing of LUTS management strategies is crucial for clinicians and patients.

The potential application of a transcriptionally regulated oncolytic herpes simplex virus for human cancer therapy.

BACKGROUND: Emerging studies have shown the potential benefit of arming oncolytic viruses with therapeutic genes. However, most of these therapeutic genes are placed under the regulation of ubiquitous viral promoters. Our goal is to generate a safer yet potent oncolytic herpes simplex virus type-1 (HSV-1) for cancer therapy. METHODS: Using bacterial artificial chromosome (BAC) recombineering, a cell cycle-regulatable luciferase transgene cassette was replaced with the infected cell protein 6 (ICP6) coding region (encoded for UL39 or large subunit of ribonucleotide reductase) of the HSV-1 genome. These recombinant viruses, YE-PC8, were further tested for its proliferation-dependent luciferase gene expression. RESULTS: The ability of YE-PC8 to confer proliferation-dependent transgene expression was demonstrated by injecting similar amount of viruses into the tumour-bearing region of the brain and the contralateral normal brain parenchyma of the same mouse. The results showed enhanced levels of luciferase activities in the tumour region but not in the normal brain parenchyma. Similar findings were observed in YE-PC8-infected short-term human brain patient-derived glioma cells compared with normal human astrocytes. intratumoural injection of YE-PC8 viruses resulted in 77% and 80% of tumour regression in human glioma and human hepatocellular carcinoma xenografts, respectively. CONCLUSION: YE-PC8 viruses confer tumour selectivity in proliferating cells and may be developed further as a feasible approach to treat human cancers.

The independent and combined effects of intensive weight loss and exercise training on bone mineral density in overweight and obese older adults with osteoarthritis.

OBJECTIVE: To determine the effects of dietary-induced weight loss (D) and weight loss plus exercise (D + E) compared to exercise alone (E) on bone mineral density (BMD) in older adults with knee osteoarthritis (OA). DESIGN: Data come from 284 older (66.0 ± 6.2 years), overweight/obese (body mass index (BMI) 33.4 ± 3.7 kg/m2), adults with knee OA enrolled in the Intensive Diet and Exercise for Arthritis (IDEA) study. Participants were randomized to 18 months of walking and strength training (E; n = 95), dietary-induced weight loss targeting 10% of baseline weight (D; n = 88) or a combination of the two (D + E; n = 101). Body weight and composition (DXA), regional BMD, were obtained at baseline and 18 months. RESULTS: E, D, and D + E groups lost 1.3 ± 4.5 kg, 9.1 ± 8.6 kg and 10.4 ± 8.0 kg, respectively (P < 0.01). Significant treatment effects were observed for BMD in both hip and femoral neck regions, with the D and D + E groups showing similar relative losses compared to E (both P < 0.01). Despite reduced BMD, fewer overall participants had T-scores indicative of osteoporosis after intervention (9 at 18 months vs 10 at baseline). Within the D and D + E groups, changes in hip and femoral neck, but not spine, BMD correlated positively with changes in body weight (r = 0.21 and 0.54 respectively, both P ≤ 0.01). CONCLUSIONS: Weight loss via an intensive dietary intervention, with or without exercise, results in bone loss at the hip and femoral neck in overweight and obese, older adults with OA. Although the exercise intervention did not attenuate weight loss-associated reductions in BMD, classification of osteoporosis and osteopenia remained unchanged. CLINICAL TRIAL REGISTRATION NUMBER: NCT00381290.

Optimising treatment parameters for Radiofrequency Induced Thermal Therapy (RFiTT): A comparison of the manufacturer's treatment guidance with a locally developed treatment protocol.

