Care and three-year outcomes of children with Benign Epilepsy with Centro-Temporal Spikes in England.

PURPOSE: Benign Epilepsy with Centro-Temporal Spikes (BECTS) is a pediatric epilepsy with typically good seizure control. Although BECTS may increase patients' risk of developing neurological comorbidities, their clinical care and short-term outcomes are poorly quantified. METHODS: We retrospectively assessed adherence to National Institute for Health and Care Excellence (NICE) guidelines relating to specialist referral, electroencephalogram (EEG) conduct and annual review in the care of patients with BECTS, and measured their seizure, neurodevelopmental and learning outcomes at three years post-diagnosis. RESULTS: Across ten centers in England, we identified 124 patients (74 male) diagnosed with BECTS between 2015 and 2017. Patients had a mean age at diagnosis of 8.0 (95% CI = 7.6-8.4) years. 24/95 (25%) patients were seen by a specialist within two weeks of presentation; 59/100 (59%) received an EEG within two weeks of request; and 59/114 (52%) were reviewed annually. At three years post-diagnosis, 32/114 (28%) experienced ongoing seizures; 26/114 (23%) had reported poor school progress; 15/114 (13%) were diagnosed with a neurodevelopmental disorder (six autism spectrum disorder, six attention-deficit/hyperactivity disorder); and 10/114 (8.8%) were diagnosed with a learning difficulty (three processing deficit, three dyslexia). Center-level random effects models estimated neurodevelopmental diagnoses in 9% (95% CI: 2-16%) of patients and learning difficulty diagnoses in 7% (95% CI: 2-12%). CONCLUSIONS: In this multicenter work, we found variable adherence to NICE guidelines in the care of patients with BECTS and identified a notable level of neurological comorbidity. Patients with BECTS may benefit from enhanced cognitive and behavioral assessment and monitoring.

The Efficacy of Gum Arabic in Managing Diseases: A Systematic Review of Evidence-Based Clinical Trials.

Gum arabic (GA) is a natural product commonly used as a household remedy for treating various diseases in the Sub-Saharan Africa region. Despite its claimed benefits, there has been a lack of research on the findings of current clinical trials (CTs) that investigated its efficacy in the treatment of various medical diseases. The aim of this systematic review was to study CTs which focused on GA and its possible use in the management of various medical diseases. A search of the extant literature was performed in the PubMed, Scopus, and Cochrane databases to retrieve CTs focusing on evidence-based clinical indications. The databases were searched using the keywords ("Gum Arabic" OR "Acacia senegal" OR "Acacia seyal" OR "Gum Acacia" OR "Acacia Arabica") AND ("Clinical Trial" OR "Randomized Controlled Trial" OR "Randomized Clinical Trial"). While performing the systematic review, data were obtained on the following parameters: title, authors, date of publication, study design, study aim, sample size, type of intervention used, targeted medical diseases, and main findings. Twenty-nine papers were included in this systematic review. The results showed that ingestion of GA altered lipid profiles, renal profiles, plaque, gingival scores, biochemical parameters, blood pressure, inflammatory markers, and adiposity. GA exhibited anti-inflammatory, prebiotic, and antibacterial properties. GA has been successfully used to treat sickle cell anemia, rheumatoid arthritis, metabolic disorders, periodontitis, gastrointestinal conditions, and kidney diseases. Herein, we discuss GA with respect to the underlying mechanisms involved in each medical disease, thereby justifying GA's future role as a therapeutic agent.

Analysis and comparison of focused ion beam milling and vibratory polishing sample surface preparation methods for porosity study of U-Mo plate fuel for research and test reactors.

Uranium-Molybdenum (U-Mo) low enriched uranium (LEU) fuels are a promising candidate for the replacement of high enriched uranium (HEU) fuels currently in use in a high power research and test reactors around the world. Contemporary U-Mo fuel sample preparation uses focused ion beam (FIB) methods for analysis of fission gas porosity. However, FIB possess several drawbacks, including reduced area of analysis, curtaining effects, and increased FIB operation time and cost. Vibratory polishing is a well understood method for preparing large sample surfaces with very high surface quality. In this research, fission gas porosity image analysis results are compared between samples prepared using vibratory polishing and FIB milling to assess the effectiveness of vibratory polishing for irradiated fuel sample preparation. Scanning electron microscopy (SEM) imaging was performed on sections of irradiated U-Mo fuel plates and the micrographs were analyzed using a fission gas pore identification and measurement script written in MatLab. Results showed that the vibratory polishing method is preferentially removing material around the edges of the pores, causing the pores to become larger and more rounded, leading to overestimation of the fission gas porosity size. Whereas, FIB preparation tends to underestimate due to poor micrograph quality and surface damage leading to inaccurate segmentations. Despite the aforementioned drawbacks, vibratory polishing remains a valid method for porosity analysis sample preparation, however, improvements should be made to reduce the preferential removal of material surrounding pores in order to minimize the error in the porosity measurements.

Plasma Protein Turnover Rates in Rats Using Stable Isotope Labeling, Global Proteomics, and Activity-Based Protein Profiling.

Protein turnover is important for general health on cellular and organism scales providing a strategy to replace old, damaged, or dysfunctional proteins. Protein turnover also informs of biomarker kinetics, as a better understanding of synthesis and degradation of proteins increases the clinical utility of biomarkers. Here, turnover rates of plasma proteins in rats were measured in vivo using a pulse-chase stable isotope labeling experiment. During the pulse, rats (n = 5) were fed 13C6-labeled lysine ("heavy") feed for 23 days to label proteins. During the chase, feed was changed to an unlabeled equivalent feed ("light"), and blood was repeatedly sampled from rats over 10 time points for 28 days. Plasma samples were digested with trypsin and analyzed with liquid chromatography-tandem mass spectrometry (LC-MS/MS). MaxQuant was used to identify peptides and proteins and quantify heavy/light lysine ratios. A system of ordinary differential equations was used to calculate protein turnover rates. Using this approach, 273 proteins were identified, and turnover rates were quantified for 157 plasma proteins with half-lives ranging 0.3-103 days. For the ∼70 most abundant proteins, variability in turnover rates among rats was low (median coefficient of variation: 0.09). Activity-based protein profiling was applied to pooled plasma samples to enrich serine hydrolases using a fluorophosphonate (FP2) activity-based probe. This enrichment resulted in turnover rates for an additional 17 proteins. This study is the first to measure global plasma protein turnover rates in rats in vivo, measure variability of protein turnover rates in any animal model, and utilize activity-based protein profiling for enhancing turnover measurements of targeted, low-abundant proteins, such as those commonly used as biomarkers. Measured protein turnover rates will be important for understanding of the role of protein turnover in cellular and organism health as well as increasing the utility of protein biomarkers through better understanding of processes governing biomarker kinetics.

Flap Reconstruction for Pressure Ulcers: An Outcomes Analysis.

BACKGROUND: Historically, complication rates after pressure ulcer reconstruction utilizing flap coverage have been high. Patients undergoing operations for pressure ulcer coverage typically have multiple risk factors for postoperative complications. The purpose of this study was to examine a large patient series in the pressure ulcer population to uncover objective evidence of the linkage between risk factors and outcomes after flap coverage. METHODS: This study was a retrospective chart review of patients who underwent flap reconstruction for a pressure ulcer between 1997 and 2015. The characteristics of patients were analyzed to determine those who had complications such as pressure ulcer recurrence, wound dehiscence, and wound infection. RESULTS: All patients (N = 276) underwent flap coverage of their pressure ulcers. The overall complication rate was 58.7% (162 patients). Wound dehiscence was the most common complication (31.2%), and the pressure ulcer recurrence rate was 28.6%. Multivariate regression for pressure ulcer recurrence revealed that body mass index <18.5 [relative risk (RR) 3.13], active smoking (RR 2.33), and ischial pressure ulcers (RR 3.46) were independent risk factors for pressure ulcer recurrence. Ischial pressure ulcers (RR 2.27) and preoperative osteomyelitis (RR 2.78) were independent risk factors for wound dehiscence. Diabetes was an independent risk factor for wound infection (RR 4.34). CONCLUSIONS: Our retrospective analysis revealed numerous factors that are associated with high rates of major postoperative complications. Risk factors must be taken into account when offering flap coverage, and risk-reducing strategies must be implemented in patients before pressure ulcer reconstruction.

Fragment-based discovery and optimization of BACE1 inhibitors.

A novel series of 2-aminobenzimidazole inhibitors of BACE1 has been discovered using fragment-based drug discovery (FBDD) techniques. The rapid optimization of these inhibitors using structure-guided medicinal chemistry is discussed.

Fragment-based discovery of BACE1 inhibitors using functional assays.

Novel nonpeptidic inhibitors of beta-secretase (BACE1) have been discovered by employing a fragment-based biochemical screening approach. A diverse library of 20000 low-molecular weight compounds were screened and yielded 26 novel hits that were confirmed by biochemical and surface plasmon resonance secondary assays. We describe here fragment inhibitors cocrystallized with BACE1 in a flap open and flap closed conformation as determined by X-ray crystallography.

A randomized controlled study of human serum albumin and serum substitute supplement as protein supplements for IVF culture and the effect on live birth rates.