OBJECTIVE: Radiofrequency induced Thermal Therapy (RFiTT) is an established endovenous device for the treatment of varicose veins. Our aim was to compare the manufacturer's treatment guidance with a locally developed treatment protocol on early truncal ablation rates between two patient cohorts. METHODS: The study was a retrospective analysis of prospectively collected data from 534 patients treated for incompetent truncal saphenous veins between June 2009 and December 2012. Patients were treated either according to the manufacturer's guidance (Treatment 1), a single pullback rate of ≥1.5 s/cm, or according to local protocol (Treatment 2), repeated vein treatment to visibly occlude the vein lumen. Follow-up at 6 weeks and 12 months included duplex examination, assessment of complications, and pain scores for the first postoperative week. RESULTS: 14 patients did not attend follow-up, leaving 98 patients (142 saphenous trunk treatments) who received Treatment 1 and 422 patients (566 saphenous trunk treatments) who received Treatment 2. The two groups were well matched for age, sex, and preoperative vein parameters. Six week occlusion rates were significantly different, with more treatment failures after Treatment 1 (Treatment 1 5.6% vs. Treatment 2 0.9%; p = .0001). Treatment 1 was more likely to produce incomplete ablation (3.5% vs. 0.9%) and non-ablation (2.1% vs. 0.0%) compared with Treatment 2. No major complications occurred in either group and functional outcomes were otherwise comparable between the two treatment methods. Longer-term follow-up at 12 months in the first 100 patients undergoing Treatment 2 demonstrated maintenance of the early advantage, with partial recanalisations in 9% and 2% for Treatments 1 and 2, respectively. CONCLUSIONS: Six weeks after treatment with RFiTT, a protocol of repeated vein treatments to visibly obliterate the vein lumen produced more reliable venous occlusion compared with manufacturer's guidance. This advantage is maintained at 12 months.

Micromechanical Dilution of PLA/PETG-Glass/Iron Nanocomposites: A More Efficient Molecular Dynamics Approach.

Polylactic acid (PLA) and poly(ethylene terephthalate glycol) (PETG) are popular thermoplastics used in additive manufacturing applications. The mechanical properties of PLA and PETG can be significantly improved by introducing fillers, such as glass and iron nanoparticles (NPs), into the polymer matrix. Molecular dynamics (MD) simulations with the reactive INTERFACE force field were used to predict the mechanical responses of neat PLA/PETG and PLA-glass/iron and PETG-glass/iron nanocomposites with relatively high loadings of glass/iron NPs. We found that the iron and glass NPs significantly increased the elastic moduli of the PLA matrix, while the PETG matrix exhibited modest increases in elastic moduli. This difference in reinforcement ability may be due to the slightly greater attraction between the glass/iron NP and PLA matrix. The NASA Multiscale Analysis Tool was used to predict the mechanical response across a range of volume percent glass/iron filler by using only the neat and highly loaded MD predictions as input. This provides a faster and more efficient approach than creating multiple MD models per volume percent per polymer/filler combination. To validate the micromechanics predictions, experimental samples incorporating hollow glass microspheres (MS) and carbonyl iron particles (CIP) into PLA/PETG were developed and tested for elastic modulus. The CIP produced a larger reinforcement in elastic modulus than the MS, with similar increases in elastic modulus between PLA/CIP and PETG/CIP at 7.77 vol % CIP. The micromechanics-based mechanical predictions compare excellently with the experimental values, validating the integrated micromechanical/MD simulation-based approach.

Changes in middle cerebral artery velocity after carotid endarterectomy do not identify patients at high-risk of suffering intracranial haemorrhage or stroke due to hyperperfusion syndrome.

OBJECTIVES: To determine if significant increases in middle cerebral artery velocity (MCAV) or pulsatility index (PI) during and immediately after carotid endarterectomy (CEA) were predictive of patients suffering a stroke due to the hyperperfusion syndrome (HS) or intracerebral haemorrhage (ICH). METHODS: Transcranial Doppler (TCD) mean/peak MCAV and PI were recorded pre-operatively; pre-clamp; 1-min post-declamping; 10-min post-declamping and 30-min post-operatively. The study was divided into two time periods; Group 1 (1995-2007); where there was no formal guidance for managing post-CEA hypertension (PEH) and Group 2 (2008-2012); where written guidelines for treating PEH were available. RESULTS: 11/1024 patients in Group 1 (1.1%) suffered a stroke due to HS/ICH, compared to 0/426 patients (0.0%) in Group 2 (p = 0.02). In Group 1; intra-operative increases >100% in mean/peak MCAV and PI at 1 and 10-min post-clamp release had positive predictive values (PPV) of 1.2%, 6.3% and 20.0% and 2.9%, 8.0% and 16.6% respectively. Post-operatively; a >100% increase in mean and peak MCAV had a PPV of 6.3% and 2.7% respectively. CONCLUSION: We were unable to demonstrate that significant increases in MCAV and PI were able to predict patients at increased risk of suffering a post-operative stroke due to HS or ICH. The provision of written guidance for managing PEH in Group 2 patients was associated with virtual abolition of ICH/HS.