BACKGROUND: It has been speculated that the addition of proteins more complex than human serum albumin (HSA) to culture media may improve IVF outcomes. Whether the expense, labor and risk of adding additional human-derived protein to IVF media are warranted is a question unanswered. METHODS: In a randomized controlled trial with couples undergoing routine IVF or ICSI, 528 patients were assigned to one of two treatment groups. Embryos were cultured in either media supplemented with HSA as a solitary protein supplement or in media supplemented with HSA+serum substitute supplement (SSS) from the 2PN stage until the time of embryo transfer. Clinical end-points monitored included implantation (total 1151 embryos) and live birth rates (total 528 patients). RESULTS: The transfer of embryos cultured in HSA+SSS resulted in higher embryo implantation (289/571, 50.6% versus 254/580, 43.8%; difference 6.8% with 95% CI 1.0-12.7, P = 0.042) and live birth rates (167/266, 62.8% versus 142/262, 54.2%; difference 8.6% with 95% CI 0.1-17.3, P = 0.043) when compared with those of women whose embryos were cultured with HSA as the sole protein supplement. CONCLUSIONS: SSS added to commercial HSA-supplemented embryo culture media resulted in an overall increase in implantation and live birth rates. It remains uncertain whether the use of human-derived blood products in culture media and the requirement for ultra-rigorous quality control measures make these findings applicable to the average IVF laboratory. Protein enrichment of media may significantly improve the blastocyst implantation rate, creating opportunities to transfer single blastocysts without compromising the live birth rate. The study was registered at clinicaltrials.gov. NCT00708383.

A controlled randomized trial evaluating the effect of lowered incubator oxygen tension on live births in a predominantly blastocyst transfer program.

BACKGROUND: The potentially damaging effect of free O(2) radicals to cultured embryos may be reduced by adding scavengers to the culture media or by reducing the incubator O(2) levels. However, lowering the O(2) in the culture environment can be expensive, troublesome and may not be justifiable. The objective of this study was to evaluate the effect of lowered incubator O(2) tension on live birth rates in a predominately Day 5 embryo transfer program. METHODS: Two hundred and thirty first-cycle women undergoing routine IVF or ICSI with ejaculated sperm were randomized in a prospective clinical trial and stratified for patient age and physician. Embryos of patients were randomly assigned for culture in either a 21% O(2) (atmospheric) or 5% O(2) (reduced) environment. Clinical endpoints monitored were rates of implantation, clinical pregnancy, live birth and blastocyst cryopreservation. RESULTS: Embryos cultured in a 5% O(2) environment consistently resulted in higher rates of live birth implantation (106/247, 42.9% versus 82/267, 30.7%; difference of 12.2% with 95% confidence interval (CI) of 3.9-20.3, P = 0.005) and live births (66/115, 57.4% versus 49/115, 42.6%; difference of 14.8% with 95% CI of 1.9-27.0, P = 0.043) when compared with rates among women whose embryos were cultured in an atmospheric O(2) environment. CONCLUSIONS: The overall increase in live births demonstrated by this study indicates that the effort and expense to culture embryos in a low-O(2) environment is justified. The study was registered at clinicaltrials.gov. NCT00708487.

Effects of intravenous nesiritide on human coronary vasomotor regulation and myocardial oxygen uptake.

BACKGROUND: Nesiritide, recombinant human B-type natriuretic peptide, has been shown to be efficacious in the treatment of decompensated heart failure. The effects of intravenous nesiritide on the human coronary vasculature have not been studied. METHODS AND RESULTS: Ten patients underwent right and left heart catheterization. Baseline coronary blood flow was determined using quantitative coronary angiography (QCA) and an intracoronary Doppler-tipped guidewire. Myocardial oxygen uptake was measured using a coronary sinus catheter. Patients then received an intravenous infusion of nesiritide (2 microg/kg bolus followed by 0.01 microg/kg per min infusion) for 30 minutes. Right atrial pressure decreased 52% (P=0.012), pulmonary artery mean pressure decreased 19% (P=0.03), pulmonary capillary wedge pressure decreased 46% (P=0.002), and mean arterial pressure decreased 11% (P=0.007). QCA demonstrated a 15% increase in coronary artery diameter from a baseline of 2.6+/-0.8 to 3.0+/-0.8 mm at 30 minutes (P=0.007). The coronary velocity measure of average peak velocity increased 14% from 20.8+/-6.4 at baseline to 23.8+/-7.2 cm/s at 5 minutes (P=0.015) and then returned to baseline for the remainder of the infusion. Coronary blood flow increased 35% (P=0.007), whereas coronary resistance decreased 23% at 15 and 30 minutes (P=0.036). Myocardial oxygen uptake decreased 8% during the nesiritide infusion (P=0.043). CONCLUSIONS: Nesiritide exerts coronary vasodilator effects on both the coronary conductance and resistance arteries. Despite a decrease in coronary perfusion pressure, coronary artery blood flow is increased, coronary resistance is decreased, and myocardial oxygen uptake is decreased